Research ArticleCell Biology

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

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Science Signaling  18 Sep 2018:
Vol. 11, Issue 548, eaap8608
DOI: 10.1126/scisignal.aap8608

Converting transient to sustained signaling

Activation of fibroblast growth factor receptors (FGFRs) stimulates downstream signaling transiently because the receptors are endocytosed and degraded after activation. Nevertheless, FGFRs stimulate both sustained and transient ERK signaling. Fafilek et al. found that the inositol phosphatase SHIP2 was required for converting transient FGFR activation into sustained ERK signaling. The catalytic activity of SHIP2 was not required. Instead, SHIP2 acted as a scaffold that recruited Src family kinases to FGFR complexes, thus enhancing the phosphorylation of adaptor proteins that mediated signal relay from FGFRs to ERK. Because sustained ERK activation due to aberrant FGFR signaling is associated with oncogenesis and developmental disorders, SHIP2 may be a potential therapeutic target for these pathologies.


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.

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