The role of endosomal signaling triggered by metastatic growth factors in tumor progression

Cellular Signalling 25 (2013) 1539–1545

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Review

The role of endosomal signaling triggered by metastatic growth factors in tumor progression Chi-Tan Hu a, Jia-Ru Wu b, Wen-Sheng Wu b,⁎ a b

Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan Institute of Medical Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan

a r t i c l e

i n f o

Article history: Received 9 February 2013 Accepted 28 March 2013 Available online 6 April 2013 Keywords: Metastatic growth factors Receptor tyrosine kinase (RTK) Endosomal signaling Migration Tumor metastasis Target therapy

a b s t r a c t Within tumor microenvironment, a lot of growth factors such as hepatocyte growth factor and epidermal growth factor may induce similar signal cascade downstream of receptor tyrosine kinase (RTK) and trigger tumor metastasis synergistically. In the past decades, the intimate relationship of RTK-mediated receptor endocytosis with signal transduction was well established. In general, most RTK undergoes clathrin-dependent endocytosis and/ or clathrin-independent endocytosis. The internalized receptors may sustain the signaling within early endosome, recycling to plasma membrane for subsequent ligand engagement or sorting to late endosomes/lysosome for receptor degradation. Moreover, receptor endocytosis influences signal transduction in a temporal and spatial manner for periodical and polarized cellular processes such as cell migration. The endosomal signalings triggered by various metastatic factors are quite similar in some critical points, which are essential for triggering cell migration and tumor progression. There are common regulators for receptor endocytosis including dynamin, Rab4, Rab5, Rab11 and Cbl. Moreover, many critical regulators within the RTK signal pathway such as Grb2, p38, PKC and Src were also modulators of endocytosis. In the future, these may constitute a new category of targets for prevention of tumor metastasis. © 2013 Elsevier Inc. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Metastatic factors within the tumor microenvironment . . . . . . . . . . . . . . . . . 1.2. Signal transduction mediating tumor progression triggered by the metastatic growth factors 1.2.1. Similarity in signal cascade induced by metastatic growth factors . . . . . . . . 1.2.2. Signal cross talk of growth factors with each other and integrin . . . . . . . . . 1.2.3. Target therapy against the metastatic growth factors: The challenge and perspective The role of endocytosis in receptor-mediated signal transduction . . . . . . . . . . . . . . . . 2.1. Endocytosis and signal transduction as a molecular network . . . . . . . . . . . . . . . 2.2. The pathophysiological process regulated by endosomal signaling . . . . . . . . . . . . 2.3. Receptor endocytosis and cell migration . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Receptor endocytosis and tumor progression . . . . . . . . . . . . . . . . . . . . . . Endosomal signaling induced by metastatic factor-implication in tumor progression . . . . . . . 3.1. HGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. EGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. PDGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. FGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. TGF-β . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. VEGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Institute of Medical Biotechnology, College of Medicine, Tzu Chi University, No. 701, Chung Yang Rd., Sec 3, Hualien 970, Taiwan. Tel.: + 886 7 03 8565301x2327; fax: + 886 7 03 8571917. E-mail address: [email protected] (W.-S. Wu). 0898-6568/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cellsig.2013.03.022

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4. Targeting the common Conflict of interest . . . . Acknowledgment . . . . . References . . . . . . . .

C.-T. Hu et al. / Cellular Signalling 25 (2013) 1539–1545

endocytic pathway . . . . . . . . . . . . . . . . . . . . . . . . . . .

for prevention . . . . . . . . . . . . . . . . . . . . .

of tumor progression: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction 1.1. Metastatic factors within the tumor microenvironment Metastasis is one of the most complicated pathological processes which causes most cancer deaths [1]. Recent studies highlighted that the tumor microenvironment plays critical role in triggering tumor metastasis. The tumor microenvironment comprises the primary tumors themselves which may recruit and interact with stromal cells. A variety of cell types populate the stromal compartment including myofibroblasts, vascular cells and immune cells [2]. The interactions between tumor cells and stromal cells lead to secretion of growth factors and cytokines for not only supporting the growth and survival of tumor cells but also triggering tumor metastasis [3]. Among the growth factors, hepatocyte growth factor (HGF) [4–8], epidermal growth factor (EGF) [9–11], transforming growth factor (TGF)-β [12–16], platelet-derived growth factor (PDGF) [17–20], basic fibroblast growth factor (bFGF) [21,22] and vascular endothelial growth factor (VEGF) [23] are capable of triggering metastatic changes including epithelial mesenchymal transition (EMT) and enhancement of motility and invasiveness of a variety of tumor cells, thus may be collectively called as the “metastatic growth factors”. 1.2. Signal transduction mediating tumor progression triggered by the metastatic growth factors 1.2.1. Similarity in signal cascade induced by metastatic growth factors In the past decades, signal transductions triggered by the metastatic growth factors were well established. Interestingly, all of them except TGF β activate receptor tyrosine kinase (RTK) triggering similar signal cascades. Engagement of the growth factors such as HGF, EGF, PDGF and FGF with their RTK receptors recruits common adaptor proteins such as Grb2 [24–28], Gab1 [29–32] and Shc [33–37]. These adaptor proteins serve as scaffold for activation of two major downstream signal cascades, Ras/Raf/MEK/ERK [38–45] and PI3K/AKT [38,46–55] (summarized in Table 1). In addition, TGFβ (acting via receptor serine threonine kinase) induces Smad pathways which frequently integrated with MEK/ERK [56,57] and/or AKT [58] cascades (summarized in Table 1). 1.2.2. Signal cross talk of growth factors with each other and integrin Due to the similarity in signal transduction, it is not surprising that these growth factors may cooperate to enhance tumor progression. For example, couples of EGF and HGF [59,60], FGF-2 and VEGF [61], TGF-beta1 and HGF [62] may synergistically trigger migration, invasion and metastasis, via collaborative activation of downstream signaling such as ERK. Moreover, HGF [63,64], EGF [65,66], PDGF [67,68], FGF [69] and TGFβ [70] can also cross talk with integrininitiated signal cascade for enhancing tumor progression (summarized in Table 1). For example, HGF may cross talk with integrin leading to activation of Ras–Rac1/Cdc42-PAK [63] and Shp2–Src [64] cascades. Also, EGF may cooperate with β4 integrin to amplify ErbB2 signaling and promote mammary tumorigenesis [65]. 1.2.3. Target therapy against the metastatic growth factors: The challenge and perspective Since these metastatic factors play an essential role in malignant cell growth, proliferation, and motility, target therapy aiming at signal pathway induced by them is promising in prevention of tumor

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progression. The most frequently used inhibitors for blocking RTK pathway are the tyrosine kinase inhibitors (TKIs), most of which are adenosine triphosphate (ATP) analogs competing with ATP-binding pockets on the intracellular catalytic kinase domain of RTKs, thereby preventing their autophosphorylation. For example, the effectiveness of synthetic TKIs including JNJ-38877605 [71], BMS-777607 [72] and ARQ-197 [73] against HGF/c-Met and Gefitinib against EGF [74] for tumor preventions was demonstrated. Also, TKI258, sorafenib, sunitinib and cediranib were used for targeting FGFR/PDFGR/VEGFR in prevention of pancreatic cancer [75] and NSCLC [76], some of which were under phase II studies (summarized in Table 1). There are, however, several common problems and main challenges in RTK-targeting approach. One of them is the non-specificity that causes side effects on normal tissues. For example, the use of EGFR inhibitors (as a single agent or in combination therapy) results in cutaneous toxicities (rashes) such as acneiform eruptions, hyperpigmentation, xerosis, trichomegaly, paronychia etc. [77]. The other problem is that the point mutation of the RTK (pre-existing or de novo) or other unidentified factors can lead to drug resistance [78,79]. To address this issue, it is worthy of exploring more detailed mechanisms of RTK signaling for devising more effective and safe targeting strategy. Recently, receptor endocytosis was highlighted to be critical for RTK-mediated signal transduction. A lot of regulators for endosomal signaling of RTK are emerging to be more suitable targets for therapeutic intervention of tumor progression. 2. The role of endocytosis in receptor-mediated signal transduction 2.1. Endocytosis and signal transduction as a molecular network In the past decade, endocytosis is well known to be an intriguing cellular process, which integrates with signal transduction thereby Table 1 Similarity in signal transduction induced by various metastatic growth factors. Growth Signal transduction factor Adaptor Downstream activation signal HGF

EGF

PDGF

FGF

GrB2 [24] Gab1 [29]

MAPK [38–41] PI3–AKT [38,46–48]

Cross talk with other ligands

TKIa used for therapy

EGF [59,60] TGFb [62]

JNJb [71] BMSc [72]

Integrin [63,64] HGF [59,60] Integrin [65,66]

ARQ-197 [73] Gefitinib [74]

Shc [33,34] GrB2 [25,26] Gab1 [30,43] Shc [35] GrB2 [27] Gab1 [31]

MAPK [44] PI3–AKT [51–53]

Integrin [67,68]

TKI258 [75] Sorafenib [76]

Shc [36] GrB2 [28] Gab1 [32]

MAPK [45] PI3–AKT [54,55]

VEGF [61] Integrin [69]

TKI258 [75] Sorafenib [76]

MAPK [56,57] PI3–AKT [58] ND

HGF [62] Integrin [70] FGF [61]

ND

TGFβ

Shc [37] NDd

VEGF

ND

MAPK [42,43] PI3–AKT [49,50]

TKI258 [75] Sunitinib [76]

The numbers in parenthesis represent the numbers of references cited in the text. TKIa: tyrosine kinase inhibitor; JNJb: JNJ-38877605; BMSc: BMS-777607; NDd: the information is not available in the literature for relevant growth factor.

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contributing to diverse pathophysiological changes [80]. The endocytosis of most RTKs such as EGFR and various G-protein coupled receptors (GPCRs), such as the β2-adrenergic receptor (β2AR) may be stimulated by ligand-induced activation. In general, most signaling receptor undergoes clathrin-dependent endocytosis (CDE) and/or clathrin-independent endocytosis (CIE). In CDE, receptors are recruited to clathrin-coated pits which invaginate inwards with the help of several adaptor proteins and pinch off to form a clathrincoated vesicle by the GTPase dynamin. On the other hand, CIE involved receptor internalization via cholesterol-rich membrane domains, such as lipid rafts and caveolae. The ligand-induced receptor endocytosis has profound impacts on receptor-mediated signal transduction in several ways. After receptor internalization, signal transduction can be sustained by specific complexes within early endosome. Also, endosome may return back to the plasma membrane via recycling compartment for subsequent ligand engagements. A lot of small GTPase such as Rab family small GTPase (including Rab5, Arf6, Rab4 or Rab11) and adaptor molecules such as Golgilocalized, gamma-ear-containing, Arf-binding proteins 3 (GGA3) [81] are required for endosomal signaling and recycling. Alternatively, the signaling can be attenuated by ubiquitin-directed sorting of the endosome into multivesicular bodies (MVbs) and late endosomes in a Rab7-dependent manner. The late endosome may fuse with lysosome resulting in receptor degradation [82]. Moreover, endosomal sorting may regulate signaling pathways in a temporal and spatial manner, required for periodic and polarized cellular processes such as cell migration [80]. On the contrary, it is also clear that signal transduction may affect endocytosis, especially on the level of internalization and endosomal sorting. Several critical signaling kinases such as protein kinase C (PKC) [83] and Src [84] may regulate endocytosis and endosomal trafficking at many points. Thus it is established that receptor endocytosis and signal transduction substantially overlap, constituting a molecular network with more efficiency and specificity.

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2.4. Receptor endocytosis and tumor progression In the past decade, defective trafficking of growth factor receptors and integrin was strongly implicated in malignant transformation [90]. Molecules involved in endocytic pathway are frequently deregulated in tumor cells [91,92]. For example, Rab5a, the essential component of early endosome, overexpressed in HCC [93]; and huntingtin-interacting protein 1 (HIP1), an adaptor for clathrin assembly, overexpressed in prostate and colon cancers [94,95]. Moreover, overexpression of the HIP1 in cancers may alter EGFR trafficking while promoting tumor formation [96]. In addition, the E3 ubiquitin ligase casitas B lineage lymphoma (Cbl), which mediates multiubiquitylation of the RTKs (for sorting to late endosome), was found to be mutated in acute myelocytic leukemia [97]. Recently, two mutants (M1268 and D1246N) of c-Met (the RTK of HGF) with elevated kinase activity exhibited enhanced c-Met endocytosis, as revealed by increased receptor internalization and recycling coupled with decreased receptor degradation. Importantly, both mutants directly trigger tumor progression both in vitro and in vivo (see below) [98]. In addition, Rab25 and CLIC3 may collaborate to promote integrin recycling from late endosomes and drive cancer progression [99]. 3. Endosomal signaling induced by metastatic factor-implication in tumor progression The endosomal signaling triggered by the aforementioned metastatic factors such as HGF, EGF and PDGF, FGF and TGFβ has been demonstrated in a multitude of recent studies. Interestingly, the mechanisms for each of them are quite similar in some critical points, as in the aspect of signal pathway described above. Importantly, receptor endocytosis triggered by each metastatic factor is found to be closely associated with signal transductions mediating cell migration and tumor progression, as described below.

2.2. The pathophysiological process regulated by endosomal signaling

3.1. HGF

The roles of endosomal signaling in essential cellular processes including morphogenesis, proliferation, motility, survival, differentiation and the physiological functions such as immune response and metabolism are fundamental [85]. The loss of any essential components of clathrin-mediated endocytosis including clathrin, clathrin adaptor protein complex AP2 and dynamin may result in embryonic lethality [86,87]. Moreover, many endocytic proteins were deregulated in numerous human disorders, such as cancer, myopathies, neuropathies, metabolic and genetic syndromes, and psychiatric and neurodegenerative diseases [85].

It was well established that the activated HGF receptor (c-Met) undergoes rapid endocytosis via the canonical clathrin-mediated and nonclathrin endocytic pathway [100]. After ligand induced c-Met internalization, signal transduction may be sustained within endosome and the receptor can be recycled to plasma membrane requiring Rab5/Rab4. Alternatively, the Cbl-dependent ubiquitination is critical for targeting c-Met for lysosomal degradation. A lot of transacting regulators for endosomal processing of c-Met have been identified. These included GGA3 (for endosomal recycling) [81], proteintyrosine phosphatase 1B (PTP1B) (for early endosome fusion and trafficking) [101], Grb2 (for recruiting Cbl to c-MET) [98] and endophilinCIN85-Cbl complex (mediating ligand-dependent downregulation of c-Met [102]). On the other hand, Cho et al. dissected a cis-acting dileucine-containing motif within C-terminal region of c-Met, which was required for its internalization [103]. The essential role of HGF/c-Met endosomal signaling in HGFinduced cell migration has been well established [81,98,103]. HGF induced clathrin- and Rab5-dependent receptor endocytoses for Rac recycling to the specific regions on plasma membrane, facilitating focal adhesion turnover [88]. Also, HGF may recruit GGA3 to associate with c-Met via Crk, thereby promoting Met recycling, and sustained ERK activation, which were required for cell migration [81]. A lot of previous investigation implicated that deregulated HGF/ Met trafficking, either at the level of the internalization step or sorting in the early endosome, was greatly associated with malignant signaling [104]. One recent report provided the direct evidence for the role of deregulated HGF/c-Met endocytosis in tumor progression. The enhanced endosomal trafficking acquired by two naturally occurring Met mutants can be amplified by HGF, resulting in augmented

2.3. Receptor endocytosis and cell migration The relationship of receptor endocytosis with cell migration, one of the critical steps in tumor metastasis, is highlighted in recent years. Cell motility consists of leading edge protrusion (lamellipodia), adhesion to the extracellular matrix, cell body traction and release of the cell rear. Endosomal sorting may facilitate the recruitment and retention of signaling molecules at specific locations on the plasma membrane, which are essential for migration cycling [80]. This was revealed in the endosomal sorting of Rac and integrin, two of the central regulators of motogenic signals. For example, Palamidessi et al. demonstrated that clathrin- and Rab5-mediated endocytoses were required for HGF-induced Rac recycling to the specific regions on plasma membrane leading to the formation of actin-based migratory protrusions [88]. Also, endocytosis and recycling play an important role in the regulation of integrin turnover and redistribution on focal adhesion, which are essential for cell migration [89].

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activation of the GTPase Rac1, loss of actin stress fibers, cell migration, anchorage independent growth and tumor metastasis [98]. 3.2. EGF EGFR endocytosis is one of the best understood receptor trafficking systems [105]. Previously, it was found that EGF triggered the internalization of the EGFR complex via the canonical clathrinmediated endocytic pathway and most EGFR signaling occurs within endosomes [25]. Also, BPGAP1, one of the RhoGAP, and its downstream effector endophilin II were required for concomitant activation of EGFR endocytosis and ERK signaling [106]. On the other hand, some of the EGFR containing endosomes developed into late endosome in a Rab7- [107] and PTP1B-dependent manner [101], which is subject to degradation. Several studies demonstrated the involvement of EGFR endocytosis in EGF-triggered cell migration and tumorigenesis. For example, EGF-induced cell migration is closely associated with Cbl activation, EGFR ubiquitination, and receptor degradation, which were mediated by p38MAPK [108]. Moreover, cortactin, which couples the endocytic machinery to dynamic actin networks, prevented EGF-induced down-regulation of EGFR, resulting in sustained ERK activation and tumor progression of head and neck cancers [109]. 3.3. PDGF As with other RTKs, the activated PDGF receptors are internalized and sorted toward different destinations. De Donatis et al. proposed that differential routes of PDGFR endocytosis were influenced by PDGF concentrations, which further determined the cellular fates [110]. Low PDGF doses induced exclusively clathrin-mediated endocytosis involved in cell migration, whereas high PDGF doses induced raft/caveolin-mediated endocytosis of PDGFR, leading to cell proliferation. In the latter case, PDGFR is able to start the mitotic process and then undergoes proteasomal degradation. A lot of signal molecules regulate the endosomal sorting of PDGF receptors. For example, tyrosine phosphorylated Gab1 can recruit dynamin II at the plasma membrane, resulting in the endocytosis of PDGFβ receptor–GPCR complexes [111]. Also, protein kinase C α can regulate the sorting of the PDGFβ-receptor toward the early endosomes in a Rab4a dependent manner [112]. The involvement of receptor endocytosis in PDGF-triggered cell migration has been demonstrated. For example, PDGF-stimulated cell movement is dependent on RhoB mediated trafficking of PDGFR and activation of the key migratory effectors Cdc42 and Rac [113]. Also, Kawada et al. demonstrated that Grb2 adaptor mediated PDGFtriggered formation of PDGFR/DOCK4/dynamin complex in the leading edge of cells. Such complex facilitated PDGFR endocytosis and Rac1 activation triggering cell migration [114]. In addition, one recent report demonstrated that H-Ras-induced macropinocytosis of PDGFRβ enhance PDGF-triggered signal transduction leading to tumor progression [115]. 3.4. FGF FGFs exerted their biological effects through binding to four high-affinity cell-surface receptors, FGFRs, which were subject to endocytosis in a similar mechanism for other RTKs. FGF/FGFR complexes were observed in early endosomes approximately 10 min after internalization and sorted to late endosomes subsequently. Previously, the intracellular fate of the four FGFRs was investigated by Haugsten et al. [116]. After endocytosis, FGFR4 and its bound ligand are sorted mainly to the recycling compartment, whereas FGFR1-3 with ligands was sorted mainly for degradation in the lysosomes. This discrepancy was largely ascribed to the lack of a conserved lysine residue (a potential ubiquitylation sites) in FGFR4 (but not FGFR1-3). Moreover, one recent report demonstrated that the heparan sulfate proteoglycans,

syndecan 4 (S4) may regulate FGFR1 endocytosis thus modulates the kinetics of MAPK activation [117]. Endocytosis of FGFR was known to play important role in development. Jean et al. demonstrated the synaptotagmin-related membrane protein E-Syt2, which is essential for Xenopus development. It can interact selectively with the activated FGF receptor, facilitated its rapid endocytosis and enhanced Ras–ERK activation, finally leading to the induction of the mesoderm [118]. The role of FGFR endocytosis in migration and tumor progression is also emerging. One previous report demonstrated FGF induced co-internalization of FGFR1 and E-cadherin into early endosomes, which may be responsible for EMT of the cells [119]. Recently, Belleudi et al. demonstrated that FGF7 and FGF10 may induce endocytosis and polarization of FGF7 receptor at the leading edge, triggering keratinocyte migration in Src- and cortactin-dependent manner [120]. 3.5. TGF-β Transforming growth factor β (TGF-β) signaling is well known to enhance EMT and migration that promote metastatic spread [121]. The TGF-β signaling pathway can be enhanced by the recruitment of effector proteins such as SARA (Smad anchor for receptor activation) during clathrin-mediated endocytosis [122]. Moreover, Lin et al. demonstrated that cytoplasmic promyelocytic leukemia tumor suppressor (PML) is required for association of Smad2/3 with SARA and for the accumulation of SARA and TGF-β receptor in the early endosome [123]. The intensity of TGF-β signaling was substantially influenced by the endocytic route of TGF-β receptor. The TGF-β receptor that internalized via clathrin pathway was found to be localized within EEA1-positive endosome, where the Smad2 anchor SARA is enriched, thus promote signaling. In contrast, the lipid raft-caveolar mediates internalization of TGF-β receptor to bind with Smad7–Smurf2, resulting in rapid receptor turnover [124]. The direct involvement of TGFβR endocytosis in tumor progression was implicated in one recent report. Gain-of-function TGF-βRII mutation, which delayed lipid-raft-dependent endocytosis of TGF-βRII enhances TGF-β signaling, leading to more invasive phenotypic changes in human oral squamous cell carcinoma [125]. 3.6. VEGF The outline of the regulation of VEGF receptor (VEGFR) signaling by membrane traffic is similar to that of EGFR [126–128]. There are, however, unique features in VEGFR signaling. Firstly, the VEGFR interacting molecules within plasma membrane, including vascular guidance receptors Neuropilins and ephrins, also regulate VEGFR endocytosis. Secondly, a Golgi-localized target membrane-soluble N-ethylmaleimide attachment protein receptor (t-SNARE) may interfere with VEGFR2 trafficking to the plasma membrane and facilitates lysosomal degradation of the VEGFR2 [129]. VEGF was well established to be the key factor inducing endothelial cell (EC) activity for angiogenesis and tumor progression. The formation and guidance of specialized endothelial tip cells is essential for angiogenesis triggered by VEGF. Interestingly, Sawamiphak et al. demonstrated that ephrin-B2 controls VEGFR-2 internalization, which is required for activation of downstream signaling leading to tip cell filopodial extension [130]. Moreover, ephrin-B2 [130] and the ubiquitin-binding, clathrin adaptors epsins [131] were strongly implicated as promising targets for blocking angiogenesis required for tumor progression. 4. Targeting the common endocytic pathway for prevention of tumor progression: A promising perspective Since the role of metastatic factor-triggered endocytosis in tumor progression is emerging, it is tempting to identify critical endocytic

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Fig 1. Blockade of growth factor-induced endosomal signaling prevents tumor cell migration and tumor progression. The metastatic growth factors as indicated in the text may trigger common pathway for clathrin-mediated receptor endocytosis. After internalization of RTK via clathrin coated pit, RTK may signal within early endosome, recycling to plasma membrane for subsequent ligand engagement or sorting to late endosomes/lysosome for degradation. Several endosomal regulators such as dynamin, Rab4/Rab5/Rab11, Cbl and dual function signal components for RTK including PKC, Src and Grb2 adaptor play important roles in endosomal signaling at each indicated step. Suppressing the activity or expression of this molecule may block tumor cell migration and tumor progression. Large arrow represents the promoting effect of PKC, Src and Grb2 on endocytic pathway as indicated. Red lines indicated the blockade of each critical regulator. The numbers in parenthesis represent the numbers of references regarding the effects of dual function signal components on endosomal signaling as cited in the text. ECM: extracellular matrix.

molecules that may be employed as targets for effective and safe therapeutic approach. Especially, the feasibility of targeting common regulators for receptor endocytosis triggered by the aforementioned metastatic factors can be evaluated. These may include Cbl, dynamin, Rab4, Rab5 and Rab11 [82]. Recent reports demonstrated that inhibition of clathrin or knock down of Cbl and dynamin prevented tumor progression of cell expressing c-Met mutant with enhanced endocytosis [98]. Moreover, many kinases with dual function in signal transduction and endocytosis such as Grb2, p38, PKC, Src, epsin, and MP1– p14–p18 complex [82] were also promising candidates. Specifically, PKC [132,133], Src [134,135] and Grb2 [136–138] were known to be critical components within signal pathway induced by the aforementioned metastatic factors. PKC was previously known to be an essential modulator of the endosomal traffic and recycling [139]. Recent study further demonstrated that activation of PKC α is necessary for sorting the PDGF β receptor to Rab4a-dependent recycling compartment [112]. Moreover, PKC α and ε and an atypical PKC control integrin traffic for cytoskeletal rearrangement and migration [140–142]. Src was previously known to be required for internalization of the PDGFαR [143]. Lately, it was found to be transported with EGFR, and their co-localization promotes EGFR-mediated signaling [84]. Moreover, Src may phosphorylate dynamin to promote focal adhesion turnover during clathrin-dependent integrin endocytosis [144]. In addition, Src may phosphorylate cortactin to trigger endocytosis and polarization (at the leading edge) of FGF7R, which is required for keratinocyte migration [120]. In regard with Grb2, it was known to be essential for formation of clathrin-coated pits accommodating the EGFR [145], PDGFR [115] and c-Met [146]. Moreover, Grb2 may serve as an adaptor protein in the formation of a PDGF receptor/ DOCK4/dynamin complex at the leading edge of cells to mediate PDGF-triggered cell migration [114]. In the future, these common

critical regulators of endocytosis triggered by the metastatic growth factors may constitute a new category of targets for prevention of tumor progression (Fig. 1). Conflict of interest The author declares that there are no conflicts of interest. Acknowledgment The author gratefully acknowledges funding from the National Science Council in Taiwan and Research Centre of Hepatology in Buddhist Tzu Chi General Hospital. References [1] C.L. Chaffer, R.A. Weinberg, Science 331 (6024) (2011) 1559–1564. [2] C.C. Park, M.J. Bissell, M.H. Barcellos-Hoff, Molecular Medicine Today 6 (8) (2000) 324–329. [3] L.A. Liotta, E.C. Kohn, Nature 411 (6835) (2001) 375–379. [4] L. Trusolino, A. Bertotti, P.M. Comoglio, Nature Reviews. Molecular Cell Biology 11 (12) (2010) 834–848. [5] H.Y. Zhou, Y.L. Pon, A.S. Wong, Current Molecular Medicine 8 (6) (2008) 469–480. [6] K. Matsumoto, T. Nakamura, K. Sakai, T. Nakamura, Proteomics 8 (16) (2008) 3360–3370. [7] S. Benvenuti, P.M. Comoglio, Journal of Cellular Physiology 213 (2) (2007) 316–325. [8] E. Lesko, M. Majka, Frontiers in Bioscience 13 (2008) 1271–1280. [9] K.M. Quesnelle, A.L. Boehm, J.R. Grandis, Journal of Cellular Biochemistry 102 (2) (2007) 311–319. [10] N. Normanno, A. De Luca, C. Bianco, L. Strizzi, M. Mancino, M.R. Maiello, A. Carotenuto, G. De Feo, F. Caponigro, D.S. Salomon, Gene 366 (1) (2006) 2–16. [11] A. De Luca, A. Carotenuto, A. Rachiglio, M. Gallo, M.R. Maiello, D. Aldinucci, A. Pinto, N. Normanno, Journal of Cellular Physiology 214 (3) (2008) 559–567. [12] D. Samanta, P.K. Datta, Frontiers in Bioscience 17 (2012) 1281–1293.

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