Protein Tyrosine Phosphatase 2 (SHP-2) Moderates Signaling by gp130 but Is Not Required for the Induction of Acute-Phase Plasma Protein Genes in Hepatic Cells

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

“…Moreover, activation of SHP-2 without concomitant STAT activation did not in¯uence the growth behavior of A375 transfectants. It will be of interest to determine whether SHP-2 may play an inhibitory role for gp130-signaling in these cells, as has been shown for other cell types (Kim et al, 1998;Schaper et al, 1998;Symes et al, 1997). This could explain why transfectants expressing the receptors Y767 and Y814 showed no apparent decrease of the STAT signal within the ®rst hour, while DNA binding activity induced by the full-length EG construct or by wild-type gp130 dramatically decreased between 30 and 60 min after stimulation.…”

“…The tyrosine phosphatase SHP-2 also binds to a speci®c phosphotyrosine motif of gp130 (Stahl et al, 1995), thereby possibly forming a link to the Ras/Raf/MAP kinase pathway, also known to be activated by IL-6-type cytokines (Boulton et al, 1994;Kumar et al, 1994). Activation of the SHP-2 phosphatase may further lead to downregulation of the signal (Kim et al, 1998;Symes et al, 1997). In addition, other molecules such as vav (Lee et al, 1997) or tyrosine kinases Hck (Ernst et al, 1994), Tec, Btk (Matsuda et al, 1995b) and Fes (Matsuda et al, 1995a) have been reported to become phosphorylated upon gp130 stimulation, but their contribution to signal transduction is unclear.…”

Modulation of hepatic acute phase gene expression by epidermal growth factor and src protein tyrosine kinases in murine and human hepatic cells

“…The following vectors have been described: FJ vector, containing avian c-Src 45 (provided by Dr. J.V. Jung, Harvard Medical School, Southborough, MA), pSV containing human EGFR, 46 pDC containing the human chimeric receptor granulocyte colony stimulatory factor receptor (G-CSFR)-gp130-FLAG or G-CSFR-gp130(Y2F)-FLAG (containing the mutated SH-2 domain containing protein tyrosine phosphatase (SHP)-2 binding site in which tyrosine 759 is substituted by phenylalanine, ϭY2F) 47,48 and pIE-MUP containing the murine major urinary protein (MUP) gene. 49 The expression vector for the constitutively active, double mutant MEK-1 (S218D/ S222D) with hematoglutinin antigen tag was purchased from Upstate Biotechnology, Lake Placid, NY.…”

“…One possibility is that activation of gp130 signaling is associated with a modification of gp130 by a Src kinase and this modification in turn attenuates signaling. Recent functional characterization of the cytoplasmic domains of gp130 48,68 has indicated that tyrosine 759 (here referred to as Y2, representing the second of the 6 tyrosine residues in the cytoplasmic domain 68 ) is a site, that when phosphorylated, serves as a binding motif for the protein tyrosine phosphatase SHP-2. Recruitment of SHP-2 to gp130 is believed to contribute to down-modulated signaling by gp130, in part by the phosphatase action.…”

“…Recruitment of SHP-2 to gp130 is believed to contribute to down-modulated signaling by gp130, in part by the phosphatase action. 48,69 To show that Csk-sensitive Src kinases, in principle, could target gp130 by modifying the Y2 site, we determined the effects of Csk on signaling mediated by the cytoplasmic domain of gp130 that contained the wild-type or the tyrosine to phenylalanine mutant (Y2F) SHP-2 binding site. We introduced into HepG2 cells the expression of the chimeric G-CSFR-gp130 receptors that carried the cytoplasmic domain of gp130 with or without the Y2F mutation.…”