Steven Hanks
Last active: 1/20/2015

The integrin-coupled signaling adaptor p130Cas suppresses Smad3 function in transforming growth factor-beta signaling.

Kim W, Seok Kang Y, Soo Kim J, Shin NY, Hanks SK, Song WK
Mol Biol Cell. 2008 19 (5): 2135-46

PMID: 18321991 · PMCID: PMC2366878 · DOI:10.1091/mbc.e07-10-0991

Reciprocal cooperative signaling by integrins and growth factor receptors at G1 phase during cell cycle progression is well documented. By contrast, little is known about the cross-talk between integrin and transforming growth factor (TGF)-beta signaling. Here, we show that integrin signaling counteracts the inhibitory effects of TGF-beta on cell growth and that this effect is mediated by p130Cas (Crk-associated substrate, 130 kDa). Adhesion to fibronectin or laminin reduces TGF-beta-induced Smad3 phosphorylation and thus inhibits TGF-beta-mediated growth arrest; loss of p130Cas abrogates these effects. Loss and gain of function studies demonstrated that, once tyrosine-phosphorylated via integrin signaling, p130Cas binds to Smad3 and reduces phosphorylation of Smad3. That in turn leads to inhibition of p15 and p21 expression and facilitation of cell cycle progression. Thus, p130Cas-mediated control of TGF-beta/Smad signaling may provide an additional clue to the mechanism underlying resistance to TGF-beta-induced growth inhibition.

MeSH Terms (19)

Animals Cell Cycle Cell Nucleus Cell Proliferation Cells, Cultured Crk-Associated Substrate Protein Extracellular Matrix Humans Integrins Mice Phosphorylation Phosphotyrosine Protein Binding Protein Transport Receptors, Transforming Growth Factor beta Signal Transduction Smad3 Protein Transcription, Genetic Transforming Growth Factor beta

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