Following Interleukin-6 (IL6) stimulation, Tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2) is recruited to IL6ST (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 PTPN11 recruitment and phosphorylation (Schaper et al. 1998).
There is a consensus that PTPN11 is involved in IL6-induced activation of the MAPK pathway but the molecular details are uncertain, in particular it is not clear whether the phosphatase activity of PTPN11 is required. Two pathways have been linked with activation of MAPK. One proposed mechanism is that PTPN11 acts as an adaptor for Growth factor receptor-bound protein 2-Son of sevenless homolog 1 (GRB2-SOS1) recruitment (Fukada et al. 1996, Kim & Baumann 1999). Kim & Baumann demonstrate IL6 induced PTPN11 recruitment to p-Tyr-759 of IL6ST but note that relatively little of the PTPN11 remains associated with IL6ST, suggesting that PTPN11 dissociates from the receptors when phosphorylated. This seems inconsistent with a GRB2:SOS1 recruitment role for PTPN11, though it is possible that only low levels or transient recruitment are required. Kim & Baumann demonstrated that IL6 induced ERK activation was not inhibited in cells transfected with a phosphatase inactive mutant of PTPN11, whereas a PTPN11 mutant missing the GRB2 interaction region significantly suppressed ERK activation. This suggests that phosphatase activity is not required for ERK activation while PTPN11 interaction with GRB2 is important. However, overexpression studies can generate artefactual interactions and this interpretation has been questioned (Dance et al. 2008). PTPN11 and the adaptor protein GRB2-associated-binding protein 1 (GAB1) have been reported to couple IL6ST signalling to ERK activation. In this proposal phosphorylated PTPN11 dissociates from IL6ST and becomes associated with membrane associated GAB1 in a complex with PI3-kinases (Takahashi-Tezuka et al. 1998, Eulenfeld & Schaper 2009). PTPN11 interaction is suggested to induce a conformational change in GAB1 that permits GAB1-PI3-kinase activation and enhancement of IL6-induced ERK pathway activation. However this is speculative, the role of PTPN11 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 IL6 and its interaction with IL6ST.