SHP2 binds gp130 phosphotyrosine-759
Species Homo sapiens
Following IL-6 stimulation, SHP2 is recruited to gp130 phosphotyrosine-759 and is subsequently tyrosine-phosphorylated in a JAK1-dependent manner (Schaper et al. 1998, Lehmann et al. 2003, Fischer, 2004). Mutation of Tyr-759 impairs SHP2 recruitment and phosphorylation (Schaper et al. 1998).
There is a consensus that SHP2 is involved in IL-6-induced activation of the MAPK pathway but the molecular details are uncertain, in particular it is not clear whether the phosphatase activity of SHP2 is required. Two pathways have been linked with activation of ERK. One proposed mechanism is that SHP2 acts as an adaptor for Grb2-Sos recruitment (Fukada et al. 1996, Kim & Baumann 1999). Kim & Baumann demonstrate IL-6 induced SHP2 recruitment to p-Tyr-759 of gp130 but note that relatively little of the SHP2 remains associated with gp130, suggesting that SHP2 dissociates from the receptors 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. Kim & Baumann demonstrated that 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 that 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). SHP2 and the adaptor protein Gab1 have been reported to 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 function 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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