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Sci Signal. 2018 Sep 18;11(548). pii: eaap8608. doi: 10.1126/scisignal.aap8608.

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

Author information

1
Department of Biology, Masaryk University, 62500 Brno, Czech Republic.
2
International Clinical Research Center, St. Anne's University Hospital, 65691 Brno, Czech Republic.
3
Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic.
4
Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire, Université Libre de Bruxelles, 1070 Bruxelles, Belgium.
5
Department of Pathological Physiology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
6
Department of Orthopedic Surgery, University of California Los Angeles, CA 90095, USA.
7
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, 0379 Oslo, Norway.
8
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0379 Oslo, Norway.
9
Department of Human Genetics, University of California Los Angeles, CA 90095, USA.
10
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, CA 90095, USA.
11
Department of Biology, Masaryk University, 62500 Brno, Czech Republic. krejcip@med.muni.cz.
12
Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, 60200 Brno, Czech Republic.

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.

PMID:
30228226
DOI:
10.1126/scisignal.aap8608

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