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Molecular and Cellular Biology, January 2005, p. 819-829, Vol. 25, No. 2
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.2.819-829.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Coordinated Regulation of Insulin Signaling by the Protein Tyrosine Phosphatases PTP1B and TCPTP

Sandra Galic,1 Christine Hauser,1 Barbara B. Kahn,2 Fawaz G. Haj,3 Benjamin G. Neel,3 Nicholas K. Tonks,4 and Tony Tiganis1*

Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia,1 Division of Endocrinology, Diabetes and Metabolism,2 Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts,3 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York4

Received 16 June 2004/ Returned for modification 19 August 2004/ Accepted 18 October 2004

The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. Our previous studies have shown that the closely related tyrosine phosphatase TCPTP might also contribute to the regulation of insulin receptor (IR) signaling in vivo (S. Galic, M. Klingler-Hoffmann, M. T. Fodero-Tavoletti, M. A. Puryer, T. C. Meng, N. K. Tonks, and T. Tiganis, Mol. Cell. Biol. 23:2096-2108, 2003). Here we show that PTP1B and TCPTP function in a coordinated and temporally distinct manner to achieve an overall regulation of IR phosphorylation and signaling. Whereas insulin-induced phosphatidylinositol 3-kinase/Akt signaling was prolonged in both TCPTP–/– and PTP1B–/– immortalized mouse embryo fibroblasts (MEFs), mitogen-activated protein kinase ERK1/2 signaling was elevated only in PTP1B-null MEFs. By using phosphorylation-specific antibodies, we demonstrate that both IR ß-subunit Y1162/Y1163 and Y972 phosphorylation are elevated in PTP1B–/– MEFs, whereas Y972 phosphorylation was elevated and Y1162/Y1163 phosphorylation was sustained in TCPTP–/– MEFs, indicating that PTP1B and TCPTP differentially contribute to the regulation of IR phosphorylation and signaling. Consistent with this, suppression of TCPTP protein levels by RNA interference in PTP1B–/– MEFs resulted in no change in ERK1/2 signaling but caused prolonged Akt activation and Y1162/Y1163 phosphorylation. These results demonstrate that PTP1B and TCPTP are not redundant in insulin signaling and that they act to control both common as well as distinct insulin signaling pathways in the same cell.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, P.O. Box 13D, Monash University, Victoria 3800, Australia. Phone: 61 3 9905 3772. Fax: 61 3 9905 4699. E-mail: Tony.Tiganis{at}med.monash.edu.au.

Molecular and Cellular Biology, January 2005, p. 819-829, Vol. 25, No. 2
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.2.819-829.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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