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Molecular and Cellular Biology, October 2002, p. 7325-7336, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7325-7336.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Pleckstrin Homology (PH) Domain-Interacting Protein Couples the Insulin Receptor Substrate 1 PH Domain to Insulin Signaling Pathways Leading to Mitogenesis and GLUT4 Translocation

Janet Farhang-Fallah,1,2 Varinder K. Randhawa,3,4 Anjaruwee Nimnual,5 Amira Klip,3,4 Dafna Bar-Sagi,5 and Maria Rozakis-Adcock1,2,6*

Department of Biology,1 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8N 3Z5,6 Hamilton Regional Cancer Centre, Hamilton, Ontario L8V 5C2,2 Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8,3 Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1A5, Canada,4 Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 117945

Received 20 August 2001/ Returned for modification 11 October 2001/ Accepted 27 June 2002

Receptor-mediated tyrosine phosphorylation of the insulin receptor substrate 1 (IRS-1) is required for the propagation of many of insulin's biological effects. The amino-terminal pleckstrin homology (PH) domain of IRS-1 plays a pivotal role in promoting insulin receptor (IR)-IRS-1 protein interactions. We have recently reported the isolation of a PH domain-interacting protein, PHIP, which selectively binds to the IRS-1 PH domain and is stably associated with IRS-1 in mammalian cells. Here we demonstrate that overexpression of PHIP in fibroblasts enhances insulin-induced transcriptional responses in a mitogen-activated protein kinase-dependent manner. In contrast, a dominant-negative mutant of PHIP (DN-PHIP) was shown to specifically block transcriptional and mitogenic signals elicited by insulin and not serum. In order to examine whether PHIP/IRS-1 complexes participate in the signal transduction pathway linking the IR to GLUT4 traffic in muscle cells, L6 myoblasts stably expressing a myc-tagged GLUT4 construct (L6GLUT4myc) were transfected with either wild-type or dominant-interfering forms of PHIP. Whereas insulin-dependent GLUT4myc membrane translocation was not affected by overexpression of PHIP, DN-PHIP caused a nearly complete inhibition of GLUT4 translocation, in a manner identical to that observed with a dominant-negative mutant of the p85 subunit of phosphatidylinositol 3-kinase ({Delta}p85). Furthermore, DN-PHIP markedly inhibited insulin-stimulated actin cytoskeletal reorganization, a process required for the productive incorporation of GLUT4 vesicles at the cell surface in L6 cells. Our results are consistent with the hypothesis that PHIP represents a physiological protein ligand of the IRS-1 PH domain, which plays an important role in insulin receptor-mediated mitogenic and metabolic signal transduction.

* Corresponding author. Mailing address: Department of Pathology and Molecular Medicine, McMaster University, 1200 Main St. West, Hamilton, L8N 3Z5 Ontario, Canada. Phone: (905) 525-9140, x22975. Fax: (905) 577-0198. E-mail: rozakisa{at}mcmaster.ca.

Molecular and Cellular Biology, October 2002, p. 7325-7336, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.7325-7336.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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