The phosphotyrosine phosphatase PTP1D, but not PTP1C, is an essential mediator of fibroblast proliferation induced by tyrosine kinase and G protein-coupled receptors.
PTP1C and PTP1D are non-transmembrane protein-tyrosine phosphatases (PTPs), which contain two src homology-2 domains. These enzymes are believed to play a role in regulating downstream signaling from receptors with intrinsic tyrosine kinase activity. The present study describes the tyrosine phosphorylation and the catalytic activity of both PTPs in CCL39 cells, a Chinese hamster lung fibroblast cell line, upon addition of a variety of growth factors. We demonstrate that PTP1C activity was significantly stimulated by insulin and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate but was not influenced by serum, platelet-derived growth factor (PDGF), or alpha-thrombin. However, tyrosine phosphorylation of PTP1C was increased in response to insulin, PDGF, and alpha-thrombin. PTP1D activity was slightly stimulated by insulin and 12-O-tetradecanoylphorbol-13-acetate but was significantly inhibited by serum, PDGF, and alpha-thrombin, although tyrosine phosphorylation is increased in response to these agonists. Mitogen-activated protein kinase phosphorylated PTP1C and PTP1D in in vitro kinase assays, suggesting that both PTPs are target proteins for mitogen-activated protein kinase. We also show that overexpression of PTP1C or PTP1D had no effect on DNA synthesis stimulated by different growth factors. However, a mutated inactive form of PTP1D strongly inhibited the stimulatory effects of both PDGF and alpha-thrombin on early gene transcription and DNA synthesis. These results demonstrate for the first time that PTP1C and PTP1D may participate in signal transduction but in different manners and that only PTP1D is a positive mediator of mitogenic signals induced by both tyrosine kinase receptors and G protein-coupled receptors in fibroblasts.
Rivard
N
N
Centre de Biochimie, CNRS-UMR134, Parc Valrose, Nice, France.
McKenzie
F R
FR
Brondello
J M
JM
Pouysségur
J
J
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000166:cytology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D019000:Phosphotyrosine; D011401:Promoter Regions, Genetic; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D018179:Receptors, Thrombin / Q000502:physiology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate