The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases

0494325 - ÚŽFG 2019 RIV US eng J - Článek v odborném periodiku
Fafílek, B. - Bálek, L. - Kunová Bosáková, M. - Vařecha, M. - Nita, A. - Gregor, T. - Gudernová, I. - Křenová, J. - Ghosh, S. - Piskáček, M. - Jonatová, L. - Cernohorsky, N. - Zieba, J. T. - Kostas, M. - Haugsten, E. M. - Wesche, J. - Erneux, C. - Trantírek, L. - Krakow, D. - Krejčí, Pavel
The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases.
Science Signaling. Roč. 11, č. 548 (2018), č. článku eaap8608. ISSN 1945-0877. E-ISSN 1937-9145
Grant CEP: GA ČR(CZ) GA17-09525S
Institucionální podpora: RVO:67985904
Klíčová slova: fibroblast growth factor * Src kinases
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6.565, rok: 2018

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.
Trvalý link: http://hdl.handle.net/11104/0287511