Positive effect of overexpressed protein-tyrosine phosphatase PTP1C on mitogen-activated signaling in 293 cells.
PTP1C, an SH2 domain-containing protein-tyrosine phosphatase, is predominantly expressed in hematopoietic cells, in which it negatively regulates cellular signaling. However, this enzyme is also expressed in many non-hematopoietic cells. We demonstrate here that in non-hematopoietic 293 cells, overexpression of a catalytically inactive mutant of PTP1C strongly suppressed the stimulatory effects of the epidermal growth factor or serum on cell proliferation, early gene transcription, and DNA synthesis. Similarly, the phosphorylation of the mitogen-activated protein kinase and mitogen-activated protein kinase kinase activity was markedly inhibited by overexpression of mutant PTP1C. The inhibitory effect of mutant PTP1C was overcome by cotransfection with wild-type PTP1C, but not with the structurally related PTP2C. Furthermore, expression of the mutant phosphatase resulted in hyperphosphorylation on tyrosine of a 95-kDa protein that was co-immunoprecipitated with the mutant, but not with the wild-type protein. These results suggest that, unlike in hematopoietic cells, PTP1C in 293 cells plays a positive role in epidermal growth factor- or serum-activated mitogenesis. Thus, PTP1C participates in multiple signaling pathways, where the enzyme, depending on its target molecules, may function as either a positive or negative mediator.
Su
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Pharmaceutical Sector, Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada.
Zhao
Z
Z
Bouchard
P
P
Banville
D
D
Fischer
E H
EH
Krebs
E G
EG
Shen
S H
SH
D002455:Cell Division; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016762:Genes, fos; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney; D020929:Mitogen-Activated Protein Kinase Kinases; D008934:Mitogens / Q000494:pharmacology*; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011994:Recombinant Proteins; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D014162:Transfection; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D008934:Mitogens; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D004247:DNA; D011494:Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases