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ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk
Biochimica et Biophysica Acta 1751 (2005) 110 – 117 http://www.elsevier.com/locate/bba
Review
ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk Shigeki Higashiyamaa,b,*, Daisuke Nanbaa a
Division of Biochemistry and Molecular Genetics, Department of Molecular and Cellular Biology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan b PRESTO, JST, Japan Received 8 September 2004; received in revised form 9 November 2004; accepted 11 November 2004 Available online 8 December 2004
Abstract All ligands of the epidermal growth factor receptor (EGFR) which has important roles in development and disease, are shed from the plasma membrane by metalloproteases. The ectodomain shedding of EGFR ligands has emerged as a critical component in the functional activation of EGFR in the interreceptor cross-talk. Identification of the sheddases for EGFR ligands using mouse embryonic cells lacking candidate sheddases (a disintegrin and metalloprotease; ADAM) has revealed that ADAM10, -12 and -17 are the sheddases of the EGFR ligands in response to various shedding stimulants such as GPCR agonists, growth factors, cytokines, osmotic stress, wounding and phorbol ester. Among the EGFR ligands, heparin-binding EGF-like growth factor (HB-EGF) is a representative ligand to understand the pathophysiological roles of the ectodomain shedding in wound healing, cardiac diseases, etc. Here we focus on the ectodomain shedding of HB-EGF by ADAMs, which is not only a key event of receptor cross-talk but also a novel intercellular signaling by the carboxy-terminal fragment (CTF signal). D 2004 Elsevier B.V. All rights reserved. Keywords: ADAM; EGFR ligand; HB-EGF; Ectodomain shedding; EGFR transactivation; Carboxy-terminal fragment signal (CTF signal)
1. Introduction Interreceptor cross-talk has received significant attention recently as an essential element in understanding the increasingly complex signaling networks identified within cells. Transactivation of the epidermal growth factor receptor (EGFR) has been shown to play a crucial role in the signaling by G-protein coupled receptors (GPCRs), cytokine receptors, receptor tyrosine kinases, and integrins to a variety of cellular responses [1,2]. Transactivation of EGFR is mediated, at least in some cases, by the EGFR ligands, which are cleaved from their membrane-anchored forms (proforms) in a process termed bectodomain sheddingQ. * Corresponding author. Division of Biochemistry and Molecular Genetics, Department of Molecular and Cellular Biology, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 7910295, Japan. Tel.: +81 89 960 5253, 5254; fax: +81 89 960 5256. E-mail address: [email protected] (S. Higashiyama). 1570-9639/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbapap.2004.11.009
A key step in elucidating the mechanism underlying the proteolytic release of EGFR ligands is the identification of the responsible sheddases. ADAM17 has been implicated in the shedding of TGF-a, HB-EGF and amphiregulin [3– 5]. Furthermore, three other ADAMs (ADAMs 9, 10 and 12) had been implicated in HB-EGF shedding [6–8]. Recently, comprehensive studies using embryonic fibroblasts derived from ADAM gene knock-out mice have revealed that ADAM10 and -17 are major sheddases [9]. However, this study was performed only under the conditions of exogenous gene transfer and TPA stimulation. Discrepancy of the analyzed data concerning the shedding of endogenous and exogenous HB-EGF in embryonic fibroblasts derived from ADAM12 knockout mouse indicates the complexity of the shedding mechanism [9,10]. On the other hand, we have advanced in knowledge as regarding the physiological significance of the ectodomain shedding of HB-EGF which evokes two independent signaling pathways, EGFR signaling and carboxy-terminal fragment (CTF) signaling [11,12].
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2. HB-EGF and the regulation of its shedding Like other members of the epidermal growth factor (EGF) family, HB-EGF is synthesized as a type I transmembrane protein [13,14]. The transmembrane form of HB-EGF (proHB-EGF) acts in a juxtacrine manner to signal neighboring cells [15], and forms heteromolecular complexes with tetraspanins (CD9, CD63, CD81 and CD82) and integrin-a3h1 on cell surface [16]. The complex formation of proHB-EGF with CD9 on cell surface dramatically up-regulates the juxtacrine growth factor activity of HB-EGF [15]. However, the physiological meaning of the complex formation with CD63, CD81, CD82 and integrin-a3h1 still remains unknown. The intracellular domain of proHB-EGF interacts with BAG-1 [17] and proHB-EGF also functions as a diphtheria toxin receptor [18,19]. ProHB-EGF can be enzymatically shed to release a soluble 14–22-kDa growth factor [13,14], which was originally identified in the conditioned medium of macrophage-like cells as a mitogen for fibroblasts and smooth muscle cells (SMC) [13]. HB-EGF is also a potent mitogen for keratinocytes [20], hepatocytes [21] and mesangial cells [22]. HB-EGF has been implicated in various physiological and pathological processes such as the development of some organs [3,23], wound healing [24,25], blastocyst implantation [26], the SMC hyperplasia that occurs in atherosclerosis [27], restenosis [28,29], pulmonary hypertension [30], liver regeneration [31], brain injury [32] and cancers [33] (see next section). Soluble HB-EGF (sHB-EGF) binds EGF receptor (EGFR)/erbB1/ HER1 [13], erbB4/HER4 [34], and N-arginine dibasic convertase (NRDc) [35]. HB-EGF also binds avidly to cell surface heparan sulfate proteoglycan (HSPG) as well as heparin [36–39], which seems to be essential for the interaction with EGFR [36]. The ectodomain shedding of proHB-EGF is induced by various stimuli such as phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) [40,41], calcium ionophore [42], and various growth factors and cytokines [33]. GPCR agonists also stimulate proHB-EGF shedding, which mediates EGFR transactivation by GPCR signaling [43,44]. The transactivation of EGFR induced, for example, by endothelin I, thrombin, lysophosphatidic acid, carbachol [44], insulin-like growth factor-1 (IGF-1) [45], estrogen [46,47], angiotensin II, phenylephrine [6,48,49], Helicobacter pylori [50], a2-adrenergic receptor agonists [51], bacterial lipoteichoic acid [8], epoxyeicosatrienoic acid [52], interleukin 8 and interleukin 1h [53] also apparently depends on proHB-EGF shedding. Wnt1 and Wnt5a induced EGFR transactivation via their GPCR receptor Frizzled [54]. Metalloproteases are responsible for the proteolytic cleavage of proHB-EGF since the ectodomain shedding of proHB-EGF is efficiently inhibited by various metalloprotease inhibitors. Protein kinase C (PKC) and mitogen-activated protein (MAP) kinase are also shown
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to be involved in the intracellular signaling pathway for proHB-EGF shedding [7,55], which might be required for the activation of appropriate metalloproteases. Metalloproteases of the ADAM family are mainly implicated as shedding enzymes of proHB-EGF. The ADAM molecules are characterized by a conserved domain structure, consisting of an N-terminal signal sequence followed by prodomain, metalloprotease and disintegrin domains, a cysteine-rich region, usually containing an EGF repeat, a transmembrane domain and a cytoplasmic tail [56,57]. The overexpression of ADAM9 resulted in the increased shedding of proHB-EGF without TPA, and ADAM9 mutants of the metalloprotease domain inhibited TPA-induced shedding in VeroH cells [7]. TPA-dependent proHB-EGF shedding, however, remains unaffected in embryonic fibroblasts derived from mice lacking ADAM9 [58], ADAM12 expression promoted proHBEGF shedding and the overexpression of dominantnegative (metalloprotease domain deleted) ADAM12, but not ADAM9, abrogated the shedding by TPA treatment in HT1080 cells [6]. Exogenous expression of dominant-negative ADAM12 inhibited phenylephrineinduced proHB-EGF shedding in cardiomyocytes [6]. TPA-dependent endogenous proHB-EGF shedding was largely impaired in embryonic fibroblasts derived from mice lacking ADAM12 [10]. Since some mice lacking the ADAM12 gene show reduction of the interscapular brown adipose tissue, ADAM12 seems to be involved in adipogenesis [10]. Transfection of wild-type ADAM10, but not metalloprotease domain-deleted ADAM10, stimulated the release of soluble HB-EGF in COS7 cells [59], and ADAM10 was implicated in proHB-EGF shedding and EGFR transactivation mediated by some GPCR signaling [8,59]. Reintroduction of ADAM17 into the immortalized fibroblasts derived from mice with eliminated zinc-binding domain of ADAM17 resulted in increased shedding of proHB-EGF [5]. Recent studies using embryonic fibroblasts derived from ADAM gene knock-out mice suggested ADAM10, -12, and -17 are involved in the shedding of proHB-EGF [9,10]. On the other hand, oxidative and osmotic stresses have been shown to induce HB-EGF shedding and subsequent EGFR transactivation and p38 MAPK activation by the different combinations of ADAM9, -10, -12 and -17 in different cell types [60]. Taken together, ADAM9, -10, 12 and -17 seem to be involved multiply in various signal-mediated HB-EGF shedding. The mechanism of ADAM activation has not been yet elucidated. However, we have identified two ADAM12docking proteins, Eve-1 and PACSIN3, that up-regulate TPA-induced ADAM12 activation [61,62]. Both Eve-1 and PACSIN3 contain Src homology 3 (SH3) domains that can interact with the proline-rich motifs of the ADAM12 cytoplasmic domain. Knockdown of each docking protein significantly reduces TPA- and angiotensin II-induced HB-EGF shedding.
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3. Pathophysiological roles of the ectodomain shedding of HB-EGF 3.1. Wound healing Successful wound healing involves several processes including inflammation, cell proliferation, cell migration, vascular permeability, angiogenesis, matrix deposition and tissue remodeling [63]. In cutaneous wound healing, keratinocytes play a central role, as not only a key structural cell type in skin repair, but also as the source of numerous growth factors, among which the EGF family are prominent. Keratinocyte proliferation and migration are in part mediated in an autocrine manner by EGFR–ligand interactions [20,64–67]. The EGFR ligands are expressed on the keratinocyte cell surface in membrane-anchored precursor forms [67], and wound fluid in skin contains soluble bioactive EGFR ligands [24], suggesting that the regulation of EGFR ligand shedding might be a physiologically important event in wound healing. Wound stimuli induce keratinocyte shedding of EGFR ligands in vitro, particularly of proHB-EGF. Released soluble HB-EGF stimulates transient EGFR activation, which is essential for keratinocyte migration [25]. HB-EGF, like EGF and TGFa, is a potent stimulator of keratinocyte proliferation. The resulting soluble ligands stimulate transient EGFR activation and the signal transduction molecule, signal transducer and activator of transcription 3 (Stat3) (unpublished observation). Metalloproteinase inhibitors such as OSU8-1 and KB-R7785, which are relatively specific for ADAM12 [6], block proHB-EGF shedding and abrogate the woundinduced activation of EGFR followed by the nuclear translocation of Stat3, which suppresses keratinocyte migration in vitro. OSU8-1 applied to wound sites in mice greatly retards reepithelialization as a result of failure in keratinocyte migration. This effect could be overcome by including recombinant soluble HB-EGF along with OSU8-1 [25]. These findings indicate that the shedding of proHB-EGF represents a critical event in keratinocyte migration leading to wound healing (Fig. 1). We recently observed that cutaneous wound healing is obviously retarded by the absence of keratinocyte migration in conditional hb-egf / mice (unpublished observation). 3.2. Cardiac diseases Cardiac hypertrophy is a primary and common adaptive response of the heart to several cardiovascular diseases [68]. Prolonged cardiac hypertrophy eventually culminates in chronic heart failure or sudden cardiac death [69]. A variety of endogenous vasoactive reagents that act via GPCRs such as phenylephrine, norepinephrine, angiotensin II, and endothelin-1 are associated with cardiac hypertrophy [70–72]. Ectodomain shedding of proHB-EGF by metalloproteinases is a key event in GPCR agonist-induced cell signaling via EGFR trans-
activation. When cardiomyocytes are stimulated by GPCR agonists, shedding of proHB-EGF via metalloproteinase ADAM12 activation and subsequent transactivation of EGFR result in cardiac hypertrophy. An inhibitor of HBEGF shedding, KB-R7785, blocks this GPCR-mediated signaling. In mice with cardiac hypertrophy, KB-R7785
Fig. 1. Wound healing model based on the ectodomain shedding of the EGFR ligands. (A) Wound healing model. Wounding (arrow in 2) induces the ectodomain shedding of the EGFR ligands, mainly proHB-EGF. The shed HB-EGF activates EGFR and induces cell migration as a healing step [25]. (B) Histology of excised mouse skin on day 6 after wounding, without or with 10 mM OSU8-1 treatment. Keratinocytes were stained with anti-keratin/cytokeratin antibody. (a) A typical tissue section from the control side of a wounded mouse. Keratinocytes are observed to have migrated from the edge of the wound (arrow), spreading under the crust and covering the wound site. Arrowheads indicate the base of keratinocyte layer. Arrow marks the edge of the wound. (b) A typical tissue section from the OSU8-1-treated side of a wounded mouse. Both keratinocyte migration and regeneration of epidermis were greatly inhibited at the edge of the wound (arrow). Arrow indicates the edge of the wound. (c) A typical tissue section from a wound treated with a cocktail of OSU8-1 and HB-EGF (5 Ag/ml). Both keratinocyte migration and regeneration of epidermis were completely restored.
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inhibits the shedding of proHB-EGF and attenuates hypertrophic changes [6]. These data suggest that proHB-EGF shedding by ADAM12 plays an important role in cardiac hypertrophy. Over half of HB-EGF-null mice die during the first postnatal week, and survivors have dysfunctional hearts with grossly enlarged ventricular chambers and reduced life spans [3,23]. Newborns lacking HB-EGF have enlarged and malformed semilunar and atrioventricular heart valves. The cardiac valve and the ventricular chamber phenotypes resembled those displayed by mice lacking EGFR [73] and ADAM17 [9], and by mice conditionally lacking ErbB2 [74,75], respectively. Furthermore, these phenotypes are similar to those observed in mice expressing the uncleavable form of proHB-EGF (HBuc mice) generated by targeted gene replacement [76]. The HBuc mice showed dilated cardiomyopathy in adult. Interestingly, dysregulated secretion of HB-EGF in mice carrying the transmembrane domain-truncated mutant of proHB-EGF (HBDtm mice) caused ventricular hypertrophy in heart [76]. These findings indicate that the balanced proteolytic processing of proHB-EGF is essential for the heart development and maintenance of the cardiac function (Fig. 2). These results indicate that proHB-EGF shedding is strictly controlled during heart development. 3.3. Others Atherogenesis in the arterial wall is characterized by the formation of fibrous lesions and the proliferation of neointimal SMC and HB-EGF is a potent chemoattractant and mitogen for vascular SMC [27,36]. Large amounts of HB-EGF mRNA and protein are generated in SMC and macrophages in human atherosclerotic plaques [27]. Balloon catheter injury of rat carotid
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arteries induces SMC migration and proliferation with subsequent neointimal formation concomitant with HBEGF mRNA and protein production in the SMC [28]. Other stimulants such as osmotic pressure, tension, and other growth factors and cytokines also up-regulate HBEGF production in SMC [33,77]. Transplant arteriosclerosis (TA) is a major obstacle to long-term graft survival after clinical organ transplantation, and the main pathology of TA is progressive neointimal thickening. The proliferation of SMC in neointima also plays a key role in the development of TA. Administration of HBEGF shedding inhibitor KB-R7785 prevents neointimal SMC proliferation in rat aortic allografts (unpublished observation). The implantation of blastocyst into a receptive uterus is associated with a series of events, the attachment reaction and decidualization of the stroma. HB-EGF is expressed in the luminal epithelium solely at the site of blastocyst apposition preceding the attachment reaction and persists during decidualization [26], and directs stromal cell polyploidy and decidualization during implantation [78]. Whether HB-EGF is crucial to implantation is still unknown, because of perinatal lethality of HB-EGF null mice [23]. However, the HBuc homo mice are fertile [76], suggesting that the ectodomain shedding of proHB-EGF would not be required for blastocyst implantation in mice, and that juxtacrine stimulation of proHB-EGF would be a major player in this system. The submandibular gland (SMG) of embryonic mice has been studied as a model system to understand the mechanisms of epithelial morphogenesis and epithelialmesenchymal interaction [79]. The SMG epithelium derived from the oral epithelium exhibits branching morphogenesis and forms a pattern like a bunch of grapes. EGFR signaling plays a role in epithelial morphogenesis of the mouse embryonic SMG [80]. At early developmental
Fig. 2. Cardiac phenotypes regulated by the ectodomain shedding of proHB-EGF. Overproduction of soluble HB-EGF causes cardiac hypertrophy, and suppression of soluble HB-EGF production causes dilated cardiomyopathy.
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stages of the SMG, HB-EGF predominantly functions as an EGFR ligand since expression levels of mRNA of EGF, TGF-a, and AR are very low [80,81]. Treatment of SMG rudiments in organ culture with HB-EGF shedding inhibitor OSU8-1 results in almost complete inhibition of SMG morphogenesis. The inhibitory effects on morphogenesis, however, are partially reversed by addition of soluble HB-EGF [81]. This result suggests that epithelial morphogenesis of the SMG requires not only EGFR activation by a soluble HB-EGF but also proHB-EGF shedding itself.
4. ADAM-mediated novel signaling, carboxy-terminal fragment (CTF) signaling The ectodomain shedding of transmembrane proteins actually produces two fragments, an extracellular fragment and a remnant fragment. The remnant fragment (carboxyterminal fragment: CTF) produced by the ectodomain shedding of proHB-EGF had not been characterized. Recently, we have identified promyelocytic leukaemia zinc finger (PLZF) protein as a binding protein of CTF of proHB-EGF (HB-EGF-C) [11]. PLZF is a transcriptional repressor and negatively regulates the cell cycle by the suppression of cyclin A expression [82–86]. PLZF produces transcriptional repression through recruitment of a repressor complex that contains N-CoR, SMRT, Sin3a, and histone deacetylases [87–92]. HB-EGF-C generated by proHB-EGF shedding is translocated from the plasma membrane into the cytoplasm [11]. Internalized HB-EGF-C associates with nuclear PLZF and causes its nuclear export. This process is impaired by the inhibition of metalloprotease activity. The PLZF export from the nucleus results in the reversal of decreased expression of cyclin A and delayed entry of Sphase by PLZF. In parallel with HB-EGF-C production, proHB-EGF shedding also generates HB-EGF, a soluble ligand of EGFR [13]. EGFR signaling promotes G1-phase progression in the cell cycle by regulating the expression of cyclin D via the Ras-MAPK signaling cascade [1,93]. Therefore, proteolytic cleavage of proHB-EGF by ADAMs generates two types of mitogenic signaling molecules, and the coordination of the dual intracellular signals mediated by HB-EGF and HB-EGF-C may be important for cell cycle progression. Various stimulants including GPCR agonists induce the cleavage of proHB-EGF (see above) by ADAMs, suggesting that posttranslational processing of proHBEGF induced by them leads to the nuclear export of PLZF. Gene expression control by transcriptional regulators occurs in the nucleus, and nuclear export of these factors results in loss of the regulation. PLZF represses cyclin A, HoxD, Hoxb2, and c-myc gene expression [86,94,95] and is expressed in a large number of tissues including the heart, lung, kidney, brain, liver, spleen, muscle, and testis [82,96]. This suggests that nuclear
export of PLZF by proHB-EGF shedding is involved in the regulation of cell proliferation and differentiation in various signaling cascades during the development and maintenance of adult tissues. Heart failure observed in HB-EGF-null, HBuc and HBDtm mice [23,76] might be, in part, due to the loss of HB-EGF-C-PLZF signaling in heart where PLZF is highly expressed [83]. HB-EGF-C has the ability to interact with transcriptional regulator(s), which suggests the integration of ErbB and CTF signaling leads to various cellular responses by controlling gene transcription (Fig. 3). BAG-1 has been reported as the binding protein of the cytoplasmic domain of proHB-EGF, and its interaction with proHB-EGF leads to decreased cell adhesion, increased resistance to apoptosis, and rapid secretion of soluble HB-EGF [17]. BAG-1 is a multifunctional protein which interacts with a diverse array of molecular targets including the Bcl-2 apoptosis regulator, the 70-kDa heat shock proteins, Hsc70 and Hsp70, nuclear hormone receptors, the RAF kinase, components of the ubiquichinylation/proteasome machinery, and DNA [97]. While BAG-1 was first identified as a proHB-EGF cytoplasmic binding protein in the cytoplasm and plasma membrane [17], BAG-1L, an isofom of BAG-1, is localized in nuclei of some types of cells [98,99]. These findings suggest that BAG-1 is a binding protein of nuclear HB-EGF-C and mediates the CTF signaling by proteolytic processing of proHB-EGF.
Fig. 3. The ectodomain shedding of proHB-EGF evokes two independent signaling pathways, EGFR signaling and CTF signaling. ADAM proteins are activated by various stimuli including wounding, Ca influx, GPCR signaling, growth factor and cytokine signaling, PKC activation, and binding of cytoplasmic docking proteins. EGFR ligand molecules are proteolytically cleaved by specific metalloprotease activity of ADAMs and yield amino- and carboxy-terminal fragments (extracellular domain and CTF). Produced soluble HB-EGF binds and activates EGFR, resulting in the activation of MAPK cascade and various gene transcriptions. HB-EGFC and HB-EGF generated by proHB-EGF shedding mediate signaling into the nucleus directly (CTF signaling) and indirectly via ErbB receptors (EGFR signaling), respectively. Dual intracellular signaling regulates gene transcription and results in cellular responses to various stimuli. GFR, growth factor receptor; CR, cytokine receptor; SH3 Pro., SH3 domaincontaining proteins; PKC, protein kinase C; MAPK, mitogen-activated protein kinase.
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5. Potential roles of the cytoplasmic domain of the EGF family molecules Membrane-anchored growth factors and their receptors provide the potential for bidirectional signaling, with a forward signal (receptor activation) mediated by the ectodomain and a reverse signal mediated by the intracellular domain of the ligand precursor. For instance, the transmembrane signaling proteins of the ephrin-B family and their EphB receptors show bidirectional signaling [100]. Ephrin-B reverse signaling is mediated by molecules that interact with the cytoplasmic domain of ephrin-B [101,102]. In the EGF family molecules, membrane-anchored TGF-a precursor activates an unidentified kinase in cells expressing it, when the precursor engages EGFR with neighboring cells [103]. Recently, it has been reported that neuregulin-1 is cleaved at the transmembrane domain and the released intracellular domain (Nrg-1-ICD) enters the nucleus to repress expression of several regulators of apoptosis [104]. Bao et al. [104] also mentioned that Nrg-1-ICD forms a complex with molecules including LIM kinase and a second zinc finger-containing protein related to PLZF. The molecular mechanism of the back signaling by Nrg-1-ICD is still unclear. While the machineries of CTF signaling of proHB-EGF and Nrg-1 seem to be different, these findings suggest that the CTF of the EGF family precursors has the ability to interact with transcriptional regulator(s) in the nucleus and controls gene expression in cells expressing the EGF family precursors. The cytoplasmic region of proHB-EGF also acts to regulate the distribution of proHB-EGF at the plasma membrane. Especially, the arrangement of the charged amino acids in the cytoplasmic domain is significant for the distribution of proHB-EGF. Furthermore, these amino acids are also required for the interaction of HB-EGF-C with PLZF [105]. These findings indicate that the cytoplasmic region of proHB-EGF is, unexpectedly, a multifunctional protein domain. The precursors of the other EGF family members have charged amino acid sequences in their cytoplasmic regions similar to that of proHB-EGF, which suggests CTF signaling by other EGF family member precursors after their proteolytic cleavage.
6. Conclusion and perspectives Metalloprotease ADAMs are widely involved in the ectodomain shedding of transmembrane proteins including not only various ligands of growth factor receptors and cytokine receptors, but also receptor themselves. Recent studies uncovered the important roles of the ADAMmediated ectodomain shedding, especially EGFR ligand shedding not only in receptor cross-talk, but also in CTF signals. However, intracellular signals leading to ADAM activation, variation of CTF signals, and biological significance of receptor cross-talk and CTF signals still remain to be elucidated in future.
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Review
ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk Shigeki Higashiyamaa,b,*, Daisuke Nanbaa a
Division of Biochemistry and Molecular Genetics, Department of Molecular and Cellular Biology, Ehime University School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan b PRESTO, JST, Japan Received 8 September 2004; received in revised form 9 November 2004; accepted 11 November 2004 Available online 8 December 2004
Abstract All ligands of the epidermal growth factor receptor (EGFR) which has important roles in development and disease, are shed from the plasma membrane by metalloproteases. The ectodomain shedding of EGFR ligands has emerged as a critical component in the functional activation of EGFR in the interreceptor cross-talk. Identification of the sheddases for EGFR ligands using mouse embryonic cells lacking candidate sheddases (a disintegrin and metalloprotease; ADAM) has revealed that ADAM10, -12 and -17 are the sheddases of the EGFR ligands in response to various shedding stimulants such as GPCR agonists, growth factors, cytokines, osmotic stress, wounding and phorbol ester. Among the EGFR ligands, heparin-binding EGF-like growth factor (HB-EGF) is a representative ligand to understand the pathophysiological roles of the ectodomain shedding in wound healing, cardiac diseases, etc. Here we focus on the ectodomain shedding of HB-EGF by ADAMs, which is not only a key event of receptor cross-talk but also a novel intercellular signaling by the carboxy-terminal fragment (CTF signal). D 2004 Elsevier B.V. All rights reserved. Keywords: ADAM; EGFR ligand; HB-EGF; Ectodomain shedding; EGFR transactivation; Carboxy-terminal fragment signal (CTF signal)
1. Introduction Interreceptor cross-talk has received significant attention recently as an essential element in understanding the increasingly complex signaling networks identified within cells. Transactivation of the epidermal growth factor receptor (EGFR) has been shown to play a crucial role in the signaling by G-protein coupled receptors (GPCRs), cytokine receptors, receptor tyrosine kinases, and integrins to a variety of cellular responses [1,2]. Transactivation of EGFR is mediated, at least in some cases, by the EGFR ligands, which are cleaved from their membrane-anchored forms (proforms) in a process termed bectodomain sheddingQ. * Corresponding author. Division of Biochemistry and Molecular Genetics, Department of Molecular and Cellular Biology, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 7910295, Japan. Tel.: +81 89 960 5253, 5254; fax: +81 89 960 5256. E-mail address: [email protected] (S. Higashiyama). 1570-9639/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbapap.2004.11.009
A key step in elucidating the mechanism underlying the proteolytic release of EGFR ligands is the identification of the responsible sheddases. ADAM17 has been implicated in the shedding of TGF-a, HB-EGF and amphiregulin [3– 5]. Furthermore, three other ADAMs (ADAMs 9, 10 and 12) had been implicated in HB-EGF shedding [6–8]. Recently, comprehensive studies using embryonic fibroblasts derived from ADAM gene knock-out mice have revealed that ADAM10 and -17 are major sheddases [9]. However, this study was performed only under the conditions of exogenous gene transfer and TPA stimulation. Discrepancy of the analyzed data concerning the shedding of endogenous and exogenous HB-EGF in embryonic fibroblasts derived from ADAM12 knockout mouse indicates the complexity of the shedding mechanism [9,10]. On the other hand, we have advanced in knowledge as regarding the physiological significance of the ectodomain shedding of HB-EGF which evokes two independent signaling pathways, EGFR signaling and carboxy-terminal fragment (CTF) signaling [11,12].
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2. HB-EGF and the regulation of its shedding Like other members of the epidermal growth factor (EGF) family, HB-EGF is synthesized as a type I transmembrane protein [13,14]. The transmembrane form of HB-EGF (proHB-EGF) acts in a juxtacrine manner to signal neighboring cells [15], and forms heteromolecular complexes with tetraspanins (CD9, CD63, CD81 and CD82) and integrin-a3h1 on cell surface [16]. The complex formation of proHB-EGF with CD9 on cell surface dramatically up-regulates the juxtacrine growth factor activity of HB-EGF [15]. However, the physiological meaning of the complex formation with CD63, CD81, CD82 and integrin-a3h1 still remains unknown. The intracellular domain of proHB-EGF interacts with BAG-1 [17] and proHB-EGF also functions as a diphtheria toxin receptor [18,19]. ProHB-EGF can be enzymatically shed to release a soluble 14–22-kDa growth factor [13,14], which was originally identified in the conditioned medium of macrophage-like cells as a mitogen for fibroblasts and smooth muscle cells (SMC) [13]. HB-EGF is also a potent mitogen for keratinocytes [20], hepatocytes [21] and mesangial cells [22]. HB-EGF has been implicated in various physiological and pathological processes such as the development of some organs [3,23], wound healing [24,25], blastocyst implantation [26], the SMC hyperplasia that occurs in atherosclerosis [27], restenosis [28,29], pulmonary hypertension [30], liver regeneration [31], brain injury [32] and cancers [33] (see next section). Soluble HB-EGF (sHB-EGF) binds EGF receptor (EGFR)/erbB1/ HER1 [13], erbB4/HER4 [34], and N-arginine dibasic convertase (NRDc) [35]. HB-EGF also binds avidly to cell surface heparan sulfate proteoglycan (HSPG) as well as heparin [36–39], which seems to be essential for the interaction with EGFR [36]. The ectodomain shedding of proHB-EGF is induced by various stimuli such as phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) [40,41], calcium ionophore [42], and various growth factors and cytokines [33]. GPCR agonists also stimulate proHB-EGF shedding, which mediates EGFR transactivation by GPCR signaling [43,44]. The transactivation of EGFR induced, for example, by endothelin I, thrombin, lysophosphatidic acid, carbachol [44], insulin-like growth factor-1 (IGF-1) [45], estrogen [46,47], angiotensin II, phenylephrine [6,48,49], Helicobacter pylori [50], a2-adrenergic receptor agonists [51], bacterial lipoteichoic acid [8], epoxyeicosatrienoic acid [52], interleukin 8 and interleukin 1h [53] also apparently depends on proHB-EGF shedding. Wnt1 and Wnt5a induced EGFR transactivation via their GPCR receptor Frizzled [54]. Metalloproteases are responsible for the proteolytic cleavage of proHB-EGF since the ectodomain shedding of proHB-EGF is efficiently inhibited by various metalloprotease inhibitors. Protein kinase C (PKC) and mitogen-activated protein (MAP) kinase are also shown
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to be involved in the intracellular signaling pathway for proHB-EGF shedding [7,55], which might be required for the activation of appropriate metalloproteases. Metalloproteases of the ADAM family are mainly implicated as shedding enzymes of proHB-EGF. The ADAM molecules are characterized by a conserved domain structure, consisting of an N-terminal signal sequence followed by prodomain, metalloprotease and disintegrin domains, a cysteine-rich region, usually containing an EGF repeat, a transmembrane domain and a cytoplasmic tail [56,57]. The overexpression of ADAM9 resulted in the increased shedding of proHB-EGF without TPA, and ADAM9 mutants of the metalloprotease domain inhibited TPA-induced shedding in VeroH cells [7]. TPA-dependent proHB-EGF shedding, however, remains unaffected in embryonic fibroblasts derived from mice lacking ADAM9 [58], ADAM12 expression promoted proHBEGF shedding and the overexpression of dominantnegative (metalloprotease domain deleted) ADAM12, but not ADAM9, abrogated the shedding by TPA treatment in HT1080 cells [6]. Exogenous expression of dominant-negative ADAM12 inhibited phenylephrineinduced proHB-EGF shedding in cardiomyocytes [6]. TPA-dependent endogenous proHB-EGF shedding was largely impaired in embryonic fibroblasts derived from mice lacking ADAM12 [10]. Since some mice lacking the ADAM12 gene show reduction of the interscapular brown adipose tissue, ADAM12 seems to be involved in adipogenesis [10]. Transfection of wild-type ADAM10, but not metalloprotease domain-deleted ADAM10, stimulated the release of soluble HB-EGF in COS7 cells [59], and ADAM10 was implicated in proHB-EGF shedding and EGFR transactivation mediated by some GPCR signaling [8,59]. Reintroduction of ADAM17 into the immortalized fibroblasts derived from mice with eliminated zinc-binding domain of ADAM17 resulted in increased shedding of proHB-EGF [5]. Recent studies using embryonic fibroblasts derived from ADAM gene knock-out mice suggested ADAM10, -12, and -17 are involved in the shedding of proHB-EGF [9,10]. On the other hand, oxidative and osmotic stresses have been shown to induce HB-EGF shedding and subsequent EGFR transactivation and p38 MAPK activation by the different combinations of ADAM9, -10, -12 and -17 in different cell types [60]. Taken together, ADAM9, -10, 12 and -17 seem to be involved multiply in various signal-mediated HB-EGF shedding. The mechanism of ADAM activation has not been yet elucidated. However, we have identified two ADAM12docking proteins, Eve-1 and PACSIN3, that up-regulate TPA-induced ADAM12 activation [61,62]. Both Eve-1 and PACSIN3 contain Src homology 3 (SH3) domains that can interact with the proline-rich motifs of the ADAM12 cytoplasmic domain. Knockdown of each docking protein significantly reduces TPA- and angiotensin II-induced HB-EGF shedding.
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3. Pathophysiological roles of the ectodomain shedding of HB-EGF 3.1. Wound healing Successful wound healing involves several processes including inflammation, cell proliferation, cell migration, vascular permeability, angiogenesis, matrix deposition and tissue remodeling [63]. In cutaneous wound healing, keratinocytes play a central role, as not only a key structural cell type in skin repair, but also as the source of numerous growth factors, among which the EGF family are prominent. Keratinocyte proliferation and migration are in part mediated in an autocrine manner by EGFR–ligand interactions [20,64–67]. The EGFR ligands are expressed on the keratinocyte cell surface in membrane-anchored precursor forms [67], and wound fluid in skin contains soluble bioactive EGFR ligands [24], suggesting that the regulation of EGFR ligand shedding might be a physiologically important event in wound healing. Wound stimuli induce keratinocyte shedding of EGFR ligands in vitro, particularly of proHB-EGF. Released soluble HB-EGF stimulates transient EGFR activation, which is essential for keratinocyte migration [25]. HB-EGF, like EGF and TGFa, is a potent stimulator of keratinocyte proliferation. The resulting soluble ligands stimulate transient EGFR activation and the signal transduction molecule, signal transducer and activator of transcription 3 (Stat3) (unpublished observation). Metalloproteinase inhibitors such as OSU8-1 and KB-R7785, which are relatively specific for ADAM12 [6], block proHB-EGF shedding and abrogate the woundinduced activation of EGFR followed by the nuclear translocation of Stat3, which suppresses keratinocyte migration in vitro. OSU8-1 applied to wound sites in mice greatly retards reepithelialization as a result of failure in keratinocyte migration. This effect could be overcome by including recombinant soluble HB-EGF along with OSU8-1 [25]. These findings indicate that the shedding of proHB-EGF represents a critical event in keratinocyte migration leading to wound healing (Fig. 1). We recently observed that cutaneous wound healing is obviously retarded by the absence of keratinocyte migration in conditional hb-egf / mice (unpublished observation). 3.2. Cardiac diseases Cardiac hypertrophy is a primary and common adaptive response of the heart to several cardiovascular diseases [68]. Prolonged cardiac hypertrophy eventually culminates in chronic heart failure or sudden cardiac death [69]. A variety of endogenous vasoactive reagents that act via GPCRs such as phenylephrine, norepinephrine, angiotensin II, and endothelin-1 are associated with cardiac hypertrophy [70–72]. Ectodomain shedding of proHB-EGF by metalloproteinases is a key event in GPCR agonist-induced cell signaling via EGFR trans-
activation. When cardiomyocytes are stimulated by GPCR agonists, shedding of proHB-EGF via metalloproteinase ADAM12 activation and subsequent transactivation of EGFR result in cardiac hypertrophy. An inhibitor of HBEGF shedding, KB-R7785, blocks this GPCR-mediated signaling. In mice with cardiac hypertrophy, KB-R7785
Fig. 1. Wound healing model based on the ectodomain shedding of the EGFR ligands. (A) Wound healing model. Wounding (arrow in 2) induces the ectodomain shedding of the EGFR ligands, mainly proHB-EGF. The shed HB-EGF activates EGFR and induces cell migration as a healing step [25]. (B) Histology of excised mouse skin on day 6 after wounding, without or with 10 mM OSU8-1 treatment. Keratinocytes were stained with anti-keratin/cytokeratin antibody. (a) A typical tissue section from the control side of a wounded mouse. Keratinocytes are observed to have migrated from the edge of the wound (arrow), spreading under the crust and covering the wound site. Arrowheads indicate the base of keratinocyte layer. Arrow marks the edge of the wound. (b) A typical tissue section from the OSU8-1-treated side of a wounded mouse. Both keratinocyte migration and regeneration of epidermis were greatly inhibited at the edge of the wound (arrow). Arrow indicates the edge of the wound. (c) A typical tissue section from a wound treated with a cocktail of OSU8-1 and HB-EGF (5 Ag/ml). Both keratinocyte migration and regeneration of epidermis were completely restored.
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inhibits the shedding of proHB-EGF and attenuates hypertrophic changes [6]. These data suggest that proHB-EGF shedding by ADAM12 plays an important role in cardiac hypertrophy. Over half of HB-EGF-null mice die during the first postnatal week, and survivors have dysfunctional hearts with grossly enlarged ventricular chambers and reduced life spans [3,23]. Newborns lacking HB-EGF have enlarged and malformed semilunar and atrioventricular heart valves. The cardiac valve and the ventricular chamber phenotypes resembled those displayed by mice lacking EGFR [73] and ADAM17 [9], and by mice conditionally lacking ErbB2 [74,75], respectively. Furthermore, these phenotypes are similar to those observed in mice expressing the uncleavable form of proHB-EGF (HBuc mice) generated by targeted gene replacement [76]. The HBuc mice showed dilated cardiomyopathy in adult. Interestingly, dysregulated secretion of HB-EGF in mice carrying the transmembrane domain-truncated mutant of proHB-EGF (HBDtm mice) caused ventricular hypertrophy in heart [76]. These findings indicate that the balanced proteolytic processing of proHB-EGF is essential for the heart development and maintenance of the cardiac function (Fig. 2). These results indicate that proHB-EGF shedding is strictly controlled during heart development. 3.3. Others Atherogenesis in the arterial wall is characterized by the formation of fibrous lesions and the proliferation of neointimal SMC and HB-EGF is a potent chemoattractant and mitogen for vascular SMC [27,36]. Large amounts of HB-EGF mRNA and protein are generated in SMC and macrophages in human atherosclerotic plaques [27]. Balloon catheter injury of rat carotid
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arteries induces SMC migration and proliferation with subsequent neointimal formation concomitant with HBEGF mRNA and protein production in the SMC [28]. Other stimulants such as osmotic pressure, tension, and other growth factors and cytokines also up-regulate HBEGF production in SMC [33,77]. Transplant arteriosclerosis (TA) is a major obstacle to long-term graft survival after clinical organ transplantation, and the main pathology of TA is progressive neointimal thickening. The proliferation of SMC in neointima also plays a key role in the development of TA. Administration of HBEGF shedding inhibitor KB-R7785 prevents neointimal SMC proliferation in rat aortic allografts (unpublished observation). The implantation of blastocyst into a receptive uterus is associated with a series of events, the attachment reaction and decidualization of the stroma. HB-EGF is expressed in the luminal epithelium solely at the site of blastocyst apposition preceding the attachment reaction and persists during decidualization [26], and directs stromal cell polyploidy and decidualization during implantation [78]. Whether HB-EGF is crucial to implantation is still unknown, because of perinatal lethality of HB-EGF null mice [23]. However, the HBuc homo mice are fertile [76], suggesting that the ectodomain shedding of proHB-EGF would not be required for blastocyst implantation in mice, and that juxtacrine stimulation of proHB-EGF would be a major player in this system. The submandibular gland (SMG) of embryonic mice has been studied as a model system to understand the mechanisms of epithelial morphogenesis and epithelialmesenchymal interaction [79]. The SMG epithelium derived from the oral epithelium exhibits branching morphogenesis and forms a pattern like a bunch of grapes. EGFR signaling plays a role in epithelial morphogenesis of the mouse embryonic SMG [80]. At early developmental
Fig. 2. Cardiac phenotypes regulated by the ectodomain shedding of proHB-EGF. Overproduction of soluble HB-EGF causes cardiac hypertrophy, and suppression of soluble HB-EGF production causes dilated cardiomyopathy.
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stages of the SMG, HB-EGF predominantly functions as an EGFR ligand since expression levels of mRNA of EGF, TGF-a, and AR are very low [80,81]. Treatment of SMG rudiments in organ culture with HB-EGF shedding inhibitor OSU8-1 results in almost complete inhibition of SMG morphogenesis. The inhibitory effects on morphogenesis, however, are partially reversed by addition of soluble HB-EGF [81]. This result suggests that epithelial morphogenesis of the SMG requires not only EGFR activation by a soluble HB-EGF but also proHB-EGF shedding itself.
4. ADAM-mediated novel signaling, carboxy-terminal fragment (CTF) signaling The ectodomain shedding of transmembrane proteins actually produces two fragments, an extracellular fragment and a remnant fragment. The remnant fragment (carboxyterminal fragment: CTF) produced by the ectodomain shedding of proHB-EGF had not been characterized. Recently, we have identified promyelocytic leukaemia zinc finger (PLZF) protein as a binding protein of CTF of proHB-EGF (HB-EGF-C) [11]. PLZF is a transcriptional repressor and negatively regulates the cell cycle by the suppression of cyclin A expression [82–86]. PLZF produces transcriptional repression through recruitment of a repressor complex that contains N-CoR, SMRT, Sin3a, and histone deacetylases [87–92]. HB-EGF-C generated by proHB-EGF shedding is translocated from the plasma membrane into the cytoplasm [11]. Internalized HB-EGF-C associates with nuclear PLZF and causes its nuclear export. This process is impaired by the inhibition of metalloprotease activity. The PLZF export from the nucleus results in the reversal of decreased expression of cyclin A and delayed entry of Sphase by PLZF. In parallel with HB-EGF-C production, proHB-EGF shedding also generates HB-EGF, a soluble ligand of EGFR [13]. EGFR signaling promotes G1-phase progression in the cell cycle by regulating the expression of cyclin D via the Ras-MAPK signaling cascade [1,93]. Therefore, proteolytic cleavage of proHB-EGF by ADAMs generates two types of mitogenic signaling molecules, and the coordination of the dual intracellular signals mediated by HB-EGF and HB-EGF-C may be important for cell cycle progression. Various stimulants including GPCR agonists induce the cleavage of proHB-EGF (see above) by ADAMs, suggesting that posttranslational processing of proHBEGF induced by them leads to the nuclear export of PLZF. Gene expression control by transcriptional regulators occurs in the nucleus, and nuclear export of these factors results in loss of the regulation. PLZF represses cyclin A, HoxD, Hoxb2, and c-myc gene expression [86,94,95] and is expressed in a large number of tissues including the heart, lung, kidney, brain, liver, spleen, muscle, and testis [82,96]. This suggests that nuclear
export of PLZF by proHB-EGF shedding is involved in the regulation of cell proliferation and differentiation in various signaling cascades during the development and maintenance of adult tissues. Heart failure observed in HB-EGF-null, HBuc and HBDtm mice [23,76] might be, in part, due to the loss of HB-EGF-C-PLZF signaling in heart where PLZF is highly expressed [83]. HB-EGF-C has the ability to interact with transcriptional regulator(s), which suggests the integration of ErbB and CTF signaling leads to various cellular responses by controlling gene transcription (Fig. 3). BAG-1 has been reported as the binding protein of the cytoplasmic domain of proHB-EGF, and its interaction with proHB-EGF leads to decreased cell adhesion, increased resistance to apoptosis, and rapid secretion of soluble HB-EGF [17]. BAG-1 is a multifunctional protein which interacts with a diverse array of molecular targets including the Bcl-2 apoptosis regulator, the 70-kDa heat shock proteins, Hsc70 and Hsp70, nuclear hormone receptors, the RAF kinase, components of the ubiquichinylation/proteasome machinery, and DNA [97]. While BAG-1 was first identified as a proHB-EGF cytoplasmic binding protein in the cytoplasm and plasma membrane [17], BAG-1L, an isofom of BAG-1, is localized in nuclei of some types of cells [98,99]. These findings suggest that BAG-1 is a binding protein of nuclear HB-EGF-C and mediates the CTF signaling by proteolytic processing of proHB-EGF.
Fig. 3. The ectodomain shedding of proHB-EGF evokes two independent signaling pathways, EGFR signaling and CTF signaling. ADAM proteins are activated by various stimuli including wounding, Ca influx, GPCR signaling, growth factor and cytokine signaling, PKC activation, and binding of cytoplasmic docking proteins. EGFR ligand molecules are proteolytically cleaved by specific metalloprotease activity of ADAMs and yield amino- and carboxy-terminal fragments (extracellular domain and CTF). Produced soluble HB-EGF binds and activates EGFR, resulting in the activation of MAPK cascade and various gene transcriptions. HB-EGFC and HB-EGF generated by proHB-EGF shedding mediate signaling into the nucleus directly (CTF signaling) and indirectly via ErbB receptors (EGFR signaling), respectively. Dual intracellular signaling regulates gene transcription and results in cellular responses to various stimuli. GFR, growth factor receptor; CR, cytokine receptor; SH3 Pro., SH3 domaincontaining proteins; PKC, protein kinase C; MAPK, mitogen-activated protein kinase.
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5. Potential roles of the cytoplasmic domain of the EGF family molecules Membrane-anchored growth factors and their receptors provide the potential for bidirectional signaling, with a forward signal (receptor activation) mediated by the ectodomain and a reverse signal mediated by the intracellular domain of the ligand precursor. For instance, the transmembrane signaling proteins of the ephrin-B family and their EphB receptors show bidirectional signaling [100]. Ephrin-B reverse signaling is mediated by molecules that interact with the cytoplasmic domain of ephrin-B [101,102]. In the EGF family molecules, membrane-anchored TGF-a precursor activates an unidentified kinase in cells expressing it, when the precursor engages EGFR with neighboring cells [103]. Recently, it has been reported that neuregulin-1 is cleaved at the transmembrane domain and the released intracellular domain (Nrg-1-ICD) enters the nucleus to repress expression of several regulators of apoptosis [104]. Bao et al. [104] also mentioned that Nrg-1-ICD forms a complex with molecules including LIM kinase and a second zinc finger-containing protein related to PLZF. The molecular mechanism of the back signaling by Nrg-1-ICD is still unclear. While the machineries of CTF signaling of proHB-EGF and Nrg-1 seem to be different, these findings suggest that the CTF of the EGF family precursors has the ability to interact with transcriptional regulator(s) in the nucleus and controls gene expression in cells expressing the EGF family precursors. The cytoplasmic region of proHB-EGF also acts to regulate the distribution of proHB-EGF at the plasma membrane. Especially, the arrangement of the charged amino acids in the cytoplasmic domain is significant for the distribution of proHB-EGF. Furthermore, these amino acids are also required for the interaction of HB-EGF-C with PLZF [105]. These findings indicate that the cytoplasmic region of proHB-EGF is, unexpectedly, a multifunctional protein domain. The precursors of the other EGF family members have charged amino acid sequences in their cytoplasmic regions similar to that of proHB-EGF, which suggests CTF signaling by other EGF family member precursors after their proteolytic cleavage.
6. Conclusion and perspectives Metalloprotease ADAMs are widely involved in the ectodomain shedding of transmembrane proteins including not only various ligands of growth factor receptors and cytokine receptors, but also receptor themselves. Recent studies uncovered the important roles of the ADAMmediated ectodomain shedding, especially EGFR ligand shedding not only in receptor cross-talk, but also in CTF signals. However, intracellular signals leading to ADAM activation, variation of CTF signals, and biological significance of receptor cross-talk and CTF signals still remain to be elucidated in future.
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