THE PHOSPHOTYROSINE PHOSPHATASE PTP1D, BUT NOT PTP1C, IS AN ESSENTIALMEDIATOR OF FIBROBLAST PROLIFERATION INDUCED BY TYROSINE KINASE AND G-PROTEIN-COUPLED RECEPTORS

PTP1C and PTP1D are non-transmembrane protein-tyrosine phosphatases (P TPs), which contain two src homology-2 domains, These enzymes are beli eved to play a role in regulating downstream signaling from receptors with intrinsic tyrosine kinase activity. The present study describes t he tyrosine phosphorylation and the catalytic activity of both PTPs in CCL39 cells, a Chinese hamster lung fibroblast cell line, upon additi on of a variety of growth factors, We demonstrate that PTP1C activity was significantly stimulated by insulin and the phorbol ester 12-O-tet radecanoylphorbol-13-acetate but was not influenced by serum, platelet derived growth factor (PDGF), or alpha-thrombin, However, tyrosine ph osphorylation 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, sugge sting that both PTPs are target proteins for mitogen-activated protein kinase, We also show that overexpression of PTP1C or PTP1D had no eff ect on DNA synthesis stimulated by different growth factors, However, a mutated inactive form of PTP1D strongly inhibited the stimulatory ef fects 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 man ners and that only PTP1D is a positive mediator of mitogenic signals i nduced by both tyrosine kinase receptors and G protein-coupled recepto rs in fibroblasts.