Editors' ChoiceCancer

Inhibiting Met

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Science Signaling  26 May 2009:
Vol. 2, Issue 72, pp. ec173
DOI: 10.1126/scisignal.272ec173

The small leucine-rich proteoglycan decorin inhibits tumor growth by binding to the epidermal growth factor receptor (EGFR) and thereby promoting its internalization and degradation. Noting that decorin can bind numerous other partners, Goldoni et al. investigated the possibility that its anti-oncogenic effects involved interactions with receptor tyrosine kinases (RTKs) other than EGFR and related ErbB receptors. Using an antibody array system to assess tyrosine phosphorylation of 42 RTKs, they found that addition of decorin affected phosphorylation of the hepatocyte growth factor (HGF) receptor Met (a receptor implicated in invasive growth) in a serum-dependent manner that resembled its effects on EGFR. In HeLa cells grown in the presence of serum, decorin inhibited Met phosphorylation as well as that of EGFR and other ErbB family receptors; in serum-starved cells, decorin stimulated the transient phosphorylation of two tyrosines in the Met catalytic domain and elicited a rapid decrease in steady-state Met abundance, effects that were independent of EGFR’s catalytic activity. Decorin also stimulated phosphorylation of a tyrosine residue associated with recruitment of the E3 ubiquitin ligase c-Cbl, but not that of a tyrosine associated with downstream signaling. Decorin bound Met (from which it could be displaced by HGF and less efficiently displaced by a bacterial Met ligand) saturably and with high affinity. Decorin both promoted tissue inhibitor of metalloproteinase (TIMP)–2– and TIMP-3–sensitive shedding of the Met ectodomain and stimulated Met internalization. Decorin treatment decreased the abundance of β-catenin (which has been implicated in mediating HGF- and Met-dependent facilitation of cell invasion); pharmacological analysis suggested that this depended on Met activity and on the proteasome but was independent of the canonical Wnt signaling pathway. Moreover, decorin inhibited cell migration in a scratch assay, through a mechanism that appeared to involve inhibition of both Met and EGFR signaling. Thus, the authors conclude that decorin represents an endogenous antagonist of Met receptor signaling as well as that of EGFR and that its anti-oncogenic effects depend on interactions with multiple receptor tyrosine kinases.

S. Goldoni, A. Humphries, A. Nyström, S. Sattar, R. T. Owens, D. J. McQuillan, K. Ireton, R. V. Iozzo, Decorin is a novel antagonistic ligand of the Met receptor. J. Cell Biol. 185, 743–754 (2009). [Abstract] [Full Text]

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