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J. Biol. Chem., Vol. 281, Issue 51, 39455-39464, December 22, 2006

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Paxillin Regulates Steroid-triggered Meiotic Resumption in Oocytes by Enhancing an All-or-None Positive Feedback Kinase Loop^*

Melissa Rasar¹, Donald B. DeFranco², and Stephen R. Hammes, A W. W. Caruth, Junior Endowed Scholar in Biomedical Research³

From the Department of Internal Medicine, Division of Endocrinology and Metabolism, Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8857 and the Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Oocyte maturation is triggered by steroids in a transcription-independent fashion that involves an unusual positive feedback loop whereby MOS (a germ cell-specific Raf) activates MEK1, which in turn activates ERK2. ERK2 then acts back on MOS to enhance its expression and amplify the kinase signaling cascade. To date, little is known regarding other factors that regulate this powerful positive feedback kinase cascade. Here we present the scaffold molecule Paxillin as a newly recognized essential regulator of meiosis in Xenopus laevis oocytes. Reduction of Paxillin expression using RNA interference or antisense oligonucleotides completely abrogates steroid-triggered meiotic resumption. Detailed signaling studies reveal that Paxillin is acting early in the kinase cascade, because it is required for accumulation of MOS protein and complete activation of downstream kinase signaling in response to steroids. Surprisingly, full Paxillin activity also requires serine phosphorylation by a kinase downstream of MOS and MEK1, possibly ERK2. Together, these data suggest that Paxillin is an important regulator of the positive feedback effects of MEK/ERK signaling on MOS protein expression. These experiments reveal a novel and critical function for Paxillin in meiosis and support the notion that Paxillin may be a general modulator of mitogen-activated protein kinase signaling.

Received for publication, September 20, 2006 , and in revised form, October 18, 2006.

^* This work was supported in part by National Institutes of Health (NIH) Grant DK59913 and the Welch Foundation (Grant I-1506). 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 Part of the University of Texas Southwestern Medical Scientist Training Program.

² Supported by NIH Grant CA43037.

³ To whom correspondence should be addressed: Division of Endocrinology, Dept. of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8857. Tel.: 214-648-3749; Fax: 214-648-7934; E-mail: stephen.hammes{at}utsouthwestern.edu.

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