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J. Biol. Chem., Vol. 282, Issue 5, 2929-2936, February 2, 2007

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Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins^*

Pavel Krejci¹, Bernard Masri, Lisa Salazar^¶, Claire Farrington-Rock, Herve Prats, Leslie Michels Thompson^¶, and William R. Wilcox^||

From the Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, the INSERM U589, Institut Louis Bugnard, 31403 Toulouse, France, the ^¶Department of Psychiatry, University of California, Irvine, California 92697, and the ^||Department of Pediatrics, UCLA School of Medicine, Los Angeles, California 90095

Fibroblast growth factors (FGFs) inhibit chondrocyte proliferation via the Erk MAP kinase pathway. Here, we explored the role of protein kinase C in FGF signaling in chondrocytes. Erk activity in FGF2-treated RCS (rat chondrosarcoma) chondrocytes or human primary chondrocytes was abolished by the protein kinase C inhibitor bisindolylmaleimide I (Bis I). Bis I inhibited FGF2-induced activation of MEK, Raf-1, and Ras members of Erk signaling module but not the FGF2-induced tyrosine phosphorylation of Frs2 or the kinase activity of FGFR3, demonstrating that it targets the Erk cascade immediately upstream of Ras. Indeed, Bis I abolished the FGF2-mediated association of Shp2 tyrosine phosphatase with Frs2 and Gab1 adaptor proteins necessary for proper Ras activation. We also determined which PKC isoform is involved in FGF2-mediated activation of Erk. When both conventional and novel PKCs expressed by RCS chondrocytes (PKC, -, -, and -) were down-regulated by phorbol ester, cells remained responsive to FGF2 with Erk activation, and this activation was sensitive to Bis I. Moreover, treatment with PKC/ pseudosubstrate lead to significant reduction of FGF2-mediated activation of Erk, suggesting involvement of an atypical PKC.

Received for publication, June 27, 2006 , and in revised form, November 7, 2006.

^* This work was supported by the Yang Sheng Tang USA Co. and by National Institutes of Health Grant 5P01-HD22657. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., SSB-3, Los Angeles, CA 90048. Tel.: 310-423-4971; Fax: 310-423-0620; E-mail: pavel.krejci{at}cshs.org.

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