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The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases
Science Signaling ( IF 7.3 ) Pub Date : 2018-09-18 , DOI: 10.1126/scisignal.aap8608
Bohumil Fafilek 1, 2 , Lukas Balek 1 , Michaela Kunova Bosakova 1, 2 , Miroslav Varecha 1, 2 , Alexandru Nita 1 , Tomas Gregor 3 , Iva Gudernova 1 , Jitka Krenova 1 , Somadri Ghosh 4 , Martin Piskacek 5 , Lucie Jonatova 1 , Nicole H Cernohorsky 1 , Jennifer T Zieba 6 , Michal Kostas 7, 8 , Ellen Margrethe Haugsten 7, 8 , Jørgen Wesche 7, 8 , Christophe Erneux 4 , Lukas Trantirek 3 , Deborah Krakow 6, 9, 10 , Pavel Krejci 1, 2, 11
Affiliation  

Sustained activation of extracellular signal–regulated kinase (ERK) drives pathologies caused by mutations in fibroblast growth factor receptors (FGFRs). We previously identified the inositol phosphatase SHIP2 (also known as INPPL1) as an FGFR-interacting protein and a target of the tyrosine kinase activities of FGFR1, FGFR3, and FGFR4. We report that loss of SHIP2 converted FGF-mediated sustained ERK activation into a transient signal and rescued cell phenotypes triggered by pathologic FGFR-ERK signaling. Mutant forms of SHIP2 lacking phosphoinositide phosphatase activity still associated with FGFRs and did not prevent FGF-induced sustained ERK activation, demonstrating that the adaptor rather than the catalytic activity of SHIP2 was required. SHIP2 recruited Src family kinases to the FGFRs, which promoted FGFR-mediated phosphorylation and assembly of protein complexes that relayed signaling to ERK. SHIP2 interacted with FGFRs, was phosphorylated by active FGFRs, and promoted FGFR-ERK signaling at the level of phosphorylation of the adaptor FRS2 and recruitment of the tyrosine phosphatase PTPN11. Thus, SHIP2 is an essential component of canonical FGF-FGFR signal transduction and a potential therapeutic target in FGFR-related disorders.



中文翻译:

肌醇磷酸酶 SHIP2 通过募集 Src 激酶使 FGF 受体下游的 ERK 持续激活

细胞外信号调节激酶 (ERK) 的持续激活会导致由成纤维细胞生长因子受体 (FGFR) 突变引起的病理变化。我们以前将肌醇磷酸酶 SHIP2(也称为 INPPL1)鉴定为 FGFR 相互作用蛋白和 FGFR1、FGFR3 和 FGFR4 酪氨酸激酶活性的靶标。我们报告说,SHIP2 的缺失将 FGF 介导的持续 ERK 激活转化为瞬时信号,并挽救了由病理性 FGFR-ERK 信号触发的细胞表型。缺乏磷酸肌醇磷酸酶活性的 SHIP2 突变形式仍然与 FGFR 相关,并且不会阻止 FGF 诱导的持续 ERK 激活,表明需要适配器而不是 SHIP2 的催化活性。SHIP2 将 Src 家族激酶招募到 FGFRs,这促进了 FGFR 介导的磷酸化和蛋白质复合物的组装,将信号传递给 ERK。SHIP2 与 FGFRs 相互作用,被活性 FGFRs 磷酸化,并在适配器 FRS2 的磷酸化水平和酪氨酸磷酸酶 PTPN11 的募集水平上促进 FGFR-ERK 信号传导。因此,SHIP2 是经典 FGF-FGFR 信号转导的重要组成部分,也是 FGFR 相关疾病的潜在治疗靶点。

更新日期:2018-09-19
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