Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression

被引:145
作者
Schaper, F
Gendo, C
Eck, M
Schmitz, J
Grimm, C
Anhuf, D
Kerr, IM
Heinrich, PC
机构
[1] Rhein Westfal TH Aachen, Dept Biochem, D-52057 Aachen, Germany
[2] Imperial Canc Res Fund, London WC2A 3PX, England
关键词
D O I
10.1042/bj3350557
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
Stimulation of the interleukin-6 (IL-6) signalling pathway occurs via the IL-6 receptor-glycoprotein 130 (IL-6R-gp130) receptor complex and results in the regulation of acute-phase protein genes in liver cells. Ligand binding to the receptor complex leads to tyrosine phosphorylation and activation of Janus kinases (Jak), phosphorylation of the signal transducing subunit gp130, followed by recruitment and phosphorylation of the signal transducer and activator of transcription factors STAT3 and STAT1 and the src homology domain (SH2)-containing protein tyrosine phosphatase (SHP2). The tyrosine phosphorylated STAT factors dissociate from the receptor, dimerize and translocate to the nucleus where they bind to enhancer sequences of IL-6 target genes. Phosphorylated SHP2 is able to bind growth factor receptor bound protein (grb2) and thus might link the Jak/STAT pathway to the ras/raf/mitogen-activated protein kinase pathway. Here we present data on the dose-dependence, kinetics and kinase requirements for SHP2 phosphorylation after the activation of the signal transducer, gp130, of the IL-6-type family receptor complex. When human fibrosarcoma cell lines deficient in Jak1, Jak2 or tyrosine kinase 2 (Tyk2) were stimulated with IL-6-soluble IL-6R complexes it was found that only in Jak1-, but not in Jak 2- or Tyk2-deficient cells, SHP2 activation was greatly impaired. It is concluded that Jak1 is required for the tyrosine phosphorylation of SHP2. This phosphorylation depends on Tyr-759 in the cytoplasmatic domain of gp130, since a Tyr-759 --> Phe exchange abrogates SHP2 activation and in turn leads to elevated and prolonged STAT3 and STAT1 activation as well as enhanced acute-phase protein gene induction. Therefore, SHP2 plays an important role in acute-phase gene regulation.
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页码:557 / 565
页数:9
相关论文
共 42 条
  • [1] Bennett AM, 1996, MOL CELL BIOL, V16, P1189
  • [2] CASE RD, 1994, J BIOL CHEM, V269, P10467
  • [3] ACUTE-PHASE RESPONSE OF HUMAN HEPATOCYTES - REGULATION OF ACUTE-PHASE PROTEIN-SYNTHESIS BY INTERLEUKIN-6
    CASTELL, JV
    GOMEZLECHON, MJ
    DAVID, M
    FABRA, R
    TRULLENQUE, R
    HEINRICH, PC
    [J]. HEPATOLOGY, 1990, 12 (05) : 1179 - 1186
  • [4] INTERLEUKIN-6 IS THE MAJOR REGULATOR OF ACUTE PHASE PROTEIN-SYNTHESIS IN ADULT HUMAN HEPATOCYTES
    CASTELL, JV
    GOMEZLECHON, MJ
    DAVID, M
    ANDUS, T
    GEIGER, T
    TRULLENQUE, R
    FABRA, R
    HEINRICH, PC
    [J]. FEBS LETTERS, 1989, 242 (02) : 237 - 239
  • [5] DECHERT U, 1994, J BIOL CHEM, V269, P5602
  • [6] A MULTIFUNCTIONAL VECTOR FAMILY FOR GENE-EXPRESSION IN MAMMALIAN-CELLS
    DIRKS, W
    SCHAPER, F
    KIRCHHOFF, S
    MORELLE, C
    HAUSER, H
    [J]. GENE, 1994, 149 (02) : 387 - 388
  • [7] FENG GS, 1994, ONCOGENE, V9, P1545
  • [8] PHOSPHOTYROSINE PHOSPHATASES WITH SH2 DOMAINS - REGULATORS OF SIGNAL-TRANSDUCTION
    FENG, GS
    PAWSON, T
    [J]. TRENDS IN GENETICS, 1994, 10 (02) : 54 - 58
  • [9] SH2-CONTAINING PHOSPHOTYROSINE PHOSPHATASE AS A TARGET OF PROTEIN-TYROSINE KINASES
    FENG, GS
    HUI, CC
    PAWSON, T
    [J]. SCIENCE, 1993, 259 (5101) : 1607 - 1611
  • [10] SYP ASSOCIATES WITH GP130 AND JANUS KINASE-2 IN RESPONSE TO INTERLEUKIN-11 IN 3T3-L1 MOUSE PREADIPOCYTES
    FUHRER, DK
    FENG, GS
    YANG, YC
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (42) : 24826 - 24830