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

被引:103
作者
Kim, HK
Hawley, TS
Hawley, RG
Baumann, H
机构
[1] Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA
[2] Toronto Hosp, Oncol Gene Therapy Program, Toronto, ON M5G 2M1, Canada
关键词
D O I
10.1128/MCB.18.3.1525
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Signals propagated via the gp130 subunit of the interleukin-6 (IL-6)-type cytokine receptors mediate, among various cellular responses, proliferation of hematopoietic cells and induction of acute-phase plasma protein (APP) genes in hepatic cells, Hematopoietic growth control by gp130 is critically dependent on activation of both STAT3 and protein tyrosine phosphatase 2 (SHP-2). To investigate whether induction of APP genes has a similar requirement for SHP-2, we constructed two chimeric receptors, G-gp130 and G-gp130(Y2F), consisting of the transmembrane and cytoplasmic domains of gp130 harboring either a wild-type or a mutated SHP-2 binding site, respectively, fused to the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor. Rat hepatoma H-35 cells stably expressing the chimeric receptors were generated by retroviral transduction. Both chimeric receptors transmitted a G-CSF-induced signal characteristic of that triggered by IL-6 through the endogenous gp130 receptor; i.e., both activated the appropriate JAK, induced DNA binding activity by STAT1 and STAT3, and up-regulated expression of the target APP genes, those for alpha-fibrinogen and haptoglobin. Notwithstanding these similarities in the patterns of signaling responses elicited, mutation of the SHP-2 interaction site in G-gp130(Y2F) abrogated ligand-activated receptor recruitment of SHP-2 as expected, Moreover, the tyrosine phosphorylation state of the chimeric receptor, the associated JAK activity, and the induced DNA binding activity of STAT1 and STAT3 were maintained at elevated levels and for an extended period of time in G-gp130(Y2F)-expressing cells following G-CSF treatment compared to, that in cells displaying the G-gp130 receptor, H-35 cells ectopically expressing G-gp130(Y2F) were also found to display an enhanced sensitivity to G-CSF and a higher level of induction of APP genes, Overexpression of the enzymatically inactive SHP-2 enhanced the signaling by the wild-type but not by the Y2F mutant G-gp130 receptor. These results indicate that gp130 signaling for APP gene induction in hepatic cells differs qualitatively from that controlling the proliferative response in hematopoietic cells in not being strictly dependent on SHP-2. The data further suggest that SHP-2 functions normally to attenuate gp130-mediated signaling in hepatic (and, perhaps, other) cells by moderating JAK action.
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页码:1525 / 1533
页数:9
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共 53 条
  • [1] Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor beta chain
    Adachi, M
    Ishino, M
    Torigoe, T
    Minami, Y
    Matozaki, T
    Miyazaki, T
    Taniguchi, T
    Hinoda, Y
    Imai, K
    [J]. ONCOGENE, 1997, 14 (13) : 1629 - 1633
  • [2] MULTIPLE REGIONS WITHIN THE CYTOPLASMIC DOMAINS OF THE LEUKEMIA INHIBITORY FACTOR-RECEPTOR AND GP130 COOPERATE IN SIGNAL-TRANSDUCTION IN HEPATIC AND NEURONAL CELLS
    BAUMANN, H
    SYMES, AJ
    COMEAU, MR
    MORELLA, KK
    WANG, YP
    FRIEND, D
    ZIEGLER, SF
    FINK, JS
    GEARING, DP
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (01) : 138 - 146
  • [3] REGULATION OF MAJOR ACUTE-PHASE PLASMA-PROTEINS BY HEPATOCYTE-STIMULATING FACTORS OF HUMAN SQUAMOUS CARCINOMA-CELLS
    BAUMANN, H
    HILL, RE
    SAUDER, DN
    JAHREIS, GP
    [J]. JOURNAL OF CELL BIOLOGY, 1986, 102 (02) : 370 - 383
  • [4] BAUMANN H, 1989, ANN NY ACAD SCI, V557, P280
  • [5] BAUMANN H, 1987, J IMMUNOL, V139, P1422
  • [6] A single STAT recruitment module in a chimeric cytokine receptor complex is sufficient for STAT activation
    Behrmann, I
    Janzen, C
    Gerhartz, C
    SchmitzVandeLeur, H
    Hermanns, H
    Heesel, B
    Graeve, L
    Horn, F
    Tavernier, J
    Heinrich, PC
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (08) : 5269 - 5274
  • [7] Bennett AM, 1996, MOL CELL BIOL, V16, P1189
  • [8] Interferon-beta interrupts interleukin-6-dependent signaling events in myeloma cells
    Berger, LC
    Hawley, RG
    [J]. BLOOD, 1997, 89 (01) : 261 - 271
  • [9] SHP1 and SHP2 protein-tyrosine phosphatases associate with beta c after interleukin-3-induced receptor tyrosine phosphorylation - Identification of potential binding sites and substrates
    Bone, H
    Dechert, U
    Jirik, F
    Schrader, JW
    Welham, MJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (22) : 14470 - 14476
  • [10] Insulin modulates STAT3 protein activation and gene transcription in hepatic cells
    Campos, SP
    Wang, YP
    Baumann, H
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (40) : 24418 - 24424