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J. Biol. Chem., Vol. 283, Issue 18, 12446-12455, May 2, 2008

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Protein Kinase C-dependent LKB1 Serine 428 Phosphorylation Increases LKB1 Nucleus Export and Apoptosis in Endothelial Cells^*

From the Section of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, 73104

LKB1 is a serine-threonine protein kinase that, when inhibited, may result in unregulated cell growth and tumor formation. However, how LKB1 is regulated remains poorly understood. The aim of the present study was to define the upstream signaling events responsible for peroxynitrite (ONOO^-)-induced LKB1 activation. Exposure of cultured human umbilical vein endothelial cells to a low concentration of ONOO^- (5 µM) significantly increased the phosphorylation of LKB1 at Ser⁴²⁸ and protein kinase C (PKC) at Thr⁴¹⁰. These effects were accompanied by increased activity of the lipid phosphatase PTEN, decreased activity and phosphorylation (Ser⁴⁷³) of Akt, and induction of apoptosis. ONOO^- enhanced Akt-Ser⁴⁷³ phosphorylation in LKB1-deficient HeLa S3 cells or in HeLa S3 cells transfected with kinase-dead LKB1. Conversely, ONOO^- inhibited Akt Ser⁴⁷³ phosphorylation when wild type LKB1 were reintroduced in HeLa S3 cells. Further analysis revealed that PKC directly phosphorylated LKB1 at Ser⁴²⁸ in vitro and in intact cells, resulting in increased PTEN phosphorylation at Ser³⁸⁰/Thr^382/383. Finally, ONOO^- enhanced PKC nuclear import and LKB1 nuclear export. We conclude that PKC mediates LKB1-dependent Akt inhibition in response to ONOO^-, resulting in endothelial apoptosis.

Received for publication, October 3, 2007 , and in revised form, March 4, 2008.

^* This work was supported by National Institutes of Health Grants HL079584, HL074399, HL080499, and HL089920, a research award from the American Diabetes Association, a research award from the Juvenile Diabetes Research Foundation, a grant from Oklahoma Center for Advancement of Science and Technology, and funds of the Travis Endowed Chair in Endocrinology, University of Oklahoma Health Sciences Center. 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: BSEB 325, Section of Endocrinology and Diabetes, Dept. of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104. Tel.: 405-271-3974; Fax: 405-271-3973; E-mail: ming-hui-zou{at}ouhsc.edu.

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