MAP2K2 binds MAPK1

Stable Identifier
R-HSA-109858
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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In the cytoplasm phosphorylated MAP2K2 (MEK2) may encounter monomeric, inactive MAPK1 (ERK2). IL-6-type receptor activation leads to induction of the MAPK cascade. Experiments using gp130 identified that the gp130 SHP2 (SH2-domain-containing tyrosine phosphatase)-binding site Tyr-759 (Stahl et al. 1995) is required for this activation. Mutation of gp130 Tyr-759 impairs IL-6 induced activation of the MAPK cascade (Kim et al. 1998). While there is a consensus that SHP2 is involved in IL-6-induced activation of the MAPK pathway, the molecular details are uncertain. One proposed mechanism suggests SHP2 acts as an adaptor for Grb2-Sos recruitment (Fukada et al. 1996, Kim & Baumann 1999). IL-6 induced SHP2 recruitment to p-Tyr-759 of gp130 was demonstrated but relatively little of the SHP2 remained associated with gp130, suggesting that SHP2 dissociates from the receptor when phosphorylated. This seems inconsistent with a Grb2-Sos recruitment role for SHP2, though it is possible that only low levels or transient recruitment are required. IL-6 induced ERK activation was not inhibited in cells transfected with a phosphatase inactive mutant of SHP2, whereas an SHP2 mutant missing the Grb2 interaction region significantly suppressed ERK activation. This suggests phosphatase activity is not required for ERK activation while SHP-2 interaction with Grb2 is important. However, overexpression studies can generate artefactual interactions and this interpretation has been questioned (Dance et al. 2008). An alternative proposal suggests that SHP2 and the adaptor protein Gab1 couple gp130 signalling to Erk activation. In this proposal phosphorylated SHP2 dissociates from gp130 and becomes associated with membrane associated Gab1 in a complex with PI3-kinase (Takahashi-Tezuka et al. 1998, Eulenfeld & Schaper 2009). SHP2 interaction is suggested to induce a conformational change in Gab1 that permits Gab1-PI3-kinase activation and enhancement of IL-6-induced Erk pathway activation. However this is speculative, the role of SHP2 phosphatase activity is unclear. Other possible mechanisms are outlined by Dance et al. (2008), extrapolated from growth factor receptor mechanisms but with unknown relevance to IL-6/gp130.

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