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MBC in Press, published online ahead of print March 19, 2008
Mol. Biol. Cell 10.1091/mbc.E07-10-0991

A more recent version of this article appeared on May 1, 2008 Originally published as MBC in Press, 10.1091/mbc.E07-10-0991 on March 5, 2008
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Submitted on October 2, 2007
Revised on February 14, 2008
Accepted on February 27, 2008

The Integrin-coupled Signaling Adaptor p130Cas Suppresses Smad3 Function in TGF-{beta} Signaling

Wook Kim,*{dagger}{ddagger} Yong Seok Kang,*{dagger} Jin Soo Kim,* Nah-Young Shin,{sect} Steven K. Hanks,|| and Woo Keun Song*

*Department of Life Science, Center for Distributed Sensor Network and Molecular Disease Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea; {sect}Department of Orthopaedics, Yale University School of Medicine, New Haven, CT 06510; ||Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232

Monitoring Editor: Richard Assoian

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 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 completely 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.

{dagger}These authors contributed equally to this work.

{ddagger}Present address: Diabetes Section, National Institute on Aging/NIH, Baltimore, MD 21224.

Address correspondence to: Woo Keun Song (wksong{at}gist.ac.kr)






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