Decorin is a novel antagonistic ligand of the Met receptor |
| |
Authors: | Silvia Goldoni Ashley Humphries Alexander Nystr?m Sampurna Sattar Rick T Owens David J McQuillan Keith Ireton Renato V Iozzo |
| |
Institution: | 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 |
| |
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. |
| |
Keywords: | |
|
|