Insulin regulation of protein translation repressor 4E-BP1, an eIF4E-binding protein, in renal epithelial cells

Basant K. Bhandari, Denis Feliers, Senthil Duraisamy, Jennifer L. Stewart, Anne Claude Gingras, Hanna E. Abboud, Goutam Ghosh Choudhury, Nahum Sonenberg, Balakuntalam S. Kasinath

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Background. Augmented protein translation by insulin involves activation of eukaryotic initiation factor 4E (eIF4E) that follows release of eIF4E from a heterodimeric complex by phosphorylation of its inhibitory binding protein, 4E-BP1. We examined insulin regulation of 4E-BP1 phosphorylation in murine proximal tubular epithelial cells. Methods and Results. Insulin (1 nmol/L) increased de novo protein synthesis by 58 ± 11% (P < 0.001). Insulin also augmented 4E-BP1 phosphorylation and phosphatidylinositol 3-kinase (PI 3-kinase) activity in antiphosphotyrosine immunoprecipitates. This could be prevented by PI 3-kinase inhibitors, Wortmannin, and LY294002. Insulin also activated Akt that lies downstream of PI 3-kinase. Rapamycin abrogated 4E-BP1 phosphorylation in response to insulin, suggesting involvement of mammalian target of rapamycin (mTOR), a kinase downstream of Akt. Insulin-stimulated phosphorylation of 4E-BP1 was also inhibited by PD098059, implying involvement of Erk-1/-2 mitogen-activated protein (MAP) kinase. An increase in Erk-1/-2 type MAP kinase activity by insulin was directly confirmed in an immunokinase assay and was found to be PI 3-kinase dependent. Conclusions. In proximal tubular epithelial cells, insulin augments 4E-BP1 phosphorylation, which is PI 3-kinase and mTOR dependent. The requirement for Erk-1/-2 MAP kinase activation for 4E-BP1 phosphorylation by insulin suggests a cross-talk between PI 3-kinase and Erk-1/-2-type MAP kinase pathways.

Original languageEnglish (US)
Pages (from-to)866-875
Number of pages10
JournalKidney International
Volume59
Issue number3
DOIs
StatePublished - Jan 1 2001

Keywords

  • Cell signaling
  • Eukaryotic initiation factor 4E binding protein-1
  • MAP kinase
  • Protein synthesis
  • Proximal tubule cell
  • Tubular epithelial cells
  • Type 2 diabetes

ASJC Scopus subject areas

  • Nephrology

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