PTPN11 binds p-Y759-IL6ST

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). <br>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.

在白介素-6（IL6）的刺激下，酪氨酸蛋白磷酸酶非受体型11（PTPN11，亦称SHP2）被招募至IL6ST（gp130）的磷酸化酪氨酸残基759，随后以JAK1依赖的方式发生酪氨酸磷酸化（Schaper等人，1998年；Lehmann等人，2003年；Fischer，2004年）。关于PTPN11在IL6诱导的MAPK通路激活中的作用，尽管存在共识，但其分子机制尚不明确，特别是PTPN11的磷酸酶活性是否必需尚无定论。已发现两条通路与MAPK的激活有关。一种提出的机制是，PTPN11作为生长因子受体结合蛋白2-Son of sevenless同源物1（GRB2-SOS1）招募的适配体（Fukada等人，1996年；Kim与Baumann，1999年）。Kim与Baumann表明，IL6诱导PTPN11被招募至IL6ST的p-Tyr-759，但指出PTPN11中有相当一部分与IL6ST保持关联，暗示PTPN11在磷酸化后与受体解离。这似乎与PTPN11作为GRB2:SOS1招募角色的作用不符，尽管可能只有低水平或短暂的招募是必需的。Kim与Baumann证明，在转染了PTPN11磷酸酶失活突变体的细胞中，IL6诱导的ERK激活并未受到抑制，而PTPN11缺失GRB2相互作用区域的突变体则显著抑制了ERK激活。这表明磷酸酶活性并非ERK激活所必需，而PTPN11与GRB2的相互作用则至关重要。然而，过表达研究可能产生人为的相互作用，这一解释已受到质疑（Dance等人，2008年）。PTPN11与适配蛋白GRB2相关结合蛋白1（GAB1）已被报道将IL6ST信号传导与ERK激活耦合。在本研究中，磷酸化的PTPN11从IL6ST解离，并与PI3-激酶形成复合物，与膜结合的GAB1相关联（Takahashi-Tezuka等人，1998年；Eulenfeld与Schaper，2009年）。PTPN11的相互作用被建议诱导GAB1的构象变化，允许GAB1-PI3-激酶的激活和IL6诱导的ERK通路激活的增强。然而，这尚属推测，PTPN11磷酸酶功能的作用尚不明确。Dance等人（2008年）概述了其他可能的机制，这些机制从生长因子受体机制中推断而来，但其与IL6及其与IL6ST相互作用的关联性尚属未知。