Phosphorylation and isoform use in p120-catenin during development and tumorigenesis

Biochimica et Biophysica Acta 1863 (2016) 102–114

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Review

Phosphorylation and isoform use in p120-catenin during development and tumorigenesis Ji Yeon Hong a,⁎, Il-Hoan Oh b, Pierre D. McCrea c,⁎ a b c

Division of Cardiology, Department of Medicine, Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea The Catholic University of Korea, Catholic High Performance Cell Therapy Center, 505 Banpo-dong, Seocho-Ku, Seoul 137-701, Republic of Korea Department of Genetics, University of Texas MD Anderson Cancer Center, University of Texas Graduate School of Biomedical Science, Houston, TX 77030, USA

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Article history: Received 21 February 2015 Received in revised form 12 October 2015 Accepted 13 October 2015 Available online 23 October 2015 Keywords: Structure-function Kinases Phosphatases Cadherins Small-GTPases (RhoA Rac1) Wnt signaling Nuclear signaling Development Cancer

a b s t r a c t P120-catenin is essential to vertebrate development, modulating cadherin and small-GTPase functions, and growing evidence points also to roles in the nucleus. A complexity in addressing p120-catenin's functions is its many isoforms, including optional splicing events, alternative points of translational initiation, and secondary modifications. In this review, we focus upon how choices in the initiation of protein translation, or the earlier splicing of the RNA transcript, relates to primary sequences that harbor established or putative regulatory phosphorylation sites. While certain p120 phosphorylation events arise via known kinases/phosphatases and have defined outcomes, in most cases the functional consequences are still to be established. In this review, we provide examples of p120-isoforms as they relate to phosphorylation events, and thereby to isoform dependent protein–protein associations and downstream functions. We also provide a view of upstream pathways that determine p120's phosphorylation state, and that have an impact upon development and disease. Because other members of the p120 subfamily undergo similar processing and phosphorylation, as well as related catenins of the plakophilin subfamily, what is learned regarding p120 will by extension have wide relevance in vertebrates. © 2015 Elsevier B.V. All rights reserved.

1. Introduction Together with cell interactions taking place with the extracellular matrix (e.g. integrin-mediated), varied cell–cell adhesion complexes contribute to development and tissue homeostasis. In vertebrate epithelial cells, three major types of cell–cell contacts tend to be discussed, including adherens, tight and desmosomal junctions. Given our focus upon p120-catenin, we note that it was initially characterized as a substrate of the Src kinase [113], and shortly thereafter was found in association with one of the principal transmembrane components of epithelial adherens junctions, E-cadherin [1,100,111]. Adherens junctions are complex both with respect to the number of components involved, and the kinds of outside-in and inside-out (etc.) signals transduced or facilitated. Two of an assortment of proteins able to bind to the cytoplasmic carboxyl-tails of classic cadherins include p120-catenin and β-catenin. Within the p120 subfamily of catenins are ARVCF-, δ- and p0071-catenin; each competes with the other as well as with p120catenin itself to bind a membrane-proximal site on the cadherin tail [17,54,86]. β-catenin (or the related γ-catenin/plakoglobin) binds to a ⁎ Corresponding authors. E-mail addresses: [email protected] (J.Y. Hong), [email protected] (P.D. McCrea).

http://dx.doi.org/10.1016/j.bbamcr.2015.10.008 0167-4889/© 2015 Elsevier B.V. All rights reserved.

more membrane-distal site on the tail, indirectly linking the cadherin complex to the contractile cortical-actin cytoskeleton, an interaction that contributes to cell adhesion and motility [91,135]. As noted, p120-catenin was originally described as a Src kinase substrate, and then as a component of the cadherin–catenin complex. P120-catenin promotes cadherin stability, lowering the complex's susceptibility to endocytosis, ubiquitination, and proteosomal destruction [25,33,56,92,149,150]. With the exception of αE-, αN- and αT-catenin, which are structurally related to vinculin, all catenins including p120 contain a central Armadillo-repeat domain that facilitates protein– protein interactions. The Armadillo domain is only modestly homologous between p120 subfamily catenins (45–55% primary sequence identity), and the amino- and carboxyl-terminal regions are yet more divergent. In addition to binding and modulating E- or other classic-cadherins, p120-catenin regulates small-GTPases (e.g. Rac1 and RhoA). This can occur while p120 is associated with or dissociated from the larger cadherin–catenin complex [6,69–71,144]. P120 can bind small-GTPases as a guanine-nucleotide dissociation inhibitor/GDI (e.g. for RhoA), or associate indirectly via GEFs, GAPs or other small-GTPase effector proteins. P120-catenin further associates with microtubules and motor proteins [23,43,155]. A final intriguing property of p120-catenin relates to its nuclear entry and association with transcriptional regulators such as Kaiso [30,31,108], Glis2 [51] and REST/CoREST [77]. In particular,

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p120-isoform 1 appears to participate in vertebrate canonical Wnt signaling [49]. In summary, p120 binds and regulates the cadherin–catenin complex (cell–cell junctions), small-GTPases and cytoskeletal factors (cell–cell junctions and elsewhere), and transcription factors (nucleus). Thus, we will address in this review how p120's phosphorylation and isoform status is relevant to an array of cellular processes. P120-catenin's phosphorylation, isoform status and intracellular localization vary with the cell type and tissue (reviewed in [70,107,114]. With respect to nuclear localization, p120 was initially suggested to contain two nuclear localization signals (NLS) [2,7], and three potential nuclear-export (NES) regions (Fig. 1) [137]. The NLS sequence between Armadillo repeats 5 and 6 modulates p120's (isoform 1) nuclear localization [63], although other findings have instead pointed to p120's (isoform 3) Armadillo region in nuclear entry (repeats 3 and 5) or export (repeat 8) [114]. For example, the Armadillo domain of p120 appears needed for it to shuttle into the nucleus in response to Rac1 [76]. Also favoring p120 nuclear entry is the transcription factor Glis2, especially in combination with Src phosphorylation of p120 [51]. At cell–cell contacts such as adherens junctions, p120 interacts with E- and other cadherins, with either's phosphorylation affecting their association [36,38,44,104,138]. Thus, as we will discuss in the context

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of p120's isoform-specificity, its phosphorylation and protein–protein interactions help to determine p120's intracellular localizations and functions. 2. Isoforms of p120-catenin Considering combinatorial possibilities that result from four distinct translation-initiation sites and four alternatively spliced exons, human p120-catenin possess in theory 64 primary-sequence isoforms (Fig. 1) [62]. P120-isoform 1 is the product of the most upstream translational initiation. It contains an amino-terminal coiled-coil domain, absent from isoforms 2 to 4. Isoform 4 is missing almost the entire aminoterminus of p120-catenin, thus lacking the coiled-coil as well as a regulatory region harboring many potential or confirmed phosphorylation sites [147]. P120-isoform 2 and -isoform 3 lack smaller regions, perhaps most noteworthy being the amino-terminal coiled-coil region that enables some of p120's interactions (Fig. 1). The differential functions of p120's isoforms are just beginning to be revealed, such as in the regulation of RhoA activity [154]. As noted, varying p120-isoforms are expressed in different ratios among varying cell types or contexts [94]. With the exception of macrophages [156], non-adherent (e.g. B- and T-)

Fig. 1. P120-catenin structural features. Structural features of human p120-catenin in relation to its direct interaction partners, alternative translational start sites (yellow boxes 1–4), alternatively spliced regions (tan boxes A-D), and subcellular localization signals (NLS black boxes; NES red boxes). An alternatively spliced region D is rarely excluded. The Armadillo domain is depicted in green; and in the case of p120-catenin and related sub-family members, it has nine repeat units each of about forty-two amino acids. Indicated are a number of putative nuclear localization sequences (NLS) [2,63,114], and nuclear export sequences (NES) [137]. An amino-terminal coiled-coil region is shown in light blue and exists solely in p120-isoform 1. Additional information on the functional differences between p120-catenin isoforms is included in the review text, while representative references relating to the indicated protein interactions of p120-catenin are included within the figure itself.

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cells express little p120-catenin. Interestingly, during epithelial-tomesenchymal transition/EMT, (e.g. promoted via the expression of Snail, c-Fos, SIP1/ZEB2, Slug, Twist or Zeppo1), switches have been observed from p120-isoform 3 to isoform 1 [20,99,118,125]. Mechanisms governing the ratio of p120's primary-sequence isoforms have been partially clarified through work upon RNA splicing factors such as ESRP1 and ESRP2 [141] (Fig. 3B). Studies also point to p120-isoform 1 more so than isoform 3 in cancer cell invasion and metastasis [89,125, 127,131,153,154,158,161]. In addition to four distinct translation initiation sites, p120 contains four alternative spliced exons, denoted A, B, C and D (Fig. 1). Exons A and C are respectively 21 and 6 amino acids long and not well characterized, while exon B's 29 amino acids appear to encode a nuclear export sequence (NES) [2]. Exon D (24 amino acids) is almost always present [107], with for example, early reports including its inclusion in fetal and adult brain tissues [3]. No potential phosphorylation sites exist within these splice insert regions, although potential sites are nearby. For example, S879 and S873 adjoin exon A, and S916 resides between exons A and B (Fig. 1). Conceivably, the presence versus absence of one of these exons could modulate phosphorylation-dependent interactions nearby. P120-catenin's function is also modulated through subcellular localization, likely to be influenced by primary-sequence elements present (or absent) in distinct p120-isoforms. An example was provided above with p120 nuclear export (cytoplasmic localization) being enhanced by the NES in isoform B (Fig. 1). Residues that instead reside within p120's amino-terminus may also have a role in determining p120 localization. For example, a larger proportion of isoform 3 than 1 (Fig. 1) enters the nucleus in cells in contact with matrix and grown in 3-D [125]. In turn, isoform 1 may be directed to cell–cell contacts and elsewhere via interactions at its very amino-terminus [85]. As discussed later, distinguishing phosphorylation sites reside in amino-terminal (translational) isoforms of p120, as well as potentially, sequences flanking p120's optional splice inserts. E-cadherin binds p120's central Armadillo domain at adherens junctions in normal epithelial cells, where p120 promotes cadherin clustering and adhesive function [157]. This occurs in part via p120's enhancement of cadherin stability at cell–cell contacts [25,33,56,57,92, 149,150]. In turn, multiple p120-isoforms as well as other Armadillo catenins would be predicted to be modulated via sequestration by cadherins. It is interesting that in the case of the structurally related β-catenin, reports have suggested to varying extents that its aminoor carboxyl-terminal tails fold in cis to affect associations of the Armadillo-domain in trans [93,26]. If this likewise applies to p120, then one can imagine that p120-isoforms 1 to 4, with distinctions in length and phosphorylation potential, may vary in their capacity to modulate p120's Armadillo-domain interactions. 3. Phosphorylation of P120-catenin Phosphorylation is one of many modifications impinging upon protein interactions and subcellular localization. Known as well as putative phosphorylation sites exist in the amino-terminal region of p120-catenin [4]. To our knowledge, no other secondary modifications with the exception of ubiquitination [49] have been evaluated. As addressed below with respect to canonical Wnt signaling, key residues are phosphorylated in the amino-terminus of p120-isoform 1 (Fig. 1) [49]. With regards to other parts of p120, such as the Armadillo or carboxyl-tail domains, other kinases or phosphatases are capable of making modifications in less isoform-specific manners. Since the varied isoforms of p120 modulate cadherins, small-GTPases and gene targets, they are relevant to development, homeostasis and disease progression. Such isoforms localize differentially and according to context, with phosphorylation altering p120's protein interactions, cytoplasmic-nuclear shuttling and nuclear activity. It is thus relevant to probe the isoform-specific roles of p120 as a function of phosphorylation.

3.1. Phosphorylation specific to p120-isoform 1 Recent work has identified four conserved serine phosphorylation sites at the very amino-terminus of p120-isoform 1 (S4, 8, 11, 15) (Fig. 1). The closely-spaced serines comprise a “destruction box” similar to that in β-catenin [49] (reviewed in [129]). These sites become phosphorylated by CK1α and GSK3β when canonical Wnt pathway activity is lacking, resulting in reduced catenin stability and thus reduced signal transduction to the nucleus (Fig. 3A). In the case of p120, nuclear partners include the transcriptional regulators Kaiso [30, 31,108], Glis2 [51], and REST/CoREST [77]; these associated factors are each distinct from the transcriptional regulators binding β-catenin (e.g. TCF/LEF). Of p120's partners, only Kaiso has been shown thus far to respond (via p120) to canonical Wnt signals [49,101,102,121]. As would be expected, isoform 1 is the most sensitive to the activity of canonical Wnt pathway components such as LRP5/6. An additional phosphorylation site in isoform 1 was resolved immediately after the coiled-coil domain (S47), phosphorylated by the kinase Dyrk1A. Interestingly, in opposition to CK1α and GSK3β, the phosphorylation of p120-isoform 1 by Dyrk1A enlarges the “signaling pool” of p120 to promote its activity in the nucleus, as well as conceivably, p120's modulation of small-GTPases and the cytoskeleton. In Xenopus and human cell lines, Dyrk1A's phosphorylation of p120-isoform 1 enhances canonical Wnt signaling [50]. For example, in a classic assay of Wnt activity in vivo, ventral co-expression of a phospho-mimic of p120-isoform 1 (T47D) enabled an otherwise sub-phenotypic dose of exogenous β-catenin to produce ectopic dorsal axes in Xenopus embryos. Recent work has furthermore identified DIPA as a binding partner specific for p120-isoform 1 [69,84,85], and an amino-terminal region preceding p120's coiled-coil domain is an important binding site for kinesin (Fig. 1). Given that other proteins associate with p120's amino-terminal region, such as NLBP, PLEKHA7 and RPTPμ, future tests must assess the isoform specificity of these interactions [23,64,71,72,85,87,109]. 3.2. Phosphorylation specific to p120-isoforms 1 and 2 There is only one potential phospho-tyrosine (Y96) between the second and third translational initiation sites of p120 (Figs. 1 & 2) [4], as well as three serines (S81, S92 and S97). These sites, however, are only weakly scored when using algorithms to predict phosphorylation (e.g. NetPhosph 2.0). Currently, no evidence suggests Y96 affects p120 function, but Y96 is phosphorylated by an unknown kinase in Src transformed cells [82]. Fer, a member of the Src tyrosine-kinase family, preferentially associates with the two longer isoforms of p120 [115]. While only one tyrosine residue selectively resides in isoforms 1 and 2 (Y96), it could conceivably provide an opportunity for tyrosine kinases such as Fer to regulate p120-isoforms 1 and 2 in the context of cadherins, small-GTPases or other protein complexes. Further study is warranted of the kinase(s) and phosphatase(s) involved at these tyrosine and serine/ threonine sites. 3.3. Phosphorylation specific to p120-isoforms 1, 2 and 3 Many known or potential phosphorylation sites reside in the region between the respective initiations of isoforms 3 and 4 (“regulatory domain” mentioned in previous reviews [4]) [107,121,148] (Fig. 2). Therefore, some of these sites are anticipated to provide shared effects upon isoforms 1–3. P120 associates with kinases such as Fer, Fyn and Yes [65,105,151], as well as interacts with a number of phosphatases such as DEP1 [48], PTP-PEST [38], RPTPμ [162], RPTPrho [13], and SHP-1 [61], which are implicated in either modulating cadherin dependent cell adhesion or motility, small-GTPases, or nuclear gene programs. As mentioned previously, the larger sequence region upstream of p120's Armadillo domain includes binding sites for partners such as NLBP [64], PLEKHA7 [72,87,109], RPTPμ [162], DIPA [69,84,85], and Gα12 [8]. While validation remains needed in most cases, the phosphorylation

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Fig. 2. Phosphorylation of p120-catenin. Outlined in the text are proposed kinases, phosphatases and signaling mechanisms modulating the level of p120-catenin phosphorylation. As reflected in this figure, multiple residues are modified in response to serine, threonine (Red) or tyrosine (Blue ovals) kinases. Black circles indicate potential phosphorylation sites that are not yet identified as phosphorylated, and that are not yet known to have functional effects. All four human translational start site isoforms are depicted (p120-isforms 1–4), so that one can easily compare which phospho-residues in p120 pertain to only one versus multiple isoforms. Given the number of phosphorylation sites involved, relevant references are included in the review text, as opposed to this legend.

state of the amino-terminal regulatory region is expected to modulate some of these interactions or be a consequence of them, and while a number of phospho-sites currently appear to have lesser functional implications [83], this could change upon applying other assays. Here, we will first discuss tyrosine and serine/threonine phosphorylation events common to isoforms 1–3. 3.3.1. Tyrosine phosphorylation P120 was first identified 20 years ago in a screen for novel substrates of the Src kinase [113]. Depending on the context, heightened tyrosine phosphorylation of cadherins and catenins has correlated with either diminished [19] (e.g. via Fer kinase) [52,68,74,115,116], enhanced [16, 19,28,97,130], or little effect upon cell–cell junctions. Similar to tyrosine phosphorylation, serine/threonine modification of p120 likewise modulates junction functions to context-dependent extents [12,98]. 3.3.1.1. Src-family kinases. P120 is enriched in potential Src-family kinase sites within its amino-terminal region (e.g. Y112, Y217, Y228) (Fig. 1). This is one of two areas where RhoA binds [19,154]. Fyn's phosphorylation of p120 at Y112 diminishes p120's association with RhoA such that RhoA is no longer inhibited (its activity rises), whereas Src phosphorylation of p120-catenin on Y217 and Y228 has the opposite effect, since Src enhances p120's interaction to further inhibit RhoA. Recently, the p120 dephospho- as opposed to phospho-form of Y112 was found to associate with Rac and Vav2 to promote Rac activity and thereby β-catenin nuclear localization, while Y217 dephosphorylation had similar effects with regards to Rac [136] (Table 1). In common with Src kinase, Fer also enhances p120:RhoA association, and both kinases favor p120's association with E-cadherin [19] (Table 1). In another report, p120's Y217 was shown to function in v-Src mediated reduction of cell–cell adhesion in L-cells [100]. Collectively, these findings indicate that functionally important phospho-residues reside with the aminoterminal region of p120-catenin, lacking in isoform 4 (Fig. 1). 3.3.1.2. Receptor tyrosine kinases. The phosphorylation of adherens junction components has also been studied in relation to the activities

of receptor tyrosine kinases/RTKs such as EGFR, VEGFR and PDGFR [37,39,55,83]. P120 Y228 is likely to be phosphorylated by EGFR signaling, but this modification occurs without obvious effects upon cell–cell junctions when evaluated using epithelial cell cultures [83], and appears not to be mediated via Src kinase. Thus, it is not currently known if a particular p120-isoform(s) is preferentially regulated by an RTK. With regard to non-receptor tyrosine kinases, as noted earlier, Fer-kinase associates to an amino-terminal region of p120 (amino acids 131–156), between p120's 3rd and 4th translational start sites (Fig. 1) [65], with Src and Fyn sites mapped relatively nearby to Y112, Y217 and Y228. Recently, the non-receptor tyrosine kinase PTK6 (Protein receptor tyrosine kinase 6) was found in association with p120-catenin, although its phosphorylation of p120-catenin has yet to be characterized [45]. In addition to the indirect activities of tyrosine kinases, there is also the question of direct RTK phosphorylation of p120, and if particular phospho-tyrosine residues display isoform-specificity. Unfortunately, specific residues directly phosphorylated by EGFR, PDGFR or VEGFR have yet to be resolved. Recent work using anti-VEGF antibodies points to Y228 as being associated with glioblastoma progression [55,138]. This residue is phosphorylated by Src [82], often a downstream RTK effector. Seven additional Src phosphorylation sites were identified, with mutation of all eight sites (Y96, Y112, Y228, Y257, Y280, Y291, Y296, Y302) eliminating p120's interaction with the phosphatase SHP-1 [82]. Since p120-isoform 4 bound more poorly to SHP-1 than did isoforms 1–3, it suggests that the greater number of Src-targeted tyrosine residues within the amino-terminus of p120 may enable a stronger SHP-1 association [61]. As phosphatases modulate many biological outcomes including those at cell–cell contacts, differential recruitment of SHP-1 (etc.) as determined by the p120-isoform present, may be a means to modulate those outcomes. In embryonal carcinoma cells, nerve growth factor or TrkA-receptor stimulation leads to p120's (as well as β-catenin's) tyrosine phosphorylation, with these effects inhibited by the Src inhibitor PP2 [28]. The residues involved are not known, a reflection of the work still needed to identify and characterize p120's phospho-tyrosines.

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3.3.2. Protein tyrosine phosphatases Given their regulation of p120's phosphorylation state, phosphatases are as central to our discussion as kinases. Phosphatases such as SHP-1, SHP-2, DEP1 and RPTPμ act upon p120-catenin. For example, the tyrosine phosphatase SHP-1 binds p120 following EGF-stimulated p120-phosphorylation as mentioned [61], and SHP-1 effectively dephosphorylates Y296 and presumably additional residues following the activity of Src [42] (Table 1). The tyrosine phosphatase DEP1 also associates with p120, although the phosphorylation sites it acts upon are not known [48]. The RPTPμ tyrosine phosphatase binds p120 in a manner independent of p120's central Armadillo domain (Fig. 1) [162]. In most cases, the p120 tyrosine residues targeted by a particular phosphatase has yet to be determined. Better knowledge of both phosphatase and kinase activity directed towards p120 should be useful in understanding p120's functions in junctional, cytoplasmic and nuclear contexts. More complete or refined assays may also be required to assess functional effects, since in many cases, negative experimental results may not accurately reflect the in vivo significance of the phosphoresidues examined, or that of the kinases or phosphatases acting upon p120. 3.3.3. Serine/threonine phosphorylation P120 is phosphorylated upon numerous serine/threonine residues, with for example, effects reported for the PKC isoforms PKCα, PKCδ [60] and PKCε [32]. PKC promotes phosphorylation of S879, and the dephosphorylation of S268, S288, T310 and T916 [15,138,147,148,160]. S268 is selectively present in p120-isoforms 1–3 and its phosphorylation is dependent upon one PKC isoform, PKCε. Phosphorylation of S288 in response to PKC promotes the binding of p120-isoform 3 to the transcription repressor Kaiso, its movement from the nucleus to cytoplasm and presumably gene target modulation [160] (Fig. 3C). Nearby to S288, residues S268 and S269 are likewise phosphorylated. Here, CK1ε responds to canonical Wnt pathway activation, with p120 phosphorylation via CK1α somehow promoting p120's release from cadherin [18] (Table 1). This increases p120's signaling pool, with S268 and S269 phosphorylation promoting p120's association with the Kaiso transcriptional regulator to activate (relieve repression of) gene targets [36], as well as activating Rac. The author's model proposes interaction of the cadherin-complex with the Wnt-pathway receptor complex, integrating their signaling to the nucleus. As the serine residues discussed (S268, S269 and S288) are present only in isoforms 1– 3, they alone would be expected to participate in such a pathway. While EGFR, VEGFR or PDGFR activation enhances p120's tyrosine phosphorylation [37,39], VEGFR has also been noted to promote the dephosphorylation of p120 upon serine/threonine [145]. This effect is thought to occur through downstream effects upon PKC and ultimately an unidentified phosphatase. Dephosphorylation of p120 also occurs in cells exposed to potentiators of PKC (e.g. phorbol esters), with effects observed upon S268, T310 and T916 in addition to other residues [139,147,148]. P120 is alternatively phosphorylated upon serine/threonine residues following activation of RTKs (e.g. PDGFR), with the effects again being in part due to the downstream engagement of PKCα [15, 138]. For example, S879 is directly or indirectly phosphorylated by PKCα. S879 is just upstream of the A splice-isoform insert in p120catenin (Figs. 1 & 2), so their juxtaposition may be relevant to either isoforms's functional activities in vivo. 3.4. Phosphorylated residues shared across p120-isoforms Less is known concerning phosphorylation events in the Armadillodomain or carboxyl-tail of p120. The Armadillo or carboxyl-tail region of p120 interacts with multiple proteins such as MUC1, REST/CoREST, Numb and p190RhoGAP, with these associations presumably being shared among isoforms 1–4 [77–79,119,159]. In both p120's amino- and Armadillo-regions, phospho-serine, -threonine and -tyrosine sites are present. Interestingly, the removal

of p120's entire upstream region, as occurs naturally in generating isoform 4, eliminates multiple phosphorylation sites and associations in this region, but not that with cadherins which instead involves p120's neighboring Armadillo domain [57,98]. For example, PDGFR activation leads to p120's phosphorylation at S879 via a PKCα-dependent pathway [15]. Upon thrombin stimulation and thereby PKCα activation, phosphorylation at S879 promotes p120's dissociation from VEcadherin. As might be predicted, S879 point-mutagenesis enhances p120:VE-cadherin association and junction function, with a reduction in cadherin endocytosis. Unlike PKCα's negative impact upon the association of p120 with VE-cadherin, and thus upon cell–cell interactions [138], atypical-PKC promotes adhesion. This occurs through atypicalPKC phosphorylation of Numb, and Numb's dissociation from the carboxyl-tail of p120. Because Numb otherwise recruits α-adaptin, Numb's loss reduces the extent of cadherin internalization [119]. It appears, therefore, that different PKC family members modify carboxyltail residues within p120, exhibiting distinct effects upon p120 and cadherin function. Depletion of the phosphatase PTP-PEST results in enhanced p120 phosphorylation (Y335). This leads to reduced p120 association with E-cadherin, with correspondingly greater p120 modulation of smallGTPases and the cytoskeleton (via Vav2 & cortactin), resulting in heightened cell motility [38]. Since Y335 is present in all p120-isoforms (Fig. 2), the downstream functional consequences of this relationship with PTP-PEST might at first seem to be shared. However, as noted earlier, p120-isoform 1 is the most effective in inhibiting RhoA, such that differences in isoform expression levels is likely to produce functional distinctions. 4. P120-catenin isoforms and phosphorylation in development P120-catenin has essential pleiotropic roles in vertebrate development and homeostasis, while interestingly, it plays modulatory but non-essential roles in invertebrates raised under laboratory conditions (Drosophila & C. elegans) (reviewed in [86]). For example, in mice, the whole animal knock-out of p120 is early embryonic lethal [34]. Additionally, several tissue specific knock-out mice have been generated, such as in salivary gland, skin, teeth, dorsal forebrain, intestine, mammary gland, eye, pancreas and endothelial cells [9,34,47,75,103,126]. Defects include those appearing at adherence junctions and in smallGTPase functions (and likely gene-regulatory responses), with gross effects being manifest in aberrant tissue morphogenesis. P120 ablation in different organ system reveals a variety of effects. In tissues such as skin, salivary gland, mammary gland, dental enamel, kidney and vasculature, p120 removal results in reduced E-cadherin levels, sometimes in conjunction with inflammation [9,34,73,81,126]. During embryonic eye development, p120 interacts functionally with Shroom3 in apical constriction, with p120 removal disrupting lens pit invagination [75]. In addition, p120 in the context of neural crest cells contributes to forming the eye and craniofacial skeleton [27,134,152]. In certain contexts other effects are observed. For example, p120 loss in the skin, intestine and pancreas promotes immune cell infiltration and proinflammatory cytokine release [47,103,126]. Reports also suggest p120 is tied to inflammation via effects upon small-GTPases, NF-κB activity and Kaiso [21,53,110]. Recently, p120 ablation in mouse pancreas progenitor cells produced embryonic defects in tubulogenesis, branching morphogenesis and acinal cell differentiation, with concurrent inflammation [47]. Aberrant tubule formation was also reported upon p120 loss during glomerulogenesis [81]. In Xenopus, p120 knock-down embryos exhibit gastrulation defects [41], with disruptions arising due to defects in cadherin, small-GTPase and nuclear (e.g. Kaiso) functions [49,66,102]. More information on p120's functions during embryonic development is provided in prior reviews [86,106, 107]. Although p120-catenin is widely expressed, specific isoforms are more apparent in certain tissue contexts. While not exclusive, the

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shorter p120-isoforms 3 or 4 are abundant in epidermis, palate and tongue epithelia, and in the ducts of excretory glands, while longer isoforms are favored at vascular-endothelial cell–cell junctions (blood vessels), junctions of serosal epithelium lining internal organs, brain choroid plexus, pigment epithelium of retina, and intercalated discs of cardiomyocytes [2,90,95]. The isoform specific roles of p120 in development are largely unknown. As discussed in this review, partial differences in function presumably derive from isoform-specific distinctions in the presence versus absence of regulatory phospho-residues. Given that p120's phosphorylation-status is likely to have roles in cadherin mediated cell–cell adhesion, cytoskeletal functions via the modulation of small-GTPases, as well as signaling processes mediated by canonical Wnt components or other pathways, it is appropriate to postulate that defined phosphorylation or dephosphorylation events upon p120 are required in development. As mentioned earlier, a number of reports indicate p120's involvement in canonical Wnt signaling. Canonical Wnt signaling, which is modulated by β-catenin, is central in development as well as tumorigenesis. In recent reports, the kinases GSK3β, CK1α and Dyrk1A phosphorylate p120-isoform 1 at defined residues to regulate p120's stability, which determines the size of its signaling pool [49,50]. The same upstream canonical Wnt ligands and destruction-components that act upon p120-isoform 1 also regulate β-catenin. An enlarged signaling-pool of p120 promotes its binding to the transcription factor Kaiso, and perhaps other transcriptional regulators. Although divergent views have arisen [14,117], the association of p120 with Kaiso association has been tied to the de-repression (activation) of p120/Kaiso sequence-specific gene targets (KBS: TCCTGCNA) [66,102]. Further, while a surprise at first, the promoters of certain genes harbor binding sites for both Kaiso and TCF/LEF, apparently to permit the coordinate regulation of such genes by p120-catenin and β-catenin in response to upstream Wnt-signals, potentially during embryogenesis [102] (Fig. 3A). Given that GSK3β and Dyrk1A phosphorylation sites were identified towards the amino-terminus of p120-isoform 1 (Table 1), p120-mediated Wnt-responsiveness would be expected in those tissues expressing isoform 1. Apart from this relationship, p120 participates in canonical Wnt signaling in other ways. For example, upon upstream Wnt-pathway stimulation, p120 is phosphorylated on S268 and S269 by CK1α, while being dephosphorylated on tyrosine Y112 and Y217. The two serine phosphorylation events release p120 from E-cadherin [18]. Upstream Wnt-activity further leads to phosphorylation upon E-cadherin and its release from the signalosome complex, favoring GSK3β internalization (removal) and the activation of β-catenin target genes [35,36,140]. Since S268, S269, S288, Y112, Y217 and Y228 exist in p120-isoforms 1–3, (but not in isoform 4), these effects may be more general. The PKCα kinase instead phosphorylates p120 at S879, promoting the dissociation of p120 from VE-cadherin in endothelial cells, and the disassembly (enhanced permeability) of junctions [138]. As noted, PKC activity has also been observed to lower p120 phosphorylation (S268), presumably indirectly and occurring via an unknown phosphatase [148]. Since S879 and T916 exist in all isoforms of p120, their examination might prove informative when considering isoform-wide effects. In another context, the dephosphorylation of p120 takes place via RPTPμ, which acts upon tyrosines and is needed for proper p120 localization, as linked to adipocyte differentiation [67]. Thus, in response to largely uncharacterized upstream signals, kinases and phosphatases produce effects upon p120 that relate to its cellular localization and protein associations, and thereby to larger pathway functions. While most of the current work has taken place in cell lines, it points to experiments that must now be undertaken in developmental models. With respect to the focus of this review, which examines phospho-residues that have isoform-selective effects, the developmental impact of a kinase or phosphatase will partially depend on the particular p120-isoforms being expressed at that time in a tissue.

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5. P120-catenin isoforms and phosphorylation in cancer In multiple cancers such as adenocarcinoma, breast cancer, bladder cancer and squamous cell carcinoma, reduced or relocalized p120 presence correlates with reduced E-cadherin presence, altered smallGTPase activity and poor prognosis [58,112,124,131,143]. Recently, p120-catenin cytoplasmic localization was correlated with poor prognosis in human colon carcinoma and esophageal squamous cell carcinoma [11,22]. Through p120's function in stabilizing cadherins, consideration has been given to p120's activities as a tumor suppressor [34,73,80,96,120,121,128,133]. For example, conditional deletion of p120 in the mouse oral cavity, esophagus and forestomach results in invasive squamous cell cancer in addition to desmoplasia and inflammation [128]. P120's relationship to E-cadherin or other partners is made more interesting by its isoforms having differing affects upon tumor progression. Given its longer N-terminus, p120-isoform 1 (relative to isoform 3) exerts greater inhibition of RhoA. This can enhance cell migration and invasion [123,127], with for example, p120isoform 1 expression being predictive of renal tumor micrometastasis [154]. Since some phosphorylation sites are specific to p120-isoform 1, they may in turn be relevant to normal or tumor cell migration. Other work likewise points to distinctions in p120-isoform expression and localization in pathology, as in the case of metastatic lung cancer [40, 123,161], breast invasive lobular carcinoma [122,123], and colon [11], ovarian [24] and pancreatic cancer [132]. Some reports indicate that cytosolic p120-catenin localization correlates with hyperplasia and the progression of E-cadherin deficient tumors (or E-cadherin mutant tumors), and is predictive of poor prognosis [127] [11,22]. Given that differing p120-isoforms exhibit distinct localizations according to context [2,114], choices involving isoform expression or the presence of E- versus other cadherins is expected to play a role in determining the roles of p120 in cancer. For example, in contrast to p120's association with E-cadherin, that with P- or N-cadherin in some instances promotes motility more so than adhesion [111,132]. Therefore, p120's contributions to pathology are likely to be determined in part by what cadherins are expressed in the tumor [121]. Multiple phosphorylation sites reside in p120's amino- and carboxyterminal regions and may have a role in tumorigenesis. Utilizing phospho-specific antibodies, cancer cell lines have been evaluated to assess p120's phosphorylation state [83,147] (Table 1). E-cadherin contributes to determining p120's phosphorylation in certain cancer cell types, presumably by recruiting p120 into complexes or regions rich in kinase activity [71,114,147]. Recently, upon Ras-PKCε activation in breast cancer cells, p120's phosphorylation at S268 was found to contribute to cellular foci formation (Table 1). Another report found that p120-isoform 3 undergoes S288 phosphorylation and greater Kaiso binding, correlating with enhanced lung-cancer cell invasion in vitro [160,161]. While the work above suggested that p120-isoform 3 was the prime modulator of Kaiso function, findings from our group instead point to p120-isoform 1 being most responsive to canonical Wnt signals. Upon pathway activation and in a manner analogous to β-catenin, p120-isoform 1 is stabilized at the protein level. The model is that isoform 1 then enters the nucleus to relieve (activate) Kaiso repressed gene targets [49,50]. Intriguingly, recent work on the whole genome level has indicated that Kaiso is largely associated with transcriptional activation as opposed to repression [14]; if this proves the case, it will be important to establish if p120 additionally has a role in this context. As part of earlier mentioned work, p120 phosphorylation at Y228 is predictive of glioblastoma multiforme (GBM) invasiveness [55], and is also elevated in invasive renal and breast tumors [71]. Further, T916 phosphorylation is high in these tumors; and while the functional role of phospho-T916 was not resolved, it was found to obstruct the epitope of the widely employed pp120 monoclonal antibody. Thus, many past studies are likely to have underestimated p120 levels in tumors. Further, tyrosine phosphatases such as PTP-PEST promote Y335's dephosphorylation and the

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Serine/Threonine residue

Serine/Threonine kinase

If undertaken, phenotype related to the kinase or phosphatase, such as overexpression or depletion

Signaling pathway(s)

References Phenotype related to the phosphorylation site(s) P120 isoform(s) containing phos. Site

S6, S8, S11, S15

CK1α & GKS3β

Wnt

4S- N 4A p120 point mutant is stabilized, w/ greater signaling capacity.

1

Hong...McCrea, J Cell Sci, 2010

T47

Dyrk1A

Wnt

P120 phospho-mimic point mutant is more stable, w/ enhanced signaling capacity.

1

Hong...McCrea, J Cell Sci, 2012

S252, T310

GSK3β

Gastrulation defects resulting from p120 overexpression are partially rescued via GSK3β overexpression. Dyrk1A overexpression produces gastrulation defects in Xenopus embryos, as well as facilitates β-catenin induced duplicate axis formation. N/A

N/A

N/A

1, 2, 3

Serum starvation, LPA, thrombin, PMA, VEGF produces p120 dephos. via effects upon PKC. N/A

Cadherin-p120 association was not altered by mutation of these phsopho-sites. Phosphorylation of p120 required its membrane assn. PKCε phenotype correlated with S268 phosphorylation, but mutant not tested.

1, 2, 3

Xia...Reynolds, Biochemistry, 2003 Xia...Reynolds, Biochemistry, 2003 Xia...Reynolds, Exp Cell Res, 2006 Wong...Staddon, Biochem J, 2000 Dann...Klippel, Oncogene, 2014

Release of p120 from cadherin and LRP5/6, Wnt pathway.

Phospho-deficient point mutant S268A, S269A failed to rescue gastrulation defect induced via p120 depletion.

1, 2, 3

S288 phosphorylation is high In lung cancer cell lines, primary cells and tissues. N/A

P120-isoform3 recruits Kaiso to the cytoplasm. N/A

Cell invasion is regulated by S288 in lung cancer cell lines (S288E mutant was utilized). N/A

3

PKCα induced p120 dissociation from VE-cadherin and AJ disassembly. PKCα depletion reduces thrombin-induced decreases in transendothelial electric resistance.

Thrombin/Par-1 and LPS-induced lung vascular permeability (2012) PDGF (2009)

P120 point mutants (S879A or S879D) indicate direct effects (2012), Correlated to the PDGF signaling (2009).

1, 2, 3, 4

S268, S288, T310, T916 PKC activation via PMA N/A results in the dephos. of these four residues S268

PKCε

S268, S269

CK1α

S288

PKC

S252, T310

GSK3β (in vitro)

S879

PKCα

PKCε overexpression leads to S268 phos., overcomes contact inhibition and results in cellular foci formation. PKCε depletion reverts Ras-induced mesenchymal morphology. N/A

1, 2, 3

1, 2, 3

Del Valle-Perez...Dunach, Mol Cell Biol, 2011 Vinyoles, Mol Cell, 2014 Valls...Dunach, J Cell Sci, 2012 Zhang...Wang, Int J Oncol, 2011 Xia...Reynolds, Biochemistry, 2003 Vandenbroucke St. Amant...Malik, Cir Res, 2012 Brown...Reynolds, Exp Cell Res, 2009

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Table 1 Phenotypes related to p120-catenin phosphorylation. Summary of observed phenotypes that relate to changes at a particular residue (column 5); or changes to the kinase or phosphatase acting upon p120-catenin in the context of that residue(s) (column 3). Indicated are the residue or residues involved (column 1), the kinase or phosphatase involved (column 2), the signaling pathway implicated or proposed (column 4), and the p120-isoforms that are potentially affected. References are included (column 7; not comprehensive), with additional references present within the review text.

N/A

Tyrosine residue Y112

Tyrosine kinase Fyn

Y112, Y217

Src/Fyn

N/A

Y217

Src

Y217, Y228

Src

v-Src overexpression reduces E-cadherin mediated cell aggregation. N/A

Y228

N/A

Certain carcinoma cell lines (e.g. HCT116, HT29 and A431) show high levels of Y228 phosphorylation.

Y228

Src

VEGF/Src family kinases.

Y228

N/A

Activation of Src family kinase is common in Glioblastoma multiforme (GBM). P120 Y228 phosphorylation is high in renal cell carcinoma and breast cancer cells.

Tyrosine residue Y296

Phosphatase SHP-1

N/A

EGF/Src

Y335

PTP-PEST

1, 2, 3, 4

Kourtidis...Anastasiadis, PLoS One, 2015

N/A

N/A

T916 phosphorylation is high in renal cell carcinoma, but T916 is not required in transforming ability

Overexpression in NIH3T3 cells reduces stress fiber formation.

Phosphorylation lowers p120 assn. w/ RhoA, Rac and Vav2, in preference to E-cadherin binding. Wnt pathway, p120 release from cadherin and LRP5/6 to enable assn. with Vav2 and Rac1. v-Src mediated signaling

In contrast to wild-type p120, the Y112E mutant 1, 2, 3 has little effect upon stress fibers.

P120 Y112E and Y217E phosphomimic mutants have reduced assn. w/ Rac1 and Vav2. Mutant failed to rescue gastrulation delay upon p120 depletion (Y112E). P120 Y217F mutant increases cell aggregation.

1, 2, 3

Valls...Dunach, J Cell Sci, 2012

1,2,3

Src and cadherin-related pathways EGFR activation induces p120 Y228 phosphorylation.

Src phos. of p120 Y217 and Y228 promotes p120 assn. w/ and inhib. RhoA. Mutation of Y228 and 7 other tyrosine residues in p120 did not prevent junction formation or compaction of cultured cells. Y228 phosphorylation is high in highly or moderately invasive GBM. Mutation of p120 simultaneously at 8 tyrosine sites (including Y228) reduces tumorigenic potential.

1, 2, 3

Ozawa...Ohkubo, J Cell Sci, 2001 Castano...Dunach, Mol Cell Biol, 2007 Mariner...Reynolds,J Cell Sci, 2004

N/A

1, 2, 3

P120 point mutant Y335F fails to associate with Vav2, activate Rac1 or induce epithelial migration (HCT116).

1, 2, 3, 4

Src family kinases.

PTP-PEST is essential for Silencing PTP-PEST reduces p120-E-cadherin junction assembly via effects association and increases p120's cytoplasmic pool. upon p120 and small-GTPases. Ectopic expression of PTP-PEST suppresses cell migration in colon carcinoma cells. Stable knock-down PTP-PEST reduces junction integrity, enhances Rac1 and reduces RhoA activity, and generates a mesenchymal-like phenotype in colon carcinoma cells.

1, 2, 3

1, 2, 3 1, 2, 3

Castano...Dunach, Mol Cell Biol, 2007

Huveldt...Anastasiadis, PLoS One, 2013 Kourtidis...Anastasiadis, PLoS One, 2015

Frank...Bohmer, J Biol Chem, 2004 Espejo...Sastry, J Cell Sci, 2014 Espejo...Sastry, Am J Physiol, 2010

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T916

109

110

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cytosolic localization of p120 in colon carcinoma cells [38]. Recently, it was determined via deep sequencing that the absence of p120's splice region B correlates with some colorectal cancers [146]. Potential phosphoresidues do not exist in splice region B, although sites present nearby (S879, T916) may conceivably respond to the presence/absence of splice region B, and be relevant to tumorigenesis. Taken together, the phosphorylation status of p120-catenin is likely to prove relevant to cancer progression, with a number of the involved residues being isoform specific. P120 may participate in epithelial-to-mesenchymal transitions (EMTs) in tumor progression, with for example, a switch from shortto-long p120-isoforms occurring in response to factors including Zeppo1 (ZNF703) [125]. In some tumor cells lacking E-cadherin, and in cells over-expressing Src, p120-catenin facilitates cell invasion and anchorage-independent growth via effects upon Rho/ROCK signaling. Studies of breast, colon and lung cancer cells indicate that heightened levels of cytosolic p120 contribute to the invasiveness of tumors deficient for E-cadherin [11,22,123,161]. For example, cytosolic p120catenin facilitates anchorage-independent tumor growth and metastasis in invasive lobular carcinoma cells via affects upon RhoA [122]. Considering that p120's phosphorylation status is responsive to being localized at the plasma membrane via cadherin, and its release from cadherin is further responsive to phosphorylation, p120's cadherinand phospho-modulated movements to the cytoplasm potentially contribute to the EMT process. Thus, changes in p120's intracellular phosphorylation, localization and isoform use in EMT are proposed to facilitate cancer progression (reviewed in [70,88,121]).

Further work with cell lines as well as lung and breast tumor samples has indicated that E-cadherin is a key determinant of p120-catenin localization and activity [29,127,161]. In epithelial cells lacking E-cadherin, p120 is often present in the cytoplasm where in common with p120 still at junctions [69,71,144], it interacts with small-GTPases modulating the cytoskeleton [5,11,103,107,122,125,161] (reviewed in [70,121]), or reaches the nucleus to engage in gene control [30,31,49,59,77,114,140, 160]. Acting through small-GTPases such as RhoA and Rac1 in EMT or cancer, p120-isoform 1 might be predominant in promoting motility and invasiveness [154]. Since certain phospho-residues exist only in p120-isoform 1 (S6, S8, S11, S15, T47), and as noted modulate p120 stability in response to Wnt-signals or the kinase Dyrk1A, they may prove worthy of further examination in the context of tumor formation or metastasis. 6. Summary In summary, the collective evidence is that isoform and phosphorylation use in p120-catenin is relevant to cell behaviors in development, homeostasis and pathology. Among others, upstream inputs include the presence versus absence of cadherins, growth factor signaling and possibly canonical Wnt signals. Future study of p120 biology will need to focus more on factors and mechanisms that determine isoform expression or retention, localization and activity, and the relevance of phosphorylation as well as additional covalent modifications in modulating p120's functional roles. Based upon a recent report showing

Fig. 3. Isoform-specific mechanisms of p120-catenin. Model of isoform-specific roles of p120-catenin. A. Canonical Wnt signals, initiated by Wnt-ligand binding to the LRP5/6 and Frizzled receptors, act to prevent destruction of p120-isoform 1, such that it is more stable and therefore active, as in the de-repression of the transcriptional repressor Kaiso depicted in (C) [49]. Canonical Wnt-signals have a lesser protective effects upon shorter p120-isoforms, since the shorter isoforms 2–4 lack the destruction box found only in isoform 1. That is, in the absence of canonical Wnt signals, (e.g. lack of Wnt-ligand binding to Frizzled/LRP5/6 co-receptors), p120-isoform 1 is acted upon by the destruction complex (containing components such as Axin, APC, GSK3beta and CK1alpha), and delivered to the proteasome for elimination (not shown). B. Switches in p120-catenin isoforms have been observed upon ectopic expression of Snail or Zeppo1, suggesting the potential role of p120-isoforms during epithelial-mesenchymal transition (Fig. 3B) [99,125]. In addition, epithelial cell type specific regulators ESRP1 and ESRP2 modulate p120's splicing events [142]. Since p120-isoform 1 more effectively inhibits RhoA than isoform 3, consequent effects arise that relate to cytoskeletal modulation, and thereby cell process-extension, motility or invasion. C. P120-catenin binds and displaces the Kaiso repressor from its consensus binding sites, leading to gene activation [49,50,160]. For simplicity, beta-catenin and alpha-catenin (etc.) are not depicted, and N-cadherin is shown without associated catenins.

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that the pp120 antibody, which is widely used in p120 biology, does not detect p120 that is phosphorylated at T916 (nearby the pp120 epitope), we likely need to reevaluate p120's localization and expression levels in multiple tissues and cancers using other reagents [70]. While nontrivial to develop, we need additional p120 antibodies that specifically report on a wider range (e.g. see Table) of p120's phosphorylation states, so as to better evaluate their relevance in development and tumorigenesis; this importantly includes having such phospho- or dephospho-specific antibodies to help identify and evaluate upstream regulatory pathways that direct p120's functions. At present, there is little known about most p120 phosphorylation events with respect to embryogenesis or disease. Ideally, select conditional and inducible mouse knock-ins of p120-isoforms engineered to contain phospho- or dephospho-mimic residues will become available to assess the developmental significance of such covalent modifications in vivo. For example, given that the phosphorylation of S288, T916 and Y228 are high in certain tumor samples, these residues would be interesting to probe. Finally, because p120-catenin is but one member of the larger p120catenin sub-family that exists in vertebrates (reviewed in [54,86,107]), with the plakophilin–catenins representing yet another related subfamily (reviewed in [10,46]), what is determined concerning p120 should provide insight upon multiple catenins and their respective isoforms having roles at cell–cell junctions, and in the cytoplasm and nucleus. Transparency document The Transparency document associated with this article can be found, online version. Acknowledgements We thank our reviewers for their helpful comments. This work was supported by National Institute of Health (grant number 1RO1GM107079 to P.D.M.); University of Texas M.D. Anderson Cancer Center National Cancer Institute Core Grant (grant number CA-16672); Korean Health Technology R&D project, Ministry of Health & Welfare, Republic of Korea (grant number A120262 to I.H.O and J.Y.H). J.Y.H is supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry (grant number NRF-2013R1A6A3A01058569). References [1] D.F. Aghib, P.D. McCrea, The E-cadherin complex contains the src substrate p120, Exp. Cell Res. 218 (1995) 359–369. [2] S. Aho, L. Levansuo, O. Montonen, C. Kari, U. Rodeck, J. Uitto, Specific sequences in p120ctn determine subcellular distribution of its multiple isoforms involved in cellular adhesion of normal and malignant epithelial cells, J. Cell Sci. 115 (2002) 1391–1402. [3] S. Aho, K. Rothenberger, J. Uitto, Human p120ctn catenin: tissue-specific expression of isoforms and molecular interactions with BP180/type XVII collagen, J. Cell. Biochem. 73 (1999) 390–399. [4] S. Alema, A.M. Salvatore, p120 catenin and phosphorylation: mechanisms and traits of an unresolved issue, Biochim. Biophys. Acta 1773 (2007) 47–58. [5] P.Z. Anastasiadis, p120-ctn: a nexus for contextual signaling via Rho GTPases, Biochim. Biophys. Acta 1773 (2007) 34–46. [6] P.Z. Anastasiadis, S.Y. Moon, M.A. Thoreson, D.J. Mariner, H.C. Crawford, Y. Zheng, A.B. Reynolds, Inhibition of RhoA by p120 catenin, Nat. Cell Biol. 2 (2000) 637–644. [7] P.Z. Anastasiadis, A.B. Reynolds, The p120 catenin family: complex roles in adhesion, signaling and cancer, J. Cell Sci. 113 (Pt 8) (2000) 1319–1334. [8] V.V. Ardawatia, M. Masia-Balague, B.F. Krakstad, B.B. Johansson, K.M. Kreitzburg, E. Spriet, A.E. Lewis, T.E. Meigs, A.M. Aragay, Galpha(12) binds to the N-terminal regulatory domain of p120(ctn), and downregulates p120(ctn) tyrosine phosphorylation induced by Src family kinases via a RhoA independent mechanism, Exp. Cell Res. 317 (2011) 293–306. [9] J.D. Bartlett, J.M. Dobeck, C.E. Tye, M. Perez-Moreno, N. Stokes, A.B. Reynolds, E. Fuchs, Z. Skobe, Targeted p120-catenin ablation disrupts dental enamel development, PLoS One 5 (2010). [10] A.E. Bass-Zubek, L.M. Godsel, M. Delmar, K.J. Green, Plakophilins: multifunctional scaffolds for adhesion and signaling, Curr. Opin. Cell Biol. 21 (2009) 708–716. [11] D.I. Bellovin, R.C. Bates, A. Muzikansky, D.L. Rimm, A.M. Mercurio, Altered localization of p120 catenin during epithelial to mesenchymal transition of colon carcinoma is prognostic for aggressive disease, Cancer Res. 65 (2005) 10938–10945.

111

[12] C. Bertocchi, M. Vaman Rao, R. Zaidel-Bar, Regulation of adherens junction dynamics by phosphorylation switches, J. Signal Transduct. 2012 (2012) 125295. [13] J.A. Besco, R. Hooft van Huijsduijnen, A. Frostholm, A. Rotter, Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT), Brain Res. 1116 (2006) 50–57. [14] A. Blattler, L. Yao, Y. Wang, Z. Ye, V.X. Jin, P.J. Farnham, ZBTB33 binds unmethylated regions of the genome associated with actively expressed genes, Epigenetics Chromatin. 6 (2013) 13. [15] M.V. Brown, P.E. Burnett, M.F. Denning, A.B. Reynolds, PDGF receptor activation induces p120-catenin phosphorylation at serine 879 via a PKCalpha-dependent pathway, Exp. Cell Res. 315 (2009) 39–49. [16] E. Calautti, S. Cabodi, P.L. Stein, M. Hatzfeld, N. Kedersha, G. Paolo Dotto, Tyrosine phosphorylation and src family kinases control keratinocyte cell–cell adhesion, J. Cell Biol. 141 (1998) 1449–1465. [17] R.H. Carnahan, A. Rokas, E.A. Gaucher, A.B. Reynolds, The molecular evolution of the p120-catenin subfamily and its functional associations, PLoS One 5 (2010), e15747. [18] D. Casagolda, B. Del Valle-Perez, G. Valls, E. Lugilde, M. Vinyoles, J. Casado-Vela, G. Solanas, E. Batlle, A.B. Reynolds, J.I. Casal, A.G. de Herreros, M. Dunach, A p120catenin-CK1epsilon complex regulates Wnt signaling, J. Cell Sci. 123 (2010) 2621–2631. [19] J. Castano, G. Solanas, D. Casagolda, I. Raurell, P. Villagrasa, X.R. Bustelo, A. Garcia de Herreros, M. Dunach, Specific phosphorylation of p120-catenin regulatory domain differently modulates its binding to RhoA, Mol. Cell. Biol. 27 (2007) 1745–1757. [20] M.A. Castilla, G. Moreno-Bueno, L. Romero-Perez, K. Van De Vijver, M. Biscuola, M.A. Lopez-Garcia, J. Prat, X. Matias-Guiu, A. Cano, E. Oliva, J. Palacios, Micro-RNA signature of the epithelial-mesenchymal transition in endometrial carcinosarcoma, J. Pathol. 223 (2011) 72–80. [21] R. Chaudhary, C.C. Pierre, K. Nanan, D. Wojtal, S. Morone, C. Pinelli, G.A. Wood, S. Robine, J.M. Daniel, The POZ-ZF transcription factor Kaiso (ZBTB33) induces inflammation and progenitor cell differentiation in the murine intestine, PLoS One 8 (2013), e74160. [22] T. Chen, C. Wang, F. Wu, X. Zhang, H. Yang, X. Deng, Q. He, W. Li, G. Li, Altered localization of p120 catenin in the cytoplasm rather than the membrane correlates with poor prognosis in esophageal squamous cell carcinoma, PLoS One 10 (2015), e0118645. [23] X. Chen, S. Kojima, G.G. Borisy, K.J. Green, p120 catenin associates with kinesin and facilitates the transport of cadherin–catenin complexes to intercellular junctions, J. Cell Biol. 163 (2003) 547–557. [24] L.W. Cheung, P.C. Leung, A.S. Wong, Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer, Oncogene 29 (2010) 2427–2440. [25] C.M. Chiasson, K.B. Wittich, P.A. Vincent, V. Faundez, A.P. Kowalczyk, p120-catenin inhibits VE-cadherin internalization through a rho-independent mechanism, Mol. Biol. Cell 20 (2009) 1970–1980. [26] H.J. Choi, A.H. Huber, W.I. Weis, Thermodynamics of beta-catenin-ligand interactions: the roles of the N- and C-terminal tails in modulating binding affinity, J. Biol. Chem. 281 (2006) 1027–1038. [27] M. Ciesiolka, M. Delvaeye, G. Van Imschoot, V. Verschuere, P. McCrea, F. van Roy, K. Vleminckx, p120 catenin is required for morphogenetic movements involved in the formation of the eyes and the craniofacial skeleton in Xenopus, J. Cell Sci. 117 (2004) 4325–4339. [28] M. Cozzolino, B. Giovannone, A. Serafino, K. Knudsen, A. Levi, S. Alema, A. Salvatore, Activation of TrkA tyrosine kinase in embryonal carcinoma cells promotes cell compaction, independently of tyrosine phosphorylation of catenins, J. Cell Sci. 113 (Pt 9) (2000) 1601–1610. [29] D.J. Dabbs, R. Bhargava, M. Chivukula, Lobular versus ductal breast neoplasms: the diagnostic utility of p120 catenin, Am. J. Surg. Pathol. 31 (2007) 427–437. [30] J.M. Daniel, A.B. Reynolds, The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor, Mol. Cell. Biol. 19 (1999) 3614–3623. [31] J.M. Daniel, C.M. Spring, H.C. Crawford, A.B. Reynolds, A. Baig, The p120(ctn)binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides, Nucleic Acids Res. 30 (2002) 2911–2919. [32] S.G. Dann, J. Golas, M. Miranda, C. Shi, J. Wu, G. Jin, E. Rosfjord, E. Upeslacis, A. Klippel, p120 catenin is a key effector of a Ras-PKCvarepsilon oncogenic signaling axis, Oncogene 33 (2014) 1385–1394. [33] M.A. Davis, R.C. Ireton, A.B. Reynolds, A core function for p120-catenin in cadherin turnover, J. Cell Biol. 163 (2003) 525–534. [34] M.A. Davis, A.B. Reynolds, Blocked acinar development, E-cadherin reduction, and intraepithelial neoplasia upon ablation of p120-catenin in the mouse salivary gland, Dev. Cell 10 (2006) 21–31. [35] B. Del Valle-Perez, O. Arques, M. Vinyoles, A.G. de Herreros, M. Dunach, Coordinated action of CK1 isoforms in canonical Wnt signaling, Mol. Cell. Biol. 31 (2011) 2877–2888. [36] B. Del Valle-Perez, D. Casagolda, E. Lugilde, G. Valls, M. Codina, N. Dave, A.G. de Herreros, M. Dunach, Wnt controls the transcriptional activity of Kaiso through CK1epsilon-dependent phosphorylation of p120-catenin, J. Cell Sci. 124 (2011) 2298–2309. [37] J.R. Downing, A.B. Reynolds, PDGF, CSF-1, and EGF induce tyrosine phosphorylation of p120, a pp60src transformation-associated substrate, Oncogene 6 (1991) 607–613. [38] R. Espejo, Y. Jeng, A. Paulucci-Holthauzen, W. Rengifo-Cam, K. Honkus, P.Z. Anastasiadis, S.K. Sastry, PTP-PEST targets a novel tyrosine site in p120 catenin

112

[39]

[40]

[41]

[42]

[43]

[44]

[45] [46] [47]

[48]

[49]

[50]

[51]

[52]

[53] [54] [55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

J.Y. Hong et al. / Biochimica et Biophysica Acta 1863 (2016) 102–114 to control epithelial cell motility and Rho GTPase activity, J. Cell Sci. 127 (2014) 497–508. S. Esser, M.G. Lampugnani, M. Corada, E. Dejana, W. Risau, Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells, J. Cell Sci. 111 (Pt 13) (1998) 1853–1865. C. Fan, G. Jiang, X. Zhang, Y. Miao, X. Lin, L. Luan, Z. Xu, Y. Zhang, H. Zhao, D. Liu, E. Wang, Zbed3 contributes to malignant phenotype of lung cancer via regulating beta-catenin and P120-catenin 1, Mol. Carcinog. (2014). X. Fang, H. Ji, S.W. Kim, J.I. Park, T.G. Vaught, P.Z. Anastasiadis, M. Ciesiolka, P.D. McCrea, Vertebrate development requires ARVCF and p120 catenins and their interplay with RhoA and Rac, J. Cell Biol. 165 (2004) 87–98. C. Frank, C. Burkhardt, D. Imhof, J. Ringel, O. Zschornig, K. Wieligmann, M. Zacharias, F.D. Bohmer, Effective dephosphorylation of Src substrates by SHP-1, J. Biol. Chem. 279 (2004) 11375–11383. C.M. Franz, A.J. Ridley, p120 catenin associates with microtubules: inverse relationship between microtubule binding and Rho GTPase regulation, J. Biol. Chem. 279 (2004) 6588–6594. Y. Fukumoto, Y. Shintani, A.B. Reynolds, K.R. Johnson, M.J. Wheelock, The regulatory or phosphorylation domain of p120 catenin controls E-cadherin dynamics at the plasma membrane, Exp. Cell Res. 314 (2008) 52–67. R.J. Haines, R.S. Beard Jr., M.H. Wu, Protein tyrosine kinase 6 mediates TNFalpha-induced endothelial barrier dysfunction, Biochem. Biophys. Res. Commun. 456 (2015) 190–196. M. Hatzfeld, A. Wolf, R. Keil, Plakophilins in desmosomal adhesion and signaling, Cell Commun. Adhes. 21 (2014) 25–42. A.M. Hendley, E. Provost, J.M. Bailey, Y.J. Wang, M.H. Cleveland, D. Blake, R.W. Bittman, J.C. Roeser, A. Maitra, A.B. Reynolds, S.D. Leach, p120 catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas, Dev. Biol. 399 (2015) 41–53. L.J. Holsinger, K. Ward, B. Duffield, J. Zachwieja, B. Jallal, The transmembrane receptor protein tyrosine phosphatase DEP1 interacts with p120(ctn), Oncogene 21 (2002) 7067–7076. J.Y. Hong, J.I. Park, K. Cho, D. Gu, H. Ji, S.E. Artandi, P.D. McCrea, Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members, J. Cell Sci. 123 (2010) 4351–4365. J.Y. Hong, J.I. Park, M. Lee, W.A. Munoz, R.K. Miller, H. Ji, D. Gu, J. Ezan, S.Y. Sokol, P.D. McCrea, Down's-syndrome-related kinase Dyrk1A modulates the p120-cateninKaiso trajectory of the Wnt signaling pathway, J. Cell Sci. 125 (2012) 561–569. C.R. Hosking, F. Ulloa, C. Hogan, E.C. Ferber, A. Figueroa, K. Gevaert, W. Birchmeier, J. Briscoe, Y. Fujita, The transcriptional repressor Glis2 is a novel binding partner for p120 catenin, Mol. Biol. Cell 18 (2007) 1918–1927. K.L. Hsu, H.J. Fan, Y.C. Chen, Y.S. Huang, C.H. Chen, J.C. Wu, S.M. Wang, Protein kinase C-Fyn kinase cascade mediates the oleic acid-induced disassembly of neonatal rat cardiomyocyte adherens junctions, Int. J. Biochem. Cell Biol. 41 (2009) 1536–1546. G. Hu, p120-catenin: a novel regulator of innate immunity and inflammation, Crit. Rev. Immunol. 32 (2012) 127–138. P. Hulpiau, I.S. Gul, F. van Roy, New insights into the evolution of metazoan cadherins and catenins, Prog. Mol. Biol. Transl. Sci. 116 (2013) 71–94. D. Huveldt, L.J. Lewis-Tuffin, B.L. Carlson, M.A. Schroeder, F. Rodriguez, C. Giannini, E. Galanis, J.N. Sarkaria, P.Z. Anastasiadis, Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion, PLoS One 8 (2013), e56505. R.C. Ireton, M.A. Davis, J. van Hengel, D.J. Mariner, K. Barnes, M.A. Thoreson, P.Z. Anastasiadis, L. Matrisian, L.M. Bundy, L. Sealy, B. Gilbert, F. van Roy, A.B. Reynolds, A novel role for p120 catenin in E-cadherin function, J. Cell Biol. 159 (2002) 465–476. N. Ishiyama, S.H. Lee, S. Liu, G.Y. Li, M.J. Smith, L.F. Reichardt, M. Ikura, Dynamic and static interactions between p120 catenin and E-cadherin regulate the stability of cell–cell adhesion, Cell 141 (2010) 117–128. Y. Ishizaki, Y. Omori, M. Momiyama, Y. Nishikawa, T. Tokairin, M. Manabe, K. Enomoto, Reduced expression and aberrant localization of p120catenin in human squamous cell carcinoma of the skin, J. Dermatol. Sci. 34 (2004) 99–108. G. Jiang, Y. Wang, S. Dai, Y. Liu, M. Stoecker, E. Wang, E. Wang, P120-catenin isoforms 1 and 3 regulate proliferation and cell cycle of lung cancer cells via beta-catenin and Kaiso respectively, PLoS One 7 (2012), e30303. E. Joseloff, C. Cataisson, H. Aamodt, H. Ocheni, P. Blumberg, A.J. Kraker, S.H. Yuspa, Src family kinases phosphorylate protein kinase C delta on tyrosine residues and modify the neoplastic phenotype of skin keratinocytes, J. Biol. Chem. 277 (2002) 12318–12323. H. Keilhack, U. Hellman, J. van Hengel, F. van Roy, J. Godovac-Zimmermann, F.D. Bohmer, The protein–tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin, J. Biol. Chem. 275 (2000) 26376–26384. A. Keirsebilck, S. Bonne, K. Staes, J. van Hengel, F. Nollet, A. Reynolds, F. van Roy, Molecular cloning of the human p120ctn catenin gene (CTNND1): expression of multiple alternatively spliced isoforms, Genomics 50 (1998) 129–146. K.F. Kelly, C.M. Spring, A.A. Otchere, J.M. Daniel, NLS-dependent nuclear localization of p120ctn is necessary to relieve Kaiso-mediated transcriptional repression, J. Cell Sci. 117 (2004) 2675–2686. C.H. Kim, H.S. Nam, E.H. Lee, S.H. Han, H.J. Cho, H.J. Chung, N.S. Lee, S.J. Choi, H. Kim, J.S. Ryu, J. Kwon, H. Kim, Overexpression of a novel regulator of p120 catenin, NLBP, promotes lung adenocarcinoma proliferation, Cell Cycle 12 (2013) 2443–2453. L. Kim, T.W. Wong, The cytoplasmic tyrosine kinase FER is associated with the catenin-like substrate pp120 and is activated by growth factors, Mol. Cell. Biol. 15 (1995) 4553–4561. S.W. Kim, J.I. Park, C.M. Spring, A.K. Sater, H. Ji, A.A. Otchere, J.M. Daniel, P.D. McCrea, Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin, Nat. Cell Biol. 6 (2004) 1212–1220.

[67] W.K. Kim, H. Jung, E.Y. Kim, H. Kim, Y.S. do, B.C. Cho, S.G. Park, Y. Park, K.H.B. Ko, S.C. Lee, RPTPmu tyrosine phosphatase promotes adipogenic differentiation via modulation of p120 catenin phosphorylation, Mol. Biol. Cell 22 (2011) 4883–4891. [68] M.S. Kinch, G.J. Clark, C.J. Der, K. Burridge, Tyrosine phosphorylation regulates the adhesions of ras-transformed breast epithelia, J. Cell Biol. 130 (1995) 461–471. [69] D. Klompstra, D.C. Anderson, J.Y. Yeh, Y. Zilberman, J. Nance, An instructive role for C. elegans E-cadherin in translating cell contact cues into cortical polarity, Nat. Cell Biol. 17 (2015) 726–735. [70] A. Kourtidis, S.P. Ngok, P.Z. Anastasiadis, p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression, Prog. Mol. Biol. Transl. Sci. 116 (2013) 409–432. [71] A. Kourtidis, M. Yanagisawa, D. Huveldt, J.A. Copland, P.Z. Anastasiadis, Pro-tumorigenic phosphorylation of p120 catenin in renal and breast cancer, PLoS One 10 (2015), e0129964. [72] S. Kurita, T. Yamada, E. Rikitsu, W. Ikeda, Y. Takai, Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells, J. Biol. Chem. 288 (2013) 29356–29368. [73] S.J. Kurley, B. Bierie, R.H. Carnahan, N.A. Lobdell, M.A. Davis, I. Hofmann, H.L. Moses, W.J. Muller, A.B. Reynolds, p120-catenin is essential for terminal end bud function and mammary morphogenesis, Development 139 (2012) 1754–1764. [74] M.G. Lampugnani, M. Corada, P. Andriopoulou, S. Esser, W. Risau, E. Dejana, Cell confluence regulates tyrosine phosphorylation of adherens junction components in endothelial cells, J. Cell Sci. 110 (Pt 17) (1997) 2065–2077. [75] R.A. Lang, K. Herman, A.B. Reynolds, J.D. Hildebrand, T.F. Plageman Jr., p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis, Development 141 (2014) 3177–3187. [76] C.C. Lanning, R. Ruiz-Velasco, C.L. Williams, Novel mechanism of the co-regulation of nuclear transport of SmgGDS and Rac1, J. Biol. Chem. 278 (2003) 12495–12506. [77] M. Lee, H. Ji, Y. Furuta, J.I. Park, P.D. McCrea, P120-catenin regulates REST/CoREST, and modulates mouse embryonic stem cell differentiation, J. Cell Sci. (2014). [78] Y. Li, D. Kufe, The human DF3/MUC1 carcinoma-associated antigen signals nuclear localization of the catenin p120(ctn), Biochem. Biophys. Res. Commun. 281 (2001) 440–443. [79] X. Liu, C. Yi, Y. Wen, P. Radhakrishnan, J.R. Tremayne, T. Dao, K.R. Johnson, M.A. Hollingsworth, Interactions between MUC1 and p120 catenin regulate dynamic features of cell adhesion, motility, and metastasis, Cancer Res. 74 (2014) 1609–1620. [80] K.M. Mann, J.M. Ward, C.C. Yew, A. Kovochich, D.W. Dawson, M.A. Black, B.T. Brett, T.E. Sheetz, A.J. Dupuy, I. Australian Pancreatic Cancer Genome, D.K. Chang, A.V. Biankin, N. Waddell, K.S. Kassahn, S.M. Grimmond, A.G. Rust, D.J. Adams, N.A. Jenkins, N.G. Copeland, Sleeping beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma, Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 5934–5941. [81] D.K. Marciano, P.R. Brakeman, C.Z. Lee, N. Spivak, D.J. Eastburn, D.M. Bryant, G.M. Beaudoin 3rd, I. Hofmann, K.E. Mostov, L.F. Reichardt, p120 catenin is required for normal renal tubulogenesis and glomerulogenesis, Development 138 (2011) 2099–2109. [82] D.J. Mariner, P. Anastasiadis, H. Keilhack, F.D. Bohmer, J. Wang, A.B. Reynolds, Identification of Src phosphorylation sites in the catenin p120ctn, J. Biol. Chem. 276 (2001) 28006–28013. [83] D.J. Mariner, M.A. Davis, A.B. Reynolds, EGFR signaling to p120-catenin through phosphorylation at Y228, J. Cell Sci. 117 (2004) 1339–1350. [84] N.O. Markham, T. Cooper, M. Goff, E.M. Gribben, R.H. Carnahan, A.B. Reynolds, Monoclonal antibodies to DIPA: a novel binding partner of p120-catenin isoform 1, Hybridoma (Larchmt). 31 (2012) 246–254. [85] N.O. Markham, C.A. Doll, M.R. Dohn, R.K. Miller, H. Yu, R.J. Coffey, P.D. McCrea, J.T. Gamse, A.B. Reynolds, DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia, Mol. Biol. Cell 25 (2014) 2592–2603. [86] P.D. McCrea, J.I. Park, Developmental functions of the P120-catenin sub-family, Biochim. Biophys. Acta 1773 (2007) 17–33. [87] W. Meng, Y. Mushika, T. Ichii, M. Takeichi, Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell–cell contacts, Cell 135 (2008) 948–959. [88] A. Menke, K. Giehl, Regulation of adherens junctions by Rho GTPases and p120catenin, Arch. Biochem. Biophys. 524 (2012) 48–55. [89] Y. Miao, N. Liu, Y. Zhang, Y. Liu, J.H. Yu, S.D. Dai, H.T. Xu, E.H. Wang, p120ctn isoform 1 expression significantly correlates with abnormal expression of Ecadherin and poor survival of lung cancer patients, Med. Oncol. 27 (2010) 880–886. [90] M. Migaldi, G. Barbolini, D. Trere, M. Criscuolo, A.M. Martinelli, E. Zunarelli, Immunohistochemical detection of nucleolar protein p120 in paraffin-embedded tissues, Histochem. J. 29 (1997) 661–668. [91] P.W. Miller, D.N. Clarke, W.I. Weis, C.J. Lowe, W.J. Nelson, The evolutionary origin of epithelial cell–cell adhesion mechanisms, Curr. Top. Membr. 72 (2013) 267–311. [92] Y. Miyashita, M. Ozawa, Increased internalization of p120-uncoupled E-cadherin and a requirement for a dileucine motif in the cytoplasmic domain for endocytosis of the protein, J. Biol. Chem. 282 (2007) 11540–11548. [93] R. Mo, T.L. Chew, M.T. Maher, G. Bellipanni, E.S. Weinberg, C.J. Gottardi, The terminal region of beta-catenin promotes stability by shielding the Armadillo repeats from the axin-scaffold destruction complex, J. Biol. Chem. 284 (2009) 28222–28231. [94] Y.Y. Mo, A.B. Reynolds, Identification of murine p120 isoforms and heterogeneous expression of p120cas isoforms in human tumor cell lines, Cancer Res. 56 (1996) 2633–2640. [95] O. Montonen, M. Aho, J. Uitto, S. Aho, Tissue distribution and cell type-specific expression of p120ctn isoforms, J. Histochem. Cytochem. 49 (2001) 1487–1496.

J.Y. Hong et al. / Biochimica et Biophysica Acta 1863 (2016) 102–114 [96] F. Mortazavi, J. An, S. Dubinett, M. Rettig, p120-catenin is transcriptionally downregulated by FOXC2 in non-small cell lung cancer cells, Mol. Cancer Res. 8 (2010) 762–774. [97] T. Muller, A. Choidas, E. Reichmann, A. Ullrich, Phosphorylation and free pool of beta-catenin are regulated by tyrosine kinases and tyrosine phosphatases during epithelial cell migration, J. Biol. Chem. 274 (1999) 10173–10183. [98] T. Ohkubo, M. Ozawa, p120(ctn) binds to the membrane-proximal region of the Ecadherin cytoplasmic domain and is involved in modulation of adhesion activity, J. Biol. Chem. 274 (1999) 21409–21415. [99] T. Ohkubo, M. Ozawa, The transcription factor snail downregulates the tight junction components independently of E-cadherin downregulation, J. Cell Sci. 117 (2004) 1675–1685. [100] M. Ozawa, T. Ohkubo, Tyrosine phosphorylation of p120(ctn) in v-Src transfected L cells depends on its association with E-cadherin and reduces adhesion activity, J. Cell Sci. 114 (2001) 503–512. [101] J.I. Park, H. Ji, S. Jun, D. Gu, H. Hikasa, L. Li, S.Y. Sokol, P.D. McCrea, Frodo links dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals, Dev. Cell 11 (2006) 683–695. [102] J.I. Park, S.W. Kim, J.P. Lyons, H. Ji, T.T. Nguyen, K. Cho, M.C. Barton, T. Deroo, K. Vleminckx, R.T. Moon, P.D. McCrea, Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets, Dev. Cell 8 (2005) 843–854. [103] M. Perez-Moreno, M.A. Davis, E. Wong, H.A. Pasolli, A.B. Reynolds, E. Fuchs, p120catenin mediates inflammatory responses in the skin, Cell 124 (2006) 631–644. [104] Y.I. Petrova, M.M. Spano, B.M. Gumbiner, Conformational epitopes at cadherin calcium-binding sites and p120-catenin phosphorylation regulate cell adhesion, Mol. Biol. Cell 23 (2012) 2092–2108. [105] J. Piedra, S. Miravet, J. Castano, H.G. Palmer, N. Heisterkamp, A. Garcia de Herreros, M. Dunach, p120 catenin-associated Fer and Fyn tyrosine kinases regulate betacatenin Tyr-142 phosphorylation and beta-catenin–alpha-catenin interaction, Mol. Cell. Biol. 23 (2003) 2287–2297. [106] T. Pieters, J. van Hengel, F. van Roy, Functions of p120ctn in development and disease, Front. Biosci. (Landmark Ed). 17 (2012) 760–783. [107] T. Pieters, F. van Roy, J. van Hengel, Functions of p120ctn isoforms in cell–cell adhesion and intracellular signaling, Front. Biosci. (Landmark Ed). 17 (2012) 1669–1694. [108] A. Prokhortchouk, B. Hendrich, H. Jorgensen, A. Ruzov, M. Wilm, G. Georgiev, A. Bird, E. Prokhortchouk, The p120 catenin partner Kaiso is a DNA methylationdependent transcriptional repressor, Genes Dev. 15 (2001) 1613–1618. [109] P. Pulimeno, C. Bauer, J. Stutz, S. Citi, PLEKHA7 is an adherens junction protein with a tissue distribution and subcellular localization distinct from ZO-1 and E-cadherin, PLoS One 5 (2010), e12207. [110] L. Qin, S. Qin, Y. Zhang, C. Zhang, H. Ma, N. Li, L. Liu, X. Wang, R. Wu, p120 modulates LPS-induced NF-kappaB activation partially through RhoA in bronchial epithelial cells, Biomed. Res. Int. 2014 (2014) 932340. [111] A.B. Reynolds, J. Daniel, P.D. McCrea, M.J. Wheelock, J. Wu, Z. Zhang, Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes, Mol. Cell. Biol. 14 (1994) 8333–8342. [112] A.B. Reynolds, A. Roczniak-Ferguson, Emerging roles for p120-catenin in cell adhesion and cancer, Oncogene 23 (2004) 7947–7956. [113] A.B. Reynolds, D.J. Roesel, S.B. Kanner, J.T. Parsons, Transformation-specific tyrosine phosphorylation of a novel cellular protein in chicken cells expressing oncogenic variants of the avian cellular src gene, Mol. Cell. Biol. 9 (1989) 629–638. [114] A. Roczniak-Ferguson, A.B. Reynolds, Regulation of p120-catenin nucleocytoplasmic shuttling activity, J. Cell Sci. 116 (2003) 4201–4212. [115] R. Rosato, J.M. Veltmaat, J. Groffen, N. Heisterkamp, Involvement of the tyrosine kinase fer in cell adhesion, Mol. Cell. Biol. 18 (1998) 5762–5770. [116] S. Roura, S. Miravet, J. Piedra, A. Garcia de Herreros, M. Dunach, Regulation of Ecadherin/catenin association by tyrosine phosphorylation, J. Biolumin. Chemilumin. 274 (1999) 36734–36740. [117] A. Ruzov, D.S. Dunican, A. Prokhortchouk, S. Pennings, I. Stancheva, E. Prokhortchouk, R.R. Meehan, Kaiso is a genome-wide repressor of transcription that is essential for amphibian development, Development 131 (2004) 6185–6194. [118] D. Sarrio, B. Perez-Mies, D. Hardisson, G. Moreno-Bueno, A. Suarez, A. Cano, J. Martin-Perez, C. Gamallo, J. Palacios, Cytoplasmic localization of p120ctn and Ecadherin loss characterize lobular breast carcinoma from preinvasive to metastatic lesions, Oncogene 23 (2004) 3272–3283. [119] K. Sato, T. Watanabe, S. Wang, M. Kakeno, K. Matsuzawa, T. Matsui, K. Yokoi, K. Murase, I. Sugiyama, M. Ozawa, K. Kaibuchi, Numb controls E-cadherin endocytosis through p120 catenin with aPKC, Mol. Biol. Cell 22 (2011) 3103–3119. [120] R.C. Schackmann, S. Klarenbeek, E.J. Vlug, S. Stelloo, M. van Amersfoort, M. Tenhagen, T.M. Braumuller, J.F. Vermeulen, P. van der Groep, T. Peeters, E. van der Wall, P.J. van Diest, J. Jonkers, P.W. Derksen, Loss of p120-catenin induces metastatic progression of breast cancer by inducing anoikis resistance and augmenting growth factor receptor signaling, Cancer Res. 73 (2013) 4937–4949. [121] R.C. Schackmann, M. Tenhagen, R.A. van de Ven, P.W. Derksen, p120-catenin in cancer — mechanisms, models and opportunities for intervention, J. Cell Sci. 126 (2013) 3515–3525. [122] R.C. Schackmann, M. van Amersfoort, J.H. Haarhuis, E.J. Vlug, V.A. Halim, J.M. Roodhart, J.S. Vermaat, E.E. Voest, P. van der Groep, P.J. van Diest, J. Jonkers, P.W. Derksen, Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance, J. Clin. Invest. 121 (2011) 3176–3188. [123] T. Shibata, A. Kokubu, S. Sekine, Y. Kanai, S. Hirohashi, Cytoplasmic p120ctn regulates the invasive phenotypes of E-cadherin-deficient breast cancer, Am. J. Pathol. 164 (2004) 2269–2278. [124] B. Silva Neto, G.L. Smith, J.A. Mandeville, A.J. Vanni, C. Wotkowicz, K.M. RiegerChrist, E. Baumgart, M.A. Jacobs, M.S. Cohen, R. Zeheb, M. Loda, J.A. Libertino, I.C.

[125]

[126]

[127]

[128]

[129] [130]

[131]

[132]

[133] [134]

[135] [136]

[137]

[138]

[139]

[140]

[141] [142]

[143]

[144]

[145]

[146]

[147]

[148]

[149]

[150]

[151]

113

Summerhayes, Prognostic significance of altered p120 ctn expression in bladder cancer, BJU Int. 101 (2008) 746–752. E.M. Slorach, J. Chou, Z. Werb, Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization, Genes Dev. 25 (2011) 471–484. W.G. Smalley-Freed, A. Efimov, P.E. Burnett, S.P. Short, M.A. Davis, D.L. Gumucio, M.K. Washington, R.J. Coffey, A.B. Reynolds, p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice, J. Clin. Invest. 120 (2010) 1824–1835. E. Soto, M. Yanagisawa, L.A. Marlow, J.A. Copland, E.A. Perez, P.Z. Anastasiadis, p120 catenin induces opposing effects on tumor cell growth depending on E-cadherin expression, J. Cell Biol. 183 (2008) 737–749. D.B. Stairs, L.J. Bayne, B. Rhoades, M.E. Vega, T.J. Waldron, J. Kalabis, A. Klein-Szanto, J.S. Lee, J.P. Katz, J.A. Diehl, A.B. Reynolds, R.H. Vonderheide, A.K. Rustgi, Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene, Cancer Cell 19 (2011) 470–483. J.L. Stamos, W.I. Weis, The beta-catenin destruction complex, Cold Spring Harb. Perspect. Biol. 5 (2013) a007898. M.L. Taddei, P. Chiarugi, P. Cirri, F. Buricchi, T. Fiaschi, E. Giannoni, D. Talini, G. Cozzi, L. Formigli, G. Raugei, G. Ramponi, Beta-catenin interacts with lowmolecular-weight protein tyrosine phosphatase leading to cadherin-mediated cell–cell adhesion increase, Cancer Res. 62 (2002) 6489–6499. K. Talvinen, J. Tuikkala, M. Nykanen, A. Nieminen, J. Anttinen, O.S. Nevalainen, S. Hurme, T. Kuopio, P. Kronqvist, Altered expression of p120catenin predicts poor outcome in invasive breast cancer, J. Cancer Res. Clin. Oncol. 136 (2010) 1377–1387. K. Taniuchi, H. Nakagawa, M. Hosokawa, T. Nakamura, H. Eguchi, H. Ohigashi, O. Ishikawa, T. Katagiri, Y. Nakamura, Overexpressed P-cadherin/CDH3 promotes motility of pancreatic cancer cells by interacting with p120ctn and activating rho-family GTPases, Cancer Res. 65 (2005) 3092–3099. M.A. Thoreson, A.B. Reynolds, Altered expression of the catenin p120 in human cancer: implications for tumor progression, Differentiation 70 (2002) 583–589. H. Tian, E. Sanders, A. Reynolds, F. van Roy, J. van Hengel, Ocular anterior segment dysgenesis upon ablation of p120 catenin in neural crest cells, Invest. Ophthalmol. Vis. Sci. 53 (2012) 5139–5153. S. Troyanovsky, Adherens junction assembly, Sub-cellular biochemistry. 60 (2012) 89–108. G. Valls, M. Codina, R.K. Miller, B. Del Valle-Perez, M. Vinyoles, C. Caelles, P.D. McCrea, A. Garcia de Herreros, M. Dunach, Upon Wnt stimulation, Rac1 activation requires Rac1 and Vav2 binding to p120-catenin, J. Cell Sci. 125 (2012) 5288–5301. J. van Hengel, P. Vanhoenacker, K. Staes, F. van Roy, Nuclear localization of the p120(ctn) armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 7980–7985. E. Vandenbroucke St Amant, M. Tauseef, S.M. Vogel, X.P. Gao, D. Mehta, Y.A. Komarova, A.B. Malik, PKCalpha activation of p120-catenin serine 879 phosphoswitch disassembles VE-cadherin junctions and disrupts vascular integrity, Circ. Res. 111 (2012) 739–749. M.H. Vaughan, X. Xia, X. Wang, E. Chronopoulou, G.J. Gao, R. Campos-Gonzalez, A.B. Reynolds, Generation and characterization of a novel phospho-specific monoclonal antibody to p120-catenin serine 879, Hybridoma (Larchmt). 26 (2007) 407–415. M. Vinyoles, B. Del Valle-Perez, J. Curto, R. Vinas-Castells, L. Alba-Castellon, A. Garcia de Herreros, M. Dunach, Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6, Mol. Cell 53 (2014) 444–457. C.C. Warzecha, T.K. Sato, B. Nabet, J.B. Hogenesch, R.P. Carstens, ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing, Mol. Cell 33 (2009) 591–601. C.C. Warzecha, S. Shen, Y. Xing, R.P. Carstens, The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events, RNA Biol. 6 (2009) 546–562. B.P. Wijnhoven, M. Pignatelli, W.N. Dinjens, H.W. Tilanus, Reduced p120ctn expression correlates with poor survival in patients with adenocarcinoma of the gastroesophageal junction, J. Surg. Oncol. 92 (2005) 116–123. G.A. Wildenberg, M.R. Dohn, R.H. Carnahan, M.A. Davis, N.A. Lobdell, J. Settleman, A.B. Reynolds, p120-catenin and p190RhoGAP regulate cell–cell adhesion by coordinating antagonism between Rac and Rho, Cell 127 (2006) 1027–1039. E.Y. Wong, L. Morgan, C. Smales, P. Lang, S.E. Gubby, J.M. Staddon, Vascular endothelial growth factor stimulates dephosphorylation of the catenins p120 and p100 in endothelial cells, Biochem. J. 346 (Pt 1) (2000) 209–216. Y. Wu, X. Wang, F. Wu, R. Huang, F. Xue, G. Liang, M. Tao, P. Cai, Y. Huang, Transcriptome profiling of the cancer, adjacent non-tumor and distant normal tissues from a colorectal cancer patient by deep sequencing, PLoS One 7 (2012), e41001. X. Xia, R.H. Carnahan, M.H. Vaughan, G.A. Wildenberg, A.B. Reynolds, p120 serine and threonine phosphorylation is controlled by multiple ligand-receptor pathways but not cadherin ligation, Exp. Cell Res. 312 (2006) 3336–3348. X. Xia, D.J. Mariner, A.B. Reynolds, Adhesion-associated and PKC-modulated changes in serine/threonine phosphorylation of p120-catenin, Biochemistry 42 (2003) 9195–9204. K. Xiao, D.F. Allison, K.M. Buckley, M.D. Kottke, P.A. Vincent, V. Faundez, A.P. Kowalczyk, Cellular levels of p120 catenin function as a set point for cadherin expression levels in microvascular endothelial cells, J. Cell Biol. 163 (2003) 535–545. K. Xiao, J. Garner, K.M. Buckley, P.A. Vincent, C.M. Chiasson, E. Dejana, V. Faundez, A.P. Kowalczyk, p120-catenin regulates clathrin-dependent endocytosis of VEcadherin, Mol. Biol. Cell 16 (2005) 5141–5151. G. Xu, A.W. Craig, P. Greer, M. Miller, P.Z. Anastasiadis, J. Lilien, J. Balsamo, Continuous association of cadherin with beta-catenin requires the non-receptor tyrosine-kinase Fer, J. Cell Sci. 117 (2004) 3207–3219.

114

J.Y. Hong et al. / Biochimica et Biophysica Acta 1863 (2016) 102–114

[152] X. Xu, W.E. Li, G.Y. Huang, R. Meyer, T. Chen, Y. Luo, M.P. Thomas, G.L. Radice, C.W. Lo, Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions, J. Cell Biol. 154 (2001) 217–230. [153] M. Yanagisawa, P.Z. Anastasiadis, p120 catenin is essential for mesenchymal cadherin-mediated regulation of cell motility and invasiveness, J. Cell Biol. 174 (2006) 1087–1096. [154] M. Yanagisawa, D. Huveldt, P. Kreinest, C.M. Lohse, J.C. Cheville, A.S. Parker, J.A. Copland, P.Z. Anastasiadis, A p120 catenin isoform switch affects Rho activity, induces tumor cell invasion, and predicts metastatic disease, J. Biol. Chem. 283 (2008) 18344–18354. [155] M. Yanagisawa, I.N. Kaverina, A. Wang, Y. Fujita, A.B. Reynolds, P.Z. Anastasiadis, A novel interaction between kinesin and p120 modulates p120 localization and function, J. Biol. Chem. 279 (2004) 9512–9521. [156] Z. Yang, D. Sun, Z. Yan, A.B. Reynolds, J.W. Christman, R.D. Minshall, A.B. Malik, Y. Zhang, G. Hu, Differential role for p120-catenin in regulation of TLR4 signaling in macrophages, J. Immunol. 193 (2014) 1931–1941. [157] A.S. Yap, C.M. Niessen, B.M. Gumbiner, The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn, J. Cell Biol. 141 (1998) 779–789.

[158] J. Yu, Y. Miao, H. Xu, Y. Liu, G. Jiang, M. Stoecker, E. Wang, E. Wang, N-terminal 1–54 amino acid sequence and Armadillo repeat domain are indispensable for P120catenin isoform 1A in regulating E-cadherin, PLoS One 7 (2012), e37008. [159] N. Zebda, Y. Tian, X. Tian, G. Gawlak, K. Higginbotham, A.B. Reynolds, A.A. Birukova, K.G. Birukov, Interaction of p190RhoGAP with C-terminal domain of p120-catenin modulates endothelial cytoskeleton and permeability, J. Biol. Chem. 288 (2013) 18290–18299. [160] P.X. Zhang, Y. Wang, Y. Liu, G.Y. Jiang, Q.C. Li, E.H. Wang, p120-catenin isoform 3 regulates subcellular localization of Kaiso and promotes invasion in lung cancer cells via a phosphorylation-dependent mechanism, Int. J. Oncol. 38 (2011) 1625–1635. [161] Y. Zhang, Y. Zhao, G. Jiang, X. Zhang, H. Zhao, J. Wu, K. Xu, E. Wang, Impact of p120catenin isoforms 1A and 3A on epithelial mesenchymal transition of lung cancer cells expressing E-cadherin in different subcellular locations, PLoS One 9 (2014), e88064. [162] G.C. Zondag, A.B. Reynolds, W.H. Moolenaar, Receptor protein–tyrosine phosphatase RPTPmu binds to and dephosphorylates the catenin p120(ctn), J. Biol. Chem. 275 (2000) 11264–11269.