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Vol. 19, Issue 5, 2135-2146, May 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E07-10-0991v1 E07-10-0991v2 19/5/2135    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kim, W. Articles by Song, W. K. PubMed PubMed Citation Articles by Kim, W. Articles by Song, W. K.

The Integrin-coupled Signaling Adaptor p130Cas Suppresses Smad3 Function in Transforming Growth Factor-β Signaling

Wook Kim^*,,, Yong Seok Kang^*,, Jin Soo Kim^*, Nah-Young Shin, Steven K. Hanks^||, and Woo Keun Song^*

*Cell Dynamics Research Center and Bioimaging Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea; Department of Orthopaedics, Yale University School of Medicine, New Haven, CT 06510; and ^||Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232

Submitted October 2, 2007; Revised February 14, 2008; Accepted February 27, 2008
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 transforming growth factor (TGF)-β signaling. Here, we show that integrin signaling counteracts the inhibitory effects of TGF-β on cell growth and that this effect is mediated by p130Cas (Crk-associated substrate, 130 kDa). Adhesion to fibronectin or laminin reduces TGF-β–induced Smad3 phosphorylation and thus inhibits TGF-β–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-β/Smad signaling may provide an additional clue to the mechanism underlying resistance to TGF-β–induced growth inhibition.

These authors contributed equally to this work.

Present address: Diabetes Section, National Institute on Aging/National Institutes of Health, Baltimore, MD 21224.

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

Abbreviations used: Ab, antibody; FN, fibronectin; FxxP, phenylalanine-Xaa-Xaa-proline; HLH, helix-loop-helix; LN, laminin; mAb, monoclonal antibody; MEF, mouse embryonic fibroblast; p130Cas, Crk-associated substrate, 130 kDa; PLL, poly-L-lysine; S3A, S⁴⁶⁴SVS⁴⁶⁷-A⁴⁶⁴AVA⁴⁶⁷ mutation; S3D, S⁴⁶⁴SVS⁴⁶⁷-D⁴⁶⁴DVD⁴⁶⁷ mutation; SD, substrate domain; TGF, transforming growth factor; TβRI, transforming growth factor-β type I receptor; TβRII, transforming growth factor-βtype II receptor; YxxP, tyrosine-Xaa-Xaa-proline.