Decorin is a novel antagonistic ligand of the Met receptor.
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 (K(d) = approximately 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 = approximately 6 min). Decorin suppresses intracellular levels of beta-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.
Department of Pathology, Anatomy, and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Silvia
S
Goldoni
Ashley
A
Humphries
Alexander
A
Nyström
Sampurna
S
Sattar
Rick T
RT
Owens
David J
DJ
McQuillan
Keith
K
Ireton
Renato V
RV
Iozzo
D001667:Binding, Competitive; D049109:Cell Proliferation; D058575:Decorin; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology; D011485:Protein Binding; D011509:Proteoglycans / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000032:analysis
C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; D008024:Ligands; D011509:Proteoglycans; D051176:beta Catenin; D050721:Proto-Oncogene Proteins c-cbl; D019859:Proto-Oncogene Proteins c-met