Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP.
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 beta-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 beta-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 beta-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.
Galic
Sandra
S
Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
Klingler-Hoffmann
Manuela
M
Fodero-Tavoletti
Michelle T
MT
Puryer
Michelle A
MA
Meng
Tzu-Ching
TC
Tonks
Nicholas K
NK
Tiganis
Tony
T
D000818:Animals; D016466:CHO Cells / Q000187:drug effects / Q000201:enzymology; D002417:Cattle; D002461:Cell Line, Transformed / Q000187:drug effects / Q000201:enzymology; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000201:enzymology; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005816:Genetic Complementation Test; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D007328:Insulin; D007527:Isoenzymes; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D011972:Receptor, Insulin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases; C516653:Ptpn2 protein, mouse