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.
Goldoni
Silvia
S
Department of Pathology, Anatomy, and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Humphries
Ashley
A
Nyström
Alexander
A
Sattar
Sampurna
S
Owens
Rick T
RT
McQuillan
David J
DJ
Ireton
Keith
K
Iozzo
Renato V
RV
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