Stimulation of IRS-1-associated Phosphatidylinositol 3-Kinase and Akt/Protein Kinase B but Not Glucose Transport by β1-Integrin Signaling in Rat Adipocytes

Adilson Guilherme,Michael P Czech

doi:10.1074/jbc.273.50.33119

Abstract

The signal transduction pathway by which insulin stimulates glucose transport is not understood, but a role for complexes of insulin receptor substrate (IRS) proteins and phosphatidylinositol (PI) 3-kinase as well as for Akt/protein kinase B (PKB) has been proposed. Here, we present evidence suggesting that formation of IRS-1/PI 3-kinase complexes and Akt/PKB activation are insufficient to stimulate glucose transport in rat adipocytes. Cross-linking of beta1-integrin on the surface of rat adipocytes by anti-beta1-integrin antibody and fibronectin was found to cause greater IRS-1 tyrosine phosphorylation, IRS-1-associated PI 3-kinase activity, and Akt/PKB activation, detected by anti-serine 473 antibody, than did 1 nM insulin. Clustering of beta1-integrin also significantly potentiated stimulation of insulin receptor and IRS-1 tyrosine phosphorylation, IRS-associated PI 3-kinase activity, and Akt/PKB activation caused by submaximal concentrations of insulin. In contrast, beta1-integrin clustering caused neither a change in deoxyglucose transport nor an effect on the ability of insulin to stimulate deoxyglucose uptake at any concentration along the entire dose-response relationship range. The data suggest that (i) beta1-integrins can engage tyrosine kinase signaling pathways in isolated fat cells, potentially regulating fat cell functions and (ii) either formation of IRS-1/PI 3-kinase complexes and Akt/PKB activation is not necessary for regulation of glucose transport in fat cells or an additional signaling pathway is required.

Highlights

One of the primary metabolic responses mediated by insulin is the stimulation of facilitated glucose transport in muscle and adipose tissues
The role of insulin receptor substrate (IRS)-1 proteins in insulin action on glucose transport is less clear, with some studies indicating that IRS protein tyrosine phosphorylation can be blocked without affecting glucose transport activation [23, 24]
We addressed the question of whether ␤1-integrin clustering in rat adipocytes activates the IRS-1/PI 3-kinase/Akt/protein kinase B (PKB) pathway and whether activation of this signaling pathway by ␤1-integrin might stimulate glucose transport as does insulin

Summary

Introduction

One of the primary metabolic responses mediated by insulin is the stimulation of facilitated glucose transport in muscle and adipose tissues. We addressed the question of whether ␤1-integrin clustering in rat adipocytes activates the IRS-1/PI 3-kinase/Akt/PKB pathway and whether activation of this signaling pathway by ␤1-integrin might stimulate glucose transport as does insulin. We show that ␤1-integrin engagement markedly enhances IRS-1-associated PI 3-kinase activity as well as Akt/PKB activation but has no effect on glucose uptake in rat adipocytes.

Results

Conclusion