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Molecular and Cellular Biology, April 2002, p. 1998-2010, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.1998-2010.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of Insulin-Like Growth Factor Type I (IGF-I) Receptor Kinase Activity by Protein Tyrosine Phosphatase 1B (PTP-1B) and Enhanced IGF-I-Mediated Suppression of Apoptosis and Motility in PTP-1B-Deficient Fibroblasts

Deirdre A. Buckley,1,{dagger} Alan Cheng,2 Patrick A. Kiely,1 Michel L. Tremblay,2 and Rosemary O'Connor1*

Cell Biology Laboratory, Department of Biochemistry and Bioscience Research Institute, National University of Ireland, Cork, Ireland,1 McGill Cancer Center and Department of Biochemistry, McGill University, Montreal, Canada2

Received 19 June 2001/ Returned for modification 30 July 2001/ Accepted 27 December 2001

The insulin-like growth factor type I (IGF-I) receptor (IGF-IR), activated by its ligands IGF-I and IGF-II, can initiate several signal transduction pathways that mediate suppression of apoptosis, proliferation, differentiation, and transformation. Here we investigated the regulation of IGF-IR activation and function by protein tyrosine phosphatase 1B (PTP-1B). Coexpression of PTP-1B with a ß-chain construct of the IGF-IR (ßWT) inhibited IGF-IR kinase activity in fission yeast Schizosaccharomyces pombe, in COS cells, and in IGF-IR-deficient fibroblasts. In both spontaneously immortalized and simian virus 40 T antigen-transformed embryonic fibroblast cell lines derived from PTP-1B knockout mice, IGF-I induced higher levels of IGF-IR autophosphorylation and kinase activity than were induced in PTP-1B-expressing control cells. PTP-1B-deficient cells exhibited enhanced IGF-I-mediated protection from apoptosis in response to serum withdrawal or etoposide killing, as well as enhanced plating efficiency and IGF-I-mediated motility. Reexpression of PTP-1B in spontaneously immortalized fibroblasts resulted in decreased IGF-IR and AKT activation, as well as decreased protection from apoptosis and decreased motility. These findings demonstrate that PTP-1B can regulate IGF-IR kinase activity and function and that loss of PTP-1B can enhance IGF-I-mediated cell survival, growth, and motility in transformed cells.

* Corresponding author. Mailing address: Cell Biology Laboratory, Department of Biochemistry and Bioscience Research Institute, National University of Ireland, Cork, Ireland. Phone: 353 21 4904212. Fax: 353 21 4904259. E-mail: r.oconnor{at}ucc.i.e

{dagger} Present address: Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.

Molecular and Cellular Biology, April 2002, p. 1998-2010, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.1998-2010.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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