FEATURES

FAMILY

inositol 1,4,5-trisphosphate 5-phosphatase family

DESCRIPTION

Also known as SHIP2_HUMAN, INPPL1, SHIP2. Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3, 4, 5-trisphosphate (PtdIns(3, 4, 5)P3) to produce PtdIns(3, 4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3, 4, 5)P3 thereby regulating membrane ruffling (PubMed:21624956). Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3, 4, 5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3, 4, 5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. May also hydrolyze PtdIns(1, 3, 4, 5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification. Interacts with tyrosine phosphorylated form of SHC1 (PubMed:9660833, PubMed:10194451, PubMed:11349134). Interacts with EGFR (PubMed:11349134). Upon stimulation by the EGF signaling pathway, it forms a complex with SHC1 and EGFR (PubMed:11349134). Interacts with cytoskeletal protein SORBS3/vinexin, promoting its localization to the periphery of cells (PubMed:16302969). Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or GP1BB) that regulates cortical and submembraneous actin (PubMed:11739414, PubMed:12676785). Interacts with c-Met/MET, when c-Met/MET is phosphorylated on 'Tyr-1356' (PubMed:15735664). Interacts with p130Cas/BCAR1 (PubMed:11158326). Interacts with CENTD3/ARAP3 via its SAM domain (PubMed:17314030). Interacts with c-Cbl/CBL and CAP/SORBS1 (PubMed:12504111). Interacts with activated EPHA2 receptor (PubMed:17135240). Interacts with receptor FCGR2A (PubMed:12690104). Interacts with receptor FCGR2B (PubMed:11016922). Interacts with tyrosine kinase ABL1 (PubMed:10194451). Interacts with tyrosine kinase TEC (By similarity). Interacts with CSF1R (By similarity). Interacts (via N-terminus) with SH3YL1 (via SH3 domain) (PubMed:21624956). Interacts with FCRL6 (tyrosine phosphorylated form) (PubMed:20933011). Interacts (via SH2 domain) with tyrosine phosphorylated KLRC1 (via ITIM).

EXTERNAL LINKS

INPPL1

Mutations

Mutation(s) distribution

Mutations table