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J. Biol. Chem., Vol. 280, Issue 31, 28402-28411, August 5, 2005

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Phospholipase C-Erk Axis in Vascular Endothelial Growth Factor-induced Eukaryotic Initiation Factor 4E Phosphorylation and Protein Synthesis in Renal Epithelial Cells^*

Meenalakshmi M. Mariappan, Duraisamy Senthil, Kavithalakshmi S. Natarajan, Goutam Ghosh Choudhury¶, and Balakuntalam S. Kasinath||

From the O'Brien Kidney Research Center, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Healthcare System, Geriatric Research, Education, and, Clinical Center, San Antonio, Texas 78229

Vascular endothelial growth factor (VEGF) increases protein synthesis and induces hypertrophy in renal tubular epithelial cells (Senthil, D., Choudhury, G. G., McLaurin, C., and Kasinath, B. S. (2003) Kidney Int. 64, 468–479). We examined the role of Erk1/2 MAP kinase in protein synthesis induced by VEGF. VEGF stimulated Erk phosphorylation that was required for induction of protein synthesis. VEGF-induced Erk activation was not dependent on phosphoinositide (PI) 3-kinase activation but required sequential phosphorylation of type 2 VEGF receptor, PLC and c-Src, as demonstrated by inhibitors SU1498, U73122, and PP1, respectively. c-Src phosphorylation was inhibited by U73122, indicating it was downstream of phospholipase (PL)C. Studies with PP1/2 showed that phosphorylation of c-Src was required for tyrosine phosphorylation of Raf-1, an upstream regulator of Erk. VEGF also stimulated phosphorylation of Pyk-2; VEGF-induced phosphorylation of Pyk2, c-Src and Raf-1 could be abolished by BAPTA/AM, demonstrating requirement for induction of intracellular calcium currents. We examined the downstream events following the phosphorylation of Erk. VEGF stimulated phosphorylation of Mnk1 and eIF4E and induced Mnk1 to shift from the cytoplasm to the nucleus upon phosphorylation. VEGF-induced phosphorylation of Mnk1 and eIF4E required phosphorylation of PLC, c-Src, and Erk. Expression of dominant negative Mnk1 abrogated eIF4E phosphorylation and protein synthesis induced by VEGF. VEGF-stimulated protein synthesis could be blocked by inhibition of PLC by a chemical inhibitor or expression of a dominant negative construct. Our data demonstrate that VEGF-stimulated protein synthesis is Erk-dependent and requires the activation of VEGF receptor 2, PLC, c-Src, Raf, and Erk pathway. VEGF also stimulates Erk-dependent phosphorylation of Mnk1 and eIF4E, crucial events in the initiation phase of protein translation.

Received for publication, May 3, 2005

^* This work was supported by Grants P50-DK 061597 (to B. S. K.), DK 55815, and DK 50190 (to G. G. C.) from the National Institutes of Health, grants from American Diabetes Association (to B. S. K.), Veterans Administration (to B. S. K. and G. G. C.), the Juvenile Diabetes Research Foundation (to G. G. C.), and the National Kidney Foundation of South and Central Texas (to M. M. M.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

^¶ A recipient of the Veterans Administration Career Scientist Award.

^|| To whom correspondence should be addressed: Dept. of Medicine, Mail Code 7882, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229. Tel.: 210-567-4707; Fax: 210-567-4712; E-mail: Kasinath{at}uthscsa.edu.

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