INPPL1
Description
The INPPL1 (inositol polyphosphate phosphatase like 1) is a protein-coding gene located on chromosome 11.
SH2-domain containing Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 is an enzyme that in humans is encoded by the INPPL1 gene. INPPL1 encodes inositol polyphosphate-5 phosphatase-like 1, a protein that in addition to the phosphatase domain contains an SH2 (src-homology domain 2) motif. INPPL1 has been shown to interact with: BCAR1, FLNC, SHC1, and SORBS1.
INPPL1 is a phosphatidylinositol (PtdIns) phosphatase that specifically breaks down phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) into PtdIns(3,4)P2. This action negatively regulates the PI3K (phosphoinositide 3-kinase) pathways. It is essential for proper mitotic spindle orientation, therefore crucial for successful cell division. INPPL1 plays a vital role in regulating insulin signaling, although the exact mechanisms are not fully understood. Overexpression of INPPL1 reduces insulin-stimulated MAP kinase and Akt activation, while its absence does not affect insulin signaling or GLUT4 trafficking. INPPL1 contributes to resistance against dietary obesity. It might regulate AKT2 phosphorylation at the plasma membrane, but not AKT1. INPPL1 is involved in a signaling pathway that controls actin cytoskeleton remodeling. It is required for maintaining and dynamically reshaping actin structures and plays a crucial role in endocytosis, significantly influencing ligand-induced EGFR internalization and degradation. INPPL1 participates in regulating cortical and submembraneous actin by breaking down PtdIns(3,4,5)P3, thus influencing membrane ruffling. It regulates cell adhesion and spreading. INPPL1 is essential for HGF-mediated lamellipodium formation, cell scattering, and spreading. It acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting PI3K-dependent Rac1 activation. It regulates neurite outgrowth by controlling PtdIns(3,4,5)P3 levels, forming initial protrusions, and later maintaining proper neurite outgrowth. INPPL1 acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). It mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a crucial role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. It is involved in the EGF signaling pathway. Upon EGF stimulation, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. It negatively regulates the PI3K-PKB pathway, possibly by inhibiting PKB activity. INPPL1 downregulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, it downregulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. It plays a role in the localization of AURKA and NEDD9/HEF1 to the basolateral membrane at interphase in polarized cysts, mediating cell cycle homeostasis, cell polarization, and cilia assembly. Additionally, cilia growth is facilitated by the hydrolysis of (PtdIns(3,4,5)P3) to PtdIns(3,4)P2. It promotes the formation of apical membrane-initiation sites during the initial stages of lumen formation via Rho family-induced actin filament organization and CTNNB1 localization to cell-cell contacts. It may also hydrolyze PtdIns(1,3,4,5)P4, potentially affecting the levels of higher inositol polyphosphates like InsP6. It is involved in endochondral ossification.
INPPL1 is also known as OPSMD, SHIP2.
