TY - JOUR
T1 - Decorin is a novel antagonistic ligand of the Met receptor
AU - Goldoni, Silvia
AU - Humphries, Ashley
AU - Nyström, Alexander
AU - Sattar, Sampurna
AU - Owens, Rick T.
AU - McQuillan, David J.
AU - Ireton, Keith
AU - Iozzo, Renato V.
PY - 2009/5/18
Y1 - 2009/5/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=66149095761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66149095761&partnerID=8YFLogxK
U2 - 10.1083/jcb.200901129
DO - 10.1083/jcb.200901129
M3 - Article
C2 - 19433454
AN - SCOPUS:66149095761
SN - 0021-9525
VL - 185
SP - 743
EP - 754
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 4
ER -