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J. Biol. Chem., Vol. 280, Issue 27, 25717-25728, July 8, 2005

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An Alliance between Ras GTPase-activating Protein, Filamin C, and Ras GTPase-activating Protein SH3 Domain-binding Protein Regulates Myocyte Growth^*

Jacqueline Lypowy, Ieng-Yi Chen, and Maha Abdellatif

From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

We have previously reported that Ras GTPase-activating protein (RasGAP) is involved in a pathway that regulates total cellular mRNA and protein synthesis in cardiac myocytes. A yeast two-hybrid screen resulted in identification of filamin C (FLN-C) as one of its targets. Knockdown of RasGAP or FLN-C, or severing their interaction, resulted in down-regulation of the RNA polymerase II kinase, cyclin-dependent kinase 7 (Cdk7). This appeared to be provoked by the release of cdk7 mRNA from RasGAP SH3 domain-binding protein, G3BP, and its subsequent degradation. In parallel, myocyte growth was also inhibited. On the other hand, overexpression of RasGAP induced a Cdk7- and FLN-C-dependent growth. Thus, we propose that the physical interaction between RasGAP and FLN-C facilitates an interaction between G3BP and cdk7 mRNA. This results in stabilization of cdk7 mRNA, an increase in its protein, which is required for cell growth.

Received for publication, December 20, 2004 , and in revised form, April 25, 2005.

^* This study was supported by National Institutes of Health Grant 2R01-HL057970-06. 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Cardiovascular Research Institute, Dept. of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103. Tel.: 973-972-1254; Fax: 973-972-7489; E-mail: abdellma{at}umdnj.edu.

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