Modulation der IL-6-abhängigen Signaltransduktion durch die Protein-Tyrosinphosphatase SHP2
Year: 2002
Type: dissertation
Abstract: In the year 1993 a protein-tyrosine phosphatase, SH2 domain containing protein-tyrosine-phosphatase 2 (SHP2), has been discovered, which seems to play an important role in the signaltransduction of many cytokines. The aim of this work was to elucidate the role of the tyrosine phosporylation of SHP2 in the IL-6 dependent signaltransduction via the Jak/STAT pathway. Therefore, first the dose-dependence, kinetic and kinase requirements for SHP2 phosphorylation after the activation of the signal transducer, gp130, was examined. 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 Jak2- or Tyk2-deficient cells, SHP2 activation was greatly impaired. It is concluded that Jak1 is required for the tyrosine phosphorylation of SHP2, although it has been shown that all kinases are constitutively associated with SHP2. This phosphorylation depends on Tyr759 in the cytoplasmatic domain of gp130, since a Tyr759Phe 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. Further reporter-gene-assays with a dominant negative SHP2 also show a greater inducibility of the examined promotors. Therefore, not only SHP2 itself, also its enzyme activity plays an important role in acute-phase gene regulation.
Source: RWTH Publications (RWTH Aachen)
Author: Henke-Gendo, Cornelia
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7020842182