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J. Biol. Chem., Vol. 283, Issue 10, 6312-6320, March 7, 2008

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Ahnak Protein Activates Protein Kinase C (PKC) through Dissociation of the PKC-Protein Phosphatase 2A Complex^*

In Hye Lee¹², Hee Jung Lim¹², Suhyeon Yoon², Je Kyung Seong, Duk Soo Bae^¶, Sue Goo Rhee, and Yun Soo Bae³

From the Department of Life Science, Ewha Womans University, Seoul 120-750, Korea, the College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea, and the ^¶Department of Obstetrics and Gynecology, Samsung Medical Center, SungKyunKwan University, Seoul 135-710, Korea

We have previously reported that central repeated units (CRUs) of Ahnak act as a scaffolding protein networking phospholipase C and protein kinase C (PKC). Here, we demonstrate that an Ahnak derivative consisting of four central repeated units binds and activates PKC- in a phosphatidylserine/1,2-dioleoyl-sn-glycerol-independent manner. Moreover, NIH3T3 cells expressing the 4 CRUs of Ahnak showed enhanced c-Raf, MEK, and Erk phosphorylation in response to phorbol 12-myristate 13-acetate (PMA) compared with parental cells. To evaluate the effect of loss-of-function of Ahnak in cell signaling, we investigated PKC activation and Raf phosphorylation in embryonic fibroblast cells (MEFs) of the Ahnak knock-out (Ahnak^-/-) mouse. Membrane translocation of PKC- and phosphorylation of Raf in response to PMA or platelet-derived growth factor were decreased in Ahnak null MEF cells compared with wild type MEFs. Several lines of evidence suggest that PKC- activity is regulated through association with protein phosphatase 2A (PP2A). A co-immunoprecipitation assay indicated that the association of PKC- with PP2A was disrupted in NIH3T3 cells expressing 4 CRUs of Ahnak in response to PMA. Consistently, Ahnak null MEF cells stimulated by PMA showed enhanced PKC-PP2A complex formation, and add-back expression of Ahnak into Ahnak null MEF cells abolished the PKC-PP2A complex formation in response to PMA. These data indicate that Ahnak potentiates PKC activation through inhibiting the interaction of PKC with PP2A.

Received for publication, August 17, 2007 , and in revised form, December 17, 2007.

^* This work was supported in part by the National Core Research Center program of the Ministry of Science and Technology/Korea Science and Engineering Foundation (Grant R15-2006-020-00000-0) through the Center for Cell Signaling and Drug Discovery Research at Ewha Womans University, Basic Research Program of the Korea Science and Engineering Foundation Grant RO1-2005-000-10480-0 (to Y. S. B.), and 21C Frontier Functional Proteomics Projects Grant FPR0502-470 (to S. G. R.). 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 Both authors contributed equally to this work.

² Recipients of BK21 scholarships.

³ To whom correspondence should be addressed: Dept. of Life Science, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul 120-750, Korea. Tel.: 82-2-3277-2729; Fax: 82-2-3277-3760; E-mail: baeys{at}ewha.ac.kr.

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