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|Title:||Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP|
|Citation:||Molecular and Cellular Biology, 2003; 23(6):2096-2108|
|Publisher:||Amer Soc Microbiology|
|Sandra Galic, Manuela Klingler-Hoffmann, Michelle T. Fodero-Tavoletti, Michelle A. Puryer, Tzu-Ching Meng, Nicholas K. Tonks, and Tony Tiganis|
|Abstract:||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.|
|Keywords:||Cells, Cultured; Cell Line, Transformed; CHO Cells; Cell Nucleus; Cytoplasm; Endoplasmic Reticulum; Fibroblasts; Animals; Mice, Knockout; Cattle; Humans; Cricetulus; Mice; Macromolecular Substances; Insulin; Isoenzymes; Protein-Serine-Threonine Kinases; Receptor, Insulin; Proto-Oncogene Proteins; Recombinant Fusion Proteins; Genetic Complementation Test; Mutagenesis, Site-Directed; Protein Interaction Mapping; Signal Transduction; MAP Kinase Signaling System; Protein Processing, Post-Translational; Enzyme Activation; Phosphorylation; Cricetinae; Proto-Oncogene Proteins c-akt; Protein Tyrosine Phosphatases; Protein Tyrosine Phosphatase, Non-Receptor Type 2|
|Rights:||© 2003, American Society for Microbiology.|
|Appears in Collections:||Molecular and Biomedical Science publications|
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