JCB_200901129 743..754

The extracellular matrix and its multiple constituents play both a structural and signaling role by interacting with surface receptors that ultimately affect gene expression, cell phenotypes, development, and cancer (Ramirez and Rifkin, 2003; Weigelt and Bissell, 2008). Decorin, a member of the small leucine-rich proteoglycan gene family that harbors one chondroitin/dermatan sulfate side chain at its N terminus, was originally named because of its ability to “decorate” collagen fibrils, thereby regulating fibrillogenesis, a key mechanism of matrix assembly and homeostasis (Schaefer and Iozzo, 2008). It was soon discovered that decorin regulates the TGF- signaling pathway and also inhibits the growth of a variety of tumor cells (Iozzo, 1998) by down-regulating the EGF receptor (EGFR; Iozzo et al., 1999b) and other members of the ErbB family of receptor tyrosine kinase (RTK; Goldoni and Iozzo, 2008). Decorin suppresses tumor cell–mediated angiogenesis by inhibiting the endogenous production of vascular endothelial cell growth factor (Grant et al., 2002) similar to neutralizing antibodies directed toward EGFR (Petit et al., 1997). Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation (Bi et al., 2008), whereas mice with a double deficiency of decorin and p53 succumb prematurely to aggressive lymphomas (Iozzo et al., 1999b). Together, these observations indicate that lack of decorin is permissive for in vivo tumorigenesis. Ectopic expression of decorin induced by stable transgenic systems, viral vectors, or inducible promoters attenuates the growth of tumor xenografts with diverse histogenetic origin (Santra et al., 1995, 2000; Csordás et al., 2000; Reed et al., 2002, 2005; Tralhão et al., 2003; Biglari et al., 2004; Seidler et al., 2006). Decorin slows the growth of squamous cell and breast carcinomas by inducing a sustained down-regulation of the EGFR (Csordás et al., 2000) and ErbB2 (Santra et al., 2000), a process that leads to a p21-mediated growth suppression and enhanced cytodifferentiation of mammary carcinoma cells (Santra et al., 2000). The basic mechanism has been partially elucidated and includes direct binding to the EGFR followed by protracted internalization of the receptor via caveolar-mediated endocytosis (Zhu et al., 2005) and the triggering of apoptosis Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that decorin binds directly and with high affinity (Kd = 1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (halflife = 6 min). Decorin suppresses intracellular levels of -catenin, a known downstream Met effector, and inhibits Met-mediated cell migration and growth. Thus, by antagonistically targeting multiple tyrosine kinase receptors, decorin contributes to reduction in primary tumor growth and metastastic spreading. Decorin is a novel antagonistic ligand of the Met receptor