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

Abstract

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.

SHIP2 inhibition alters redox‐induced PI3K/AKT and MAP kinase pathways via PTEN over‐activation in cervical cancer cells

“…Consistently, lipid phosphate-independent roles of SHIP2 in signal transduction have been reported recently. Indeed, in human embryonic kidney cells, HEK293T, loss of SHIP2 alters ERK activation in response to fibroblast growth factor stimulation [55]. In accordance with these findings, our observations suggest that the inhibitor might not only block the catalytic activity of SHIP2 but also its scaffolding function by altering SHIP2 interaction with its partners.…”

Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance

“…For example, the inositol phosphatase SHIP2 acts as a scaffold to enable recruitment of the fibroblast growth factor receptor (FGFR) to focal adhesions, promoting activation of SFKs and hyperphosphorylation of FRS2. This mechanism contributes to prolong ERK activation in response to FGF (Fafilek et al, 2018). Furthermore, and perhaps of equal importance, integrins and growth factor receptors jointly activate key downstream signaling components, such as Shc, PI3K, Rac, and MEK, in an additive, co-dependent, or synergistic manner (Figure 2B).…”

Molecular characterization of organoids derived from pancreatic intraductal papillary mucinous neoplasms

“…Of note, several other genes with inactivating somatic mutations in our study may play a role in the development of IPMN. These include AXIN2 , a Wnt pathway regulator; INPPL1 , a component of FGFR signaling; HES1 , a target of Notch signaling that can affect Hedgehog signaling; and RREB1 , a regulator of zinc homeostasis recurrently mutated in PDAC [30–34]. Additional studies to determine the prevalence of somatic alterations in these genes in larger cohorts of IPMNs and their functional role in pancreatic tumorigenesis are warranted.…”

“…B Huang, MA Trujillo et al signaling; and RREB1, a regulator of zinc homeostasis recurrently mutated in PDAC [30][31][32][33][34]. Additional studies to determine the prevalence of somatic alterations in these genes in larger cohorts of IPMNs and their functional role in pancreatic tumorigenesis are warranted.…”