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Symbol INPPL1 contributors: mct/npt/pgu - updated : 13-06-2018
HGNC name inositol polyphosphate phosphatase-like 1
HGNC id 6080
Corresponding disease
OPSMD opsismodysplasia
Location 11q13.4      Physical location : 71.935.881 - 71.950.186
Synonym name
  • SH2 containing inositol phosphate 2
  • 51C protein
  • SH2 domain containing inositol polyphosphate 5-phosphatase-2
  • phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2
  • Synonym symbol(s) SHIP2, OPSMD
    EC.number, 3.1.3.n1
    TYPE functioning gene
    STRUCTURE 14.31 kb     28 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status provisional
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    28 - 4726 - 1258 - 2005 15964236
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  highly
    Lymphoid/Immunelymph node   highly
     thymus   highly
    Visualeye   highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    cell lineage
    cell lines
    at STAGE
    physiological period pregnancy
    Text placenta
  • N-terminal SH2 domain, that is the minimal and sufficient protein motif responsible for the interaction between the two phosphatases, domain showing apparent slow-binding behavior, with role in the regulation of its newly identified monoubiquitination
  • a conserved catalytic 5-phosphatase domain,
  • C-terminal proline-rich region with consensus sites for SH3 domain interactions, a ubiquitin interacting motif, and a sterile alpha motif (SAM), and only the proline-rich domain (AAs 885-1184) has a strong ability to bind to ubiquitin (the ubiquitin-binding region resides within the C terminus, between AAs 885 and 1184 and a putative UIM domain resides between AAs 1117 and 1137)
  • inositol-1,4,5-trisphosphate 5-phosphatase family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
    basic FUNCTION
  • potent negative regulator of insulin signaling and insulin sensitivity in vivo
  • involved in the control of vascular smooth muscle cells proliferation and the pathogenesis of vascular proliferative disorders
  • playing an important role in the control of insulin sensitivity
  • dephosphorylates phosphatidylinositol 3,4,5-trisphosphate generated by the activated phosphatidylinositol 3'-kinase
  • down-regulates insulin signaling and is present at higher levels in diabetes and obesity
  • functioning in the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation
  • involved in receptor endocytosis regulation
  • could be polyubiquitinated but not degraded by the 26 S proteasome
  • able to recognize other ubiquitinated proteins by a UIM domain and its monoubiquitination is a process that is actively controlled by the ability of its SH2 domain to mask the monoubiquitination site
  • may have functions such as scaffold properties in the c-Jun N-terminal kinase cascade, negative regulation of EGFR internalization and degradation, EphA2 endocytosis, and angiotensin II signaling
  • downregulates insulin signalling in podocytes
  • regulates endocytic clathrin-coated pit dynamics
  • INPPK5 and INPPL1, inhibit actin cytoskeletal reorganization by opposing PI3K/Akt signaling
  • major negative regulator of the phosphatidylinositol-3-kinase pathway in lymphocytes
  • its function is different at the plasma membrane where it recognizes PtdIns(3,4,5)P3, and in the nucleus where it may interact with PtdIns(4,5)P2, particularly in speckles
  • two previously unrecognized functions of INPPL1 in suppressing ligand-induced activation of EPHA2 and in promoting receptor coordinated chemotactic cell migration
  • key and specific role in the endochondral ossification process, through either its role in postranslational modifications (phosphorylation or ubiquitination) or its interaction with specific protein network
  • role of INPPL1 in development in normal cells and at least in cell proliferation in some cancer derived cells
  • associates with receptors that are associated in lymphedema, implicating its direct involvement in the lymphatic vasculature
  • its expression level is a key determinant of hepatic lipogenesis and lipoprotein secretion
  • catalyses the dephosphorylation of the phospholipid phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3) to form PI(3,4)P2
  • endothelial INPPL1 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction
    PHYSIOLOGICAL PROCESS endocytosis transport
    a component
  • BAG4 forms a complex with several 5-ptase family members, including INPPL1, INPP5D, INPP5K
    small molecule
  • associates with BCAR1 and filamin, regulators of cell adhesion/migration and cytoskeleton, influencing cell adhesion/spreading
  • interacting with SORBS3 (promotes the localization of INPPL1 at the periphery of the cells leaving its catalytic site intact)
  • binding to ITSN1
  • interaction between ARAP3 and INPPL1 was observed with endogenous proteins and shown to be mediated by the SAM domain of ARAP3 and INPPL1
  • molecular link between INPPL1 and ITSN1 which are involved in receptor endocytosis regulation
  • association with CBL proteins, which presents an E3 ubiquitin ligase activity
  • interacts with CD2AP in glomeruli and is expressed in podocytes, where it translocates to plasma membrane after insulin stimulation
  • interacting with SH3KBP1 (this interaction might synergistically facilitate the down-regulation of phosphatidylinositol-3,4,5-trisphosphate levels)
  • NPHS1 recruits and regulates a protein complex that includes INPPL1, FLNA and RAPH1, proteins important in regulation of actin and focal adhesion dynamics, as well as lamellipodia formation
  • interacts with RHOA in a GTP-dependent manner (RHOA associates with INPPL1 to regulate cell polarization and migration)
  • cell & other
    corresponding disease(s) OPSMD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in diabetes and obesity
  • to type 2 diabetes
  • to hypertension in metabolic syndrome patients
  • to metabolic syndrome in men with Type 1 diabetes, but not with diabetic nephropathy
  • Variant & Polymorphism SNP
  • highly significant associations of single nucleotide polymorphisms (SNPs) with hypertension as well as with other components of the metabolic syndrome in type 2 diabetes
  • rs2276048 (silent mutation) and rs2276047 (intronic), were associated with the metabolic syndrome in men
  • Candidate gene
  • identified as a useful prognostic marker in Colorectal cancer (CRC)
  • Therapy target
    diabetetype 2 
    significant therapeutic target for the treatment of both obesity and type 2 diabetes
    inhibition of INPP5D and INPPL1 may have broad clinical application in the treatment of multiple tumor types
    its inhibition could be considered as a potential target for treatment of dyslipidemia
    targeting CRC may provide novel strategy for CRC treatment