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Molecular and Cellular Biology, March 2003, p. 2096-2108, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.2096-2108.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Insulin Receptor Signaling by the Protein Tyrosine Phosphatase TCPTP

Sandra Galic,1 Manuela Klingler-Hoffmann,1 Michelle T. Fodero-Tavoletti,1 Michelle A. Puryer,1 Tzu-Ching Meng,2 Nicholas K. Tonks,2 and Tony Tiganis1*

Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia,1 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 117242

Received 13 August 2002/ Returned for modification 18 September 2002/ Accepted 11 December 2002

The human protein tyrosine phosphatase TCPTP exists as two forms: an endoplasmic reticulum-targeted 48-kDa form (TC48) and a nuclear 45-kDa form (TC45). Although targeted to the nucleus, TC45 can exit in response to specific stimuli to dephosphorylate cytoplasmic substrates. In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A "substrate-trapping" mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR ß-subunit in 293 cells. Moreover, in response to insulin stimulation, the TC45-D182A mutant accumulated in the cytoplasm of cells overexpressing the IR and in part colocalized with the IR ß-subunit at the cell periphery. These results indicate that the IR may serve as a cellular substrate for both TC48 and TC45. In immortalized TCPTP-/- murine embryo fibroblasts, insulin-induced IR ß-subunit tyrosine phosphorylation and protein kinase PKB/Akt activation were enhanced relative to the values in TCPTP+/+ cells. Importantly, the expression of TC45 or TC48 to physiological levels suppressed the enhanced insulin-induced signaling in TCPTP-/- cells. These results indicate that the differentially localized variants of TCPTP may dephosphorylate the IR and downregulate insulin-induced signaling in vivo.

* 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, March 2003, p. 2096-2108, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.2096-2108.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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