Decorin
2012; Elsevier BV; Volume: 181; Issue: 2 Linguagem: Inglês
10.1016/j.ajpath.2012.04.029
ISSN1525-2191
AutoresThomas Neill, Liliana Schaefer, Renato V. Iozzo,
Tópico(s)Cell Adhesion Molecules Research
ResumoDecorin, an archetypal member of the small leucine-rich proteoglycan gene family, has a broad binding repertoire that encompasses matrix structural components, such as collagens, and growth factors, particularly those that belong to the transforming growth factor–β ligand superfamily. Within the tumor microenvironment, stromal decorin has an inherent proclivity to directly bind and down-regulate several receptor tyrosine kinases, which are often overexpressed in cancer cells. The decorin interactome commands a powerful antitumorigenic signal by potently repressing and attenuating tumor cell proliferation, survival, migration, and angiogenesis. This collection of interacting molecules also regulates key downstream signaling processes indirectly via the sequestration of growth factors or directly via the antagonism of receptor tyrosine kinases. We propose that decorin can be considered a "guardian from the matrix" because of its innate ability to oppose pro-tumorigenic cues. Decorin, an archetypal member of the small leucine-rich proteoglycan gene family, has a broad binding repertoire that encompasses matrix structural components, such as collagens, and growth factors, particularly those that belong to the transforming growth factor–β ligand superfamily. Within the tumor microenvironment, stromal decorin has an inherent proclivity to directly bind and down-regulate several receptor tyrosine kinases, which are often overexpressed in cancer cells. The decorin interactome commands a powerful antitumorigenic signal by potently repressing and attenuating tumor cell proliferation, survival, migration, and angiogenesis. This collection of interacting molecules also regulates key downstream signaling processes indirectly via the sequestration of growth factors or directly via the antagonism of receptor tyrosine kinases. We propose that decorin can be considered a "guardian from the matrix" because of its innate ability to oppose pro-tumorigenic cues. Neoplastic growth has long been viewed in the paradigm of activating mutations in oncogenes and silencing of tumor suppressor genes that confer, collectively over time, selective advantages to fundamental cellular processes such as cell proliferation, survival, migration, and metastasis. However, relatively recently, the profound importance of the surrounding tumor stroma, encompassing that of abnormal synthesis and deposition of several proteoglycans, has emerged as an active participant in coordinating many aspects of tumor growth and progression. Indeed, an early defining histopathological feature of certain carcinomas is the presence of a strong desmoplastic reaction surrounding the tumor proper that is inherently enriched in various proteoglycan species.1Iozzo R.V. Sanderson R.D. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.J Cell Mol Med. 2011; 15: 1013-1031Crossref PubMed Scopus (434) Google Scholar, 2Goldoni S. Iozzo R.V. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs.Int J Cancer. 2008; 123: 2473-2479Crossref PubMed Scopus (140) Google Scholar Decorin represents a prototypical member of the small leucine-rich proteoglycan (SLRP) gene family that houses 18 distinct members segregating into five discrete classes with sequence conservation across multiple species.3Iozzo R.V. Schaefer L. Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans.FEBS J. 2010; 277: 3864-3875Crossref PubMed Scopus (252) Google Scholar Decorin contains a single glycosaminoglycan (GAG) chain composed of either dermatan or chondroitin sulfate, and 12 leucine-rich repeats comprising the protein core. Decorin is a stromal proteoglycan synthesized chiefly by fibroblasts, stressed vascular endothelial cells, and smooth muscle cells. Initially, decorin was named for and characterized by its high-affinity interactions with collagen fibers and for the subsequent regulation of collagen fibrillogenesis.4Danielson K.G. Baribault H. Holmes D.F. Graham H. Kadler K.E. Iozzo R.V. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility.J Cell Biol. 1997; 136: 729-743Crossref PubMed Scopus (1199) Google Scholar, 5Keene D.R. San Antonio J.D. Mayne R. McQuillan D.J. Sarris G. Santoro S.A. Iozzo R.V. Decorin binds near the C terminus of type I collagen.J Biol Chem. 2000; 275: 21801-21804Crossref PubMed Scopus (181) Google Scholar, 6Zhang G. Ezura Y. Chervoneva I. Robinson P.S. Beason D.P. Carine E.T. Soslowsky L.J. Iozzo R.V. Birk D.E. Decorin regulates assembly of collagen fibrils and acquisition of biomechanical properties during tendon development.J Cell Biochem. 2006; 98: 1436-1449Crossref PubMed Scopus (331) Google Scholar, 7Zhang G. Chen S. Goldoni S. Calder B.W. Simpson H.C. Owens R.T. McQuillan D.J. Young M.F. Iozzo R.V. Birk D.E. Genetic evidence for the coordinated regulation of collagen fibrillogenesis in the cornea by decorin and biglycan.J Biol Chem. 2009; 284: 8888-8897Crossref PubMed Scopus (170) Google Scholar It was subsequently discovered that decorin sequesters multiple growth factors, such as transforming growth factor (TGF)–β1, and directly antagonizes several members of the receptor tyrosine kinase (RTK) family, including the epidermal growth factor receptor (EGFR), the insulin-like growth factor receptor I (IGF-IR), and the hepatocyte growth factor receptor (Met)1Iozzo R.V. Sanderson R.D. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.J Cell Mol Med. 2011; 15: 1013-1031Crossref PubMed Scopus (434) Google Scholar (Figure 1). Consequently, these latter bioactivities have been attributed to evoke potent tumor repression. The unique nature of this repressive activity is that it functions wholly within the extracellular matrix to attenuate, in an integrated and protracted fashion, key pro-survival, migratory, proliferative, and angiogenic signaling pathways.2Goldoni S. Iozzo R.V. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs.Int J Cancer. 2008; 123: 2473-2479Crossref PubMed Scopus (140) Google Scholar In a novel discovery, decorin has been implicated in modulating inflammatory responses as they pertain to cancer progression via engagement of Toll-like receptors (TLRs).8Merline R. Moreth K. Beckmann J. Nastase M.V. Zeng-Brouwers J. Tralhão J.G. Lemarchand P. Pfeilschifter J. Schaefer R.M. Iozzo R.V. Schaefer L. Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and microRNA-21.Sci Signal. 2011; 4: ra75Crossref PubMed Scopus (268) Google Scholar Moreover, reduced decorin within the tumor stroma has been established as a poor prognosticator of invasive breast cancer and in murine models of spontaneous breast cancer with mammary gland carcinogenesis.2Goldoni S. Iozzo R.V. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs.Int J Cancer. 2008; 123: 2473-2479Crossref PubMed Scopus (140) Google Scholar Endogenously, certain neoplasms have a proclivity to hypermethylate the decorin promoter, effectively silencing expression and allowing tumor progression.2Goldoni S. Iozzo R.V. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs.Int J Cancer. 2008; 123: 2473-2479Crossref PubMed Scopus (140) Google Scholar, 9Adany R. Heimer R. Caterson B. Sorrell J.M. Iozzo R.V. Altered expression of chondroitin sulfate proteoglycan in the stroma of human colon carcinoma Hypomethylation of PG-40 gene correlates with increased PG-40 content and mRNA levels.J Biol Chem. 1990; 265: 11389-11396PubMed Google Scholar Thus, loss of decorin expression may also favor tumor growth. In this review, we propose the concept of decorin as a "guardian from the matrix"—that is, a powerful endogenous tumor repressor acting in a paracrine fashion to limit tumor growth and angiogenesis. A rapidly emerging hallmark of cancer involves inflammatory processes as active and critical participants in tumorigenesis.10Hanahan D. Winberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (46766) Google Scholar Several articles have been published to indicate an immunomodulatory role of decorin to recruit monocytes to injury sites by induction of MCP-1,11Köninger J. Giese N.A. Bartel M. di Mola F.F. Berberat P.O. di Sebastiano P. Giese T. Büchler M.W. Friess H. The ECM proteoglycan decorin links desmoplasia and inflammation in chronic pancreatitis.J Clin Pathol. 2012; 59: 21-27Crossref Scopus (31) Google Scholar inhibiting apoptotic death of macrophages,12Xaus J. Comalada M. Cardó M. Valledor A.F. Celada A. Decorin inhibits macrophage colony-stimulating factor proliferation of macrophages and enhances cell survival through induction of p27Kip1 and p21Waf1.Blood. 2001; 98: 2124-2133Crossref PubMed Scopus (113) Google Scholar and modulating allergen-induced asthma.13Marchica C.L. Pinelli V. Borges M. Zummer J. Narayanan V. Iozzo R.V. Ludwig M.S. A role for decorin in a murine model of allergen-induced asthma.Am J Physiol Lung Cell Mol Physiol. 2011; 300: 863-873Crossref Scopus (28) Google Scholar A recently identified mechanism was elucidated, linking decorin, inflammation, and tumor growth.8Merline R. Moreth K. Beckmann J. Nastase M.V. Zeng-Brouwers J. Tralhão J.G. Lemarchand P. Pfeilschifter J. Schaefer R.M. Iozzo R.V. Schaefer L. Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and microRNA-21.Sci Signal. 2011; 4: ra75Crossref PubMed Scopus (268) Google Scholar This process entails direct binding of soluble decorin to TLR 2 and 4 on macrophages, leading to enhanced production of the pro-inflammatory protein programed cell death 4 (PDCD4) and the oncomir miR-21, thus causing stabilization and increased translation of PDCD4. The increased abundance of PDCD4 concurrently causes a decrease of anti-inflammatory cytokines such as interleukin (IL)–10 (Figure 2). As an endogenous inhibitor of TGFβ1 by sequestration (Figure 1), decorin also attenuates TGFβ1 signaling pathways, thereby further curbing tumor growth and inflammation.8Merline R. Moreth K. Beckmann J. Nastase M.V. Zeng-Brouwers J. Tralhão J.G. Lemarchand P. Pfeilschifter J. Schaefer R.M. Iozzo R.V. Schaefer L. Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and microRNA-21.Sci Signal. 2011; 4: ra75Crossref PubMed Scopus (268) Google Scholar Thus, by antagonizing TGFβ1, decorin circumvents PDCD4 translational repression to generate a pro-inflammatory tumor microenvironment. It also induces the synthesis of pro-inflammatory modulators (eg, TNFα, and IL-12b) for the suppression of tumorigenic growth. It is important to note that TNFα is a binding partner for decorin14Tufvesson E. Westergren-Thorsson G. Tumor necrosis factor-α interacts with biglycan and decorin.FEBS Lett. 2002; 530: 124-128Crossref PubMed Scopus (99) Google Scholar (Figure 1) and shows a moderate affinity for this ligand, thus highlighting an important regulatory function to further modify TNFα activities. Recent experiments using an animal model of delayed-type hypersensitivity in decorin-null mice are also supportive of a role of decorin for stimulating a more pro-inflammatory environment.15Seidler D.G. Mohamed N.A. Bocian C. Stadtmann A. Hermann S. Schäfers K. Schäfers M. Iozzo R.V. Zarbock A. Götte M. The role for decorin in delayed-type hypersensitivity.J Immunol. 2011; 187: 6108-6199Crossref PubMed Scopus (43) Google Scholar In this setting, lack of decorin is associated with reduced TNFα levels, and increased expression of leukocyte adhesion molecules coincides with an increased adherence of leukocytes to the endothelium.15Seidler D.G. Mohamed N.A. Bocian C. Stadtmann A. Hermann S. Schäfers K. Schäfers M. Iozzo R.V. Zarbock A. Götte M. The role for decorin in delayed-type hypersensitivity.J Immunol. 2011; 187: 6108-6199Crossref PubMed Scopus (43) Google Scholar Finally, the closest relative of decorin, biglycan, has been previously shown to modulate immune responses16Schaefer L. Babelova A. Kiss E. Hausser H.-J. Baliova M. Krzyzankova M. Marsche G. Young M.F. Mihalik D. Götte M. Malle E. Schaefer R.M. Gröne H.-J. The matrix component biglycan is proinflammatory and signals through toll-like receptors 4 and 2 in macrophages.J Clin Invest. 2005; 115: 2223-2233Crossref PubMed Scopus (672) Google Scholar, 17Moreth K. Brodbeck R. Babelova A. Gretz N. Spieker T. Zeng-Brouwers J. Pfeilschifter J. Young M.F. Schaefer R.M. Schaefer L. The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis.J Clin Invest. 2010; 120: 4251-4272Crossref PubMed Scopus (160) Google Scholar by acting as an endogenous ligand for TLR-2/4 to increase pro-inflammatory signals. Thus, these studies offer a new functional paradigm for SLRPs and inflammation. Decorin has exquisite binding affinities for members of the TGFβ superfamily (Figure 1), including TGFβ1, TGFβ2, and myostatin,1Iozzo R.V. Sanderson R.D. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.J Cell Mol Med. 2011; 15: 1013-1031Crossref PubMed Scopus (434) Google Scholar, 2Goldoni S. Iozzo R.V. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs.Int J Cancer. 2008; 123: 2473-2479Crossref PubMed Scopus (140) Google Scholar and through this interaction can effectively trap ligands within the matrix and indirectly attenuate downstream signaling pathways mediated by the TGFβ receptor complex, as recently shown in a murine model of hepatic fibrosis.18Baghy K. Dezsó K. László V. Fullár A. Péterfia B. Paku S. Nagy P. Schaff Z. Iozzo R.V. Kovalszky I. Ablation of the decorin gene enhances experimental hepatic fibrosis and impairs hepatic healing in mice.Lab Invest. 2011; 91: 439-451Crossref PubMed Scopus (76) Google Scholar However, bone-derived decorin seems to enhance TGFβ activity.19Takeuchi Y. Kodama Y. Matsumoto T. Bone matrix decorin binds transforming growth factor-β and enhances its bioactivity.J Biol Chem. 1994; 269: 32634-32638Abstract Full Text PDF PubMed Google Scholar This finding has broad implications on tumorigenicity, as it can advocate tumor immunosuppression and growth retardation.20Schaefer L. Iozzo R.V. Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction.J Biol Chem. 2008; 283: 21305-21309Crossref PubMed Scopus (411) Google Scholar However, it is not known whether decorin influences the assembly of the large latent TGFβ1 complex on collagen fibers. In the case of myostatin, decorin sequestration quenches myostatin growth inhibitory effects and thus promotes myoblastic growth in vitro.21Miura T. Kishioka Y. Wakamatsu J. Hattori A. Hennebry A. Berry C.J. Sharma M. Kambadur R. Nishimura T. Decorin binds myostatin and modulates its activity to muscle cells.Biochem Biophys Res Commun. 2006; 340: 675-680Crossref PubMed Scopus (137) Google Scholar In an analogous antagonistic activity, direct sequestration of platelet-derived growth factor (PDGF) results in a potent decrease of PDGF-dependent phosphorylation of the PDGF receptor and attenuation of PDGF-evoked cellular migration.22Nili N. Cheema A.N. Giordano F.J. Barolet A.W. Babaei S. Hickey R. Eskandarian M.R. Smeets M. Butany J. Pasterkamp G. Strauss B.H. Decorin inhibition of PDGF-stimulated vascular smooth muscle cell function Potential mechanism for inhibition of intimal hyperplasia after balloon angioplasty.Am J Pathol. 2003; 163: 869-878Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Decorin binds to low-density lipoprotein receptor–related protein 1 (LRP-1) and causes endocytosis of the complex, leading to PI3K activation and indirect cross-talk and modulation of TGFβ signaling via Smad 2/3/7.23Cabello-Verrugio C. Brandan E. A novel modulatory mechanism of transforming growth factor-β signaling through decorin and LRP-1.J Biol Chem. 2007; 282: 18842-18850Crossref PubMed Scopus (110) Google Scholar Although the interaction with LRP-1 has not yet been evaluated in cancer models, it could have implications for tumor cell bioenergetics. Another binding partner of decorin is Wnt-1–induced secreted protein 1 (WISP-1), a protein mainly confined to the stroma of colon tumors.24Desnoyers L. Arnott D. Pennica D. WISP-1 binds to decorin and biglycan.J Biol Chem. 2001; 276: 47599-47607Crossref PubMed Scopus (96) Google Scholar Decorin binding to WISP-1 results in an inhibition of WISP-1 interactions with other partners, thus suggesting a regulatory function of decorin in Wnt signaling.24Desnoyers L. Arnott D. Pennica D. WISP-1 binds to decorin and biglycan.J Biol Chem. 2001; 276: 47599-47607Crossref PubMed Scopus (96) Google Scholar It is not known whether WISP-1 activity is further modulated or antagonized in either a Wnt-1–dependent or –independent manner by decorin in colon tumors. Notably, decorin down-regulates β-catenin in a non-canonical way after binding to Met,25Young C.S. Kitamura M. Hardy S. Kitajewski J. Wnt-1 induces growth, cytosolic β-Catenin, and Tcf/Lef transcriptional activation in Rat-1 fibroblasts.Mol Cell Biol. 1998; 18: 2474-2485Crossref PubMed Google Scholar and decorin-null mice have increased β-catenin levels in the intestinal epithelium.26Bi X. Tong C. Dokendorff A. Banroft L. Gallagher L. Guzman-Hartman G. Iozzo R.V. Augenlicht L.H. Yang W. Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation.Carcinogenesis. 2008; 29: 1435-1440Crossref PubMed Scopus (114) Google Scholar In addition to the aforementioned interactions and attenuation of growth factors by direct binding, decorin also binds a multitude of structural components within the extracellular matrix, particularly numerous collagen molecules, tenascin X27Elefteriou F. Exposito J.-Y. Garrone R. Lethias C. Binding of tenascin-X to decorin.FEBS Lett. 2001; 495: 44-47Crossref PubMed Scopus (93) Google Scholar, and elastin28Reinboth B. Hanssen E. Cleary E.G. Gibson M.A. Molecular interactions of biglycan and decorin with elastic fiber components: biglycan forms a ternary complex with tropoelastin and microfibril-associated glycoprotein 1.J Biol Chem. 2002; 277: 3950-3957Crossref PubMed Scopus (140) Google Scholar (Figure 1). Aside from binding fibrillar collagens I, II, and III, decorin also binds saturably to collagen XIV. Thus, decorin may mediate binding to fibril-forming collagens while simultaneously affecting collagen XIV biology. Analyses of the supramolecular composition of collagen VI complexes have determined that decorin and matrilin directly bind to link collagen VI to either aggrecan or collagen type II fibrils.29Wiberg C. Klatt A.R. Wagener R. Paulsson M. Bateman J.F. Heinegård D. Mörgelin M. Complexes of matrilin-1 and biglycan or decorin connect collagen VI microfibrils to both collagen II and aggrecan.J Biol Chem. 2003; 278: 37698-37704Crossref PubMed Scopus (220) Google Scholar Taking these findings together, it seems plausible that decorin can certainly participate in regulating desmoplastic reactions and higher-order matrix structure formation in the tumor stroma. The abundant presence of decorin in the tumor stroma of solid tumors has been proposed to represent a negative-feedback loop on the activity of adjacent RTKs expressed by growing malignant cells.1Iozzo R.V. Sanderson R.D. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.J Cell Mol Med. 2011; 15: 1013-1031Crossref PubMed Scopus (434) Google Scholar The initial finding that decorin bound with avid affinity to RTKs (Figure 1) heralded a paradigm shift in the study of SLRPs and their contributions to cancer biology. EGFR was the first RTK discovered to bind decorin30Iozzo R.V. Moscatello D. McQuillan D.J. Eichstetter I. Decorin is a biological ligand for the epidermal growth factor receptor.J Biol Chem. 1999; 274: 4489-4492Crossref PubMed Scopus (325) Google Scholar and was considered the primary target of decorin in various types of cancer cells,2Goldoni S. Iozzo R.V. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs.Int J Cancer. 2008; 123: 2473-2479Crossref PubMed Scopus (140) Google Scholar as it triggered dimerization, internalization via caveosomes, and ultimately the degradation of the receptor complex within lysosomes,31Zhu J.-X. Goldoni S. Bix G. Owens R.A. McQuillan D. Reed C.C. Iozzo R.V. Decorin evokes protracted internalization and degradation of the EGF receptor via caveolar endocytosis.J Biol Chem. 2005; 280: 32468-32479Crossref PubMed Scopus (174) Google Scholar presumably terminating EGFR signaling. This finding is in contrast to EGF–EGFR complexes that are competent to signal from endosomes after internalization where EGF is still capable of maximally stimulating tyrosine phosphorylation. Furthermore, this stimulation engages several signaling pathways, such as PLC-γ1, that are required for cell motility.32Haugh J.M. Schooler K. Wells A. Wiley H.S. Lauffenburger D.A. Effect of epidermal growth factor receptor internalization on regulation of the phospholipase C-γ1 signaling pathway.J Biol Chem. 1999; 274: 8958-8965Crossref PubMed Scopus (103) Google Scholar However, it is currently unknown whether decorin is proficient to stimulate signaling postinternalization in a fashion analogous to that of EGF. Systemic delivery of decorin, or viral vectors expressing decorin, affects the growth of several types of solid cancers in which RTKs play key roles.33Reed C.C. Gauldie J. Iozzo R.V. Suppression of tumorigenicity by adenovirus-mediated gene transfer of decorin.Oncogene. 2002; 21: 3688-3695Crossref PubMed Scopus (127) Google Scholar, 34Tralhão J.G. Schaefer L. Micegova M. Evaristo C. Schönherr E. Kayal S. Veiga-Fernandes H. Danel C. Iozzo R.V. Kresse H. Lemarchand P. In vivo selective and distant killing of cancer cells using adenovirus-mediated decorin gene transfer.FASEB J. 2003; 17: 464-466PubMed Google Scholar, 35Reed C.C. Waterhouse A. Kirby S. Kay P. Owens R.A. McQuillan D.J. Iozzo R.V. Decorin prevents metastatic spreading of breast cancer.Oncogene. 2005; 24: 1104-1110Crossref PubMed Scopus (182) Google Scholar, 36Goldoni S. Seidler D.G. Heath J. Fassan M. Baffa R. Thakur M.L. Owens R.A. McQuillan D.J. Iozzo R.V. An anti-metastatic role for decorin in breast cancer.Am J Pathol. 2008; 173: 844-855Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Paramount to this feature is the ability of decorin to compete with EGF and to exert a potent physiological down-regulation of the receptor at the cell surface of tumor cells.2Goldoni S. Iozzo R.V. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs.Int J Cancer. 2008; 123: 2473-2479Crossref PubMed Scopus (140) Google Scholar However, in 2009, a new target of decorin was discovered via the use of an RTK phosphotyrosine array, which clearly demonstrated a rapid burst of phosphorylation of Met.37Goldoni S. Humphries A. Nyström A. Sattar S. Owens R.T. McQuillan D.J. Ireton K. Iozzo R.V. Decorin is a novel antagonistic ligand of the Met receptor.J Cell Biol. 2009; 185: 743-754Crossref PubMed Scopus (197) Google Scholar It was further shown that Met is the main target of decorin in HeLa cells, as inhibition of the kinase domain of EGFR with the small molecule inhibitor AG1478 or with the monoclonal blocking antibody mAb425 did not block the down-regulation of Met evoked by decorin. Moreover, Met exhibits a higher binding affinity for decorin when compared with that of EGFR.37Goldoni S. Humphries A. Nyström A. Sattar S. Owens R.T. McQuillan D.J. Ireton K. Iozzo R.V. Decorin is a novel antagonistic ligand of the Met receptor.J Cell Biol. 2009; 185: 743-754Crossref PubMed Scopus (197) Google Scholar It is a curious biological feature of decorin to evoke differential phosphorylation signatures in EGFR and Met on binding. This observation might reflect altered structural conformations of the receptors postbinding relative to the active conformation that the receptor adopts after binding natural ligands. EGFR, for example, undergoes rapid phosphorylation to stimulate the MAPK signaling cascade, which paradoxically aids in cell cycle arrest and caspase-3 activation38Seidler D.G. Goldoni S. Agnew C. Cardi C. Thakur M.L. Owens R.A. McQuillan D.J. Iozzo R.V. Decorin protein core inhibits in vivo cancer growth and metabolism by hindering epidermal growth factor receptor function and triggering apoptosis via caspase-3 activation.J Biol Chem. 2006; 281: 26408-26418Crossref PubMed Scopus (153) Google Scholar despite total EGFR levels decreasing up to 50%.2Goldoni S. Iozzo R.V. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs.Int J Cancer. 2008; 123: 2473-2479Crossref PubMed Scopus (140) Google Scholar Further proof-of-concept for this phenomenon involves Met. A rapid burst of phosphorylation of the tyrosine residues of the intracellular tail of Met ensues and lasts up to 30 minutes, whereas increased phospho-Y1003 recruits the E3 ubiquitin ligase c-Cbl for receptor internalization and degradation.37Goldoni S. Humphries A. Nyström A. Sattar S. Owens R.T. McQuillan D.J. Ireton K. Iozzo R.V. Decorin is a novel antagonistic ligand of the Met receptor.J Cell Biol. 2009; 185: 743-754Crossref PubMed Scopus (197) Google Scholar It is possible that these signatures, particularly that of Met, has biological significance to convey the properties of decorin bioactivity. However, at this time, experimental evidence to evaluate these differential phosphorylation patterns is lacking but would be essential to gain a more mechanistic understanding of the biology of decorin. This is of critical importance, considering the lack of endogenous ligands for Met, which, at present, include only hepatocyte growth factor (HGF), internalin B, and decorin.37Goldoni S. Humphries A. Nyström A. Sattar S. Owens R.T. McQuillan D.J. Ireton K. Iozzo R.V. Decorin is a novel antagonistic ligand of the Met receptor.J Cell Biol. 2009; 185: 743-754Crossref PubMed Scopus (197) Google Scholar, 39Niemann H.H. Structural insights into Met receptor activation.Eur J Cell Biol. 2011; 90: 972-981Crossref PubMed Scopus (27) Google Scholar Along these same lines, engagement of HGF with Met induces association of the receptor complex with clathrin-coated pits40Buraschi S. Pal N. Tyler-Rubinstein N. Owens R.T. Neill T. Iozzo R.V. Decorin antagonizes Met receptor activity and downregulates β-catenin and Myc levels.J Biol Chem. 2010; 285: 42075-42085Crossref PubMed Scopus (110) Google Scholar in HeLa cells for endosomal sorting and eventual recycling to the plasma membrane. However, this is not the case for decorin, as it drives caveolin-1 to associate with Met40Buraschi S. Pal N. Tyler-Rubinstein N. Owens R.T. Neill T. Iozzo R.V. Decorin antagonizes Met receptor activity and downregulates β-catenin and Myc levels.J Biol Chem. 2010; 285: 42075-42085Crossref PubMed Scopus (110) Google Scholar and concomitant lysosomal degradation in the same fashion as EGFR. Clearly, the differential phosphorylation patterns are encoding messages pertinent for decorin activity to selectively dictate finite biological outcomes. Additional members of the Erb family of RTKs are also affected by decorin via degradation and signal suppression, including ErbB2 and ErbB4, presumably via titration of EGFR away from functional signaling complexes composed of ErbB2 or ErbB4 heterodimers. However, new findings indicate a direct antagonism of ErbB4 signaling by decorin.41Minor K.H. Bournat J.C. Toscano N. Giger R.J. Davies S.J.A. Decorin, erythroblastic leukaemia viral oncogene homologue B4 and signal transducer and activator of transcription 3 regulation of semaphorin 3A in central nervous system scar tissue.Brain. 2011; 134: 1140-1155Crossref PubMed Scopus (31) Google Scholar During scar tissue repair in the central nervous system, employment of small molecule inhibitors and siRNAs specific for ErbB4 also blocks the decorin-mediated down-regulation of semaphorin 3A, a target of ErbB4 activity.41Minor K.H. Bournat J.C. Toscano N. Giger R.J. Davies S.J.A. Decorin, erythroblastic leukaemia viral oncogene homologue B4 and signal transducer and activator of transcription 3 regulation of semaphorin 3A in central nervous system scar tissue.Brain. 2011; 134: 1140-1155Crossref PubMed Scopus (31) Google Scholar Opposing roles of decorin in the signaling cascades of endothelial cells have also been documented. Because decorin binds collagen with nanomolar affinity, it has been reported that an interaction among α2β1 integrin, collagen type I, and decorin increases endothelial cell migration by enhancing integrin–collagen interactions.42Fiedler L.R. Schönherr E. Waddington R. Niland S. Seidler D.G. Aeschlimann D. Eble J.A. Decorin regulates endothelial cell motility on collagen I through activation of insulin-like growth factor I receptor and modulation of α2β1 integrin activity.J Biol Chem. 2008; 283: 17406-17415Crossref PubMed Scopus (90) Google Scholar However, VEGF-R2 has been reported to be antagonized by decorin and, more specifically, by an engineered fragment encoding LRR5 via downstream attenuation of ERK1/2 signaling in human extravillous trophoblastic (EVT) cells.43Khan G.A. Girish G.V. Lala N. DiGuglielmo G.M. Lala P.K. Decorin is a novel VEGFR-2-binding antagonist for the human extravillous trophoblast.Mol Endocrinol. 2011; 25: 1431-1443Crossref PubMed Scopus (108) Google Scholar A recurring theme concerning this form of receptor antagonism is the concept of receptor internalization and degradat
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