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J. Cell Biol. 185 (4): 743-754

Copyright © 2009 by the Rockefeller University Press.

Article

Decorin is a novel antagonistic ligand of the Met receptor

Silvia Goldoni1,2, Ashley Humphries1,2, Alexander Nyström1,2, Sampurna Sattar1,2, Rick T. Owens3, David J. McQuillan3, Keith Ireton4, , and Renato V. Iozzo1,2

1 Department of Pathology, Anatomy, and Cell Biology and 2 Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
3 LifeCell Corporation, Branchburg, NJ 08876
4 Department of Molecular Biology and Microbiology, College of Medicine, Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32826

Correspondence to Renato V. Iozzo: iozzo{at}mail.jci.tju.edu

Abstract: 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 (half-life = ~6 min). Decorin suppresses intracellular levels of β-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.

Abbreviations used in this paper: EGFR, EGF receptor; HGF, hepatocyte growth factor; IC, inhibitory concentration; PARP, poly ADP-ribose polymerase; RTK, receptor tyrosine kinase.

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