IL6:Tyrosine phosphorylated hexameric IL-6 receptor:Activated JAKs:p-SHP2 SHP2 is phosphorylated Authored: Ray, K, 2010-12-13 EC Number: 2.7.10.2 Edited: Jupe, S, 2010-12-10 Pubmed10409724 Pubmed11684012 Pubmed9285712 Pubmed9794795 Reactome Database ID Release 431112703 Reactome, http://www.reactome.org ReactomeREACT_27185 Reviewed: Rose-John, S, 2011-02-11 SHP2 is tyrosine-phosphorylated in a JAK1-dependent manner (Schaper et al. 1998, Lehmann et al. 2003, Fischer, 2004). Cells lacking JAK1 showed drastically reduced SHP2 phosphorylation following IL-6 treatment, but it is not entirely clear whether JAK1 directly phosphorylates SHP2 or alternatively is required for gp130 activation, which indirectly leads to SHP2 phosphorylation (Schaper et al, 1998). SHP2 tyrosine phosphorylation at Y546 or Y584 (usually described as Y542 or Y580 in literature references where numbering is based on a short isoform) relieves the PTP domain from the N-SH2 domain-mediated inhibition (Lu et al. 2001). Studies using catalytically-inactive SHP2 (Symes et al. 1997) suggest that it may dephosphorylate gp130 and/or associated signaling factors such as JAKs and STATs, limiting acute phase gene expression (Kim and Baumann, 1999). There is a consensus that SHP2 is involved in IL-6-induced activation of the MAPK pathway, but the molecular details are unclear. has a Stoichiometric coefficient of 2 Tyrosine phosphorylated IL6 receptor hexamer:Activated JAKs:SHP2