Abstract
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, PLCgamma 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)Cgamma. 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 PLCgamma, 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 PLCgamma 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, PLCgamma, 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.
Highlights
Vascular endothelial growth factor (VEGF) increases protein synthesis and induces hypertrophy in renal tubular epithelial cells
VEGF-induced Protein Synthesis Is Erk1/2 MAP kinase (Erk)-dependent in MCT Cells—We investigated whether VEGF induced Erk phosphorylation and whether VEGF-induced protein synthesis was Erk-dependent because Erk occupies a central position in transducing signals from the extracellular milieu to the nucleus
In this report we demonstrated that VEGF augments protein synthesis in an Erk phosphorylation-dependent manner
Summary
Vol 280, No 31, Issue of August 5, pp. 28402–28411, 2005 Printed in U.S.A. Phospholipase C␥-Erk Axis in Vascular Endothelial Growth Factor-induced Eukaryotic Initiation Factor 4E Phosphorylation and Protein Synthesis in Renal Epithelial Cells*□S. Vascular endothelial growth factor (VEGF) increases protein synthesis and induces hypertrophy in renal tubular epithelial cells VEGF stimulates Erk-dependent phosphorylation of Mnk and eIF4E, crucial events in the initiation phase of protein translation. Our recent observations have shown that VEGF increases protein synthesis and induces hypertrophy in renal proximal tubular epithelial (MCT) cells, suggesting a role for VEGF in non-angiogenic processes in non-endothelial cells [7]. We have shown that VEGF stimulation of protein synthesis and hypertrophy in MCT cells recruit PI 3-kinase-Akt axis to induce phosphorylation of 4E-BP1 [7]. Increase in Erk phosphorylation in the renal cortex of mice with type 2 diabetes occurs simultaneously with the onset of kidney hypertrophy that mostly involves renal tubular epithelial cells [8]. Downstream of Erk, we studied whether VEGF regulated Mnk phosphorylation and its target, eIF4E
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