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J. Biol. Chem., Vol. 278, Issue 23, 21168-21177, June 6, 2003

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Eicosanoid Activation of Protein Kinase C

INVOLVEMENT IN GROWTH CONE REPELLENT SIGNALING^*

Keith Mikule , Somkiat Sunpaweravong , Jesse C. Gatlin and Karl H. Pfenninger ¶

From the Department of Cellular and Structural Biology and University of Colorado Cancer Center, University of Colorado School of Medicine, Denver, Colorado 80262

Exposure of growing neurons to thrombin or semaphorin 3A stimulates a receptor-mediated signaling cascade that results in collapse of their growth cones. This collapse response necessitates eicosanoid production, as we have shown earlier. The present report investigates whether and which protein kinase C (PKC) isoforms may be activated by such eicosanoids. To examine these questions, we isolated growth cones from fetal rat brain and tested whether thrombin or the eicosanoid, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), could activate endogenous growth cone PKC. We show that both thrombin and 12(S)-HETE stimulate the phosphorylation of the myristoylated alanine-rich protein kinase C substrate, an 87-kDa adhesion site protein. Furthermore, we show both with immunoprecipitated and with recombinant PKC that 12(S)-HETE activation is selective for the isoform and does not require accessory proteins. Last, we demonstrate that PKC activation is necessary for thrombin-induced growth cone collapse. These data indicate that eicosanoid-mediated repellent effects result from the direct and selective activation of PKC and suggest the involvement of myristoylated alanine-rich protein kinase C substrate phosphorylation in growth cone collapse.

Received for publication, November 20, 2002 , and in revised form, March 26, 2003.

^* This work was supported by National Institutes of Health Grants 1R01 NS41029 and 5F31 NS44705. 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.

Present address: Dept. of Molecular Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605.

Guest investigator from the Faculty of Medicine, Prince of Songkla University, Thailand.

^¶ To whom correspondence should be addressed: Dept. of Cellular and Structural Biology and University of Colorado Cancer Center, University of Colorado School of Medicine, 4200 East 9th Ave., Denver, CO 80262. Tel.: 303-315-4704; Fax: 303-315-4729; E-mail: karl.pfenninger{at}uchsc.edu.

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