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FLASH GENE
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 3.1.3.56, 3.1.3.n1
    DNA
    TYPE functioning gene
    STRUCTURE 14.31 kb     28 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status provisional
    Physical map
    DHCR7 11q13.2-q13.5 7-dehydrocholesterol reductase NADSYN1 11q13.2 NAD synthetase 1 LOC57830 11q13.2 UHS KerB KRN1 11q13.5 keratin, cuticle, ultrahigh sulphur 1 LOC390219 11 LOC390219 OR7E3P 11q13 olfactory receptor, family 7, subfamily E, member 3 pseudogene LOC255620 11q13.2 hypothetical gene supported by NM_030930; AY007125 OR7E4P 11p15 olfactory receptor, family 7, subfamily E, member 4 pseudogene FLJ10661 11q13.3 hypothetical protein FLJ10661 LOC283202 11q13.3 hypothetical LOC283202 OR7E10P 8p22 olfactory receptor, family 7, subfamily E, member 10 pseudogene RNF121 11q13.3 ring finger protein 121 IL18BP 11q13 interleukin 18 binding protein NUMA1 11q13.3-q13.5 nuclear mitotic apparatus protein 1 LOC220074 11q13.3 Hypothetical 55.1 kDa protein F09G8.5 in chromosome III FLJ20625 11q13.3 hypothetical protein FLJ20625 LOC390220 11 similar to Catechol-O-methyltransferase DKFZP564M082 11q13.3 DKFZP564M082 protein FOLR3 11q13 folate receptor 3 (gamma) LOC390221 11 similar to folate receptor 1 precursor LOC390222 11 hypothetical gene supported by U08471; Z32564; NM_000804 FOLR1 11q13.3-q13.5 folate receptor 1 (adult) FOLR2 11q13.3-q13.5 folate receptor 2 (fetal) INPPL1 11q23 inositol polyphosphate phosphatase-like 1 PHOX2A 11q13.3-q13.4 paired-like (aristaless) homeobox 2a LOC220077 11q13.3 hypothetical gene supported by AF229166 LOC390223 11 similar to Splicing factor U2AF 35 kDa subunit (U2 auxiliary factor 35 kDa subunit) (U2 snRNP auxiliary factor small subunit) SKD3 11q13.3 suppressor of potassium transport defect 3 ART2P 11q13 ADP-ribosyltransferase 2 pseudogene (RT6 antigen homolog, rat) PDE2A 11cen-q12.1 phosphodiesterase 2A, cGMP-stimulated CENTD2 11q13.3 centaurin, delta 2 STARD10 11q13 START domain containing 10 FLJ00012 11q13.3 hypothetical protein FLJ00012 KIAA0769 11q13.2 hypothetical protein FLJ00012
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    28 - 4726 - 1258 - 2005 15964236
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  highly
    Lymphoid/Immunelymph node   highly
     thymus   highly
    Respiratorylung    
    Visualeye   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • 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)
  • HOMOLOGY
    Homologene
    FAMILY
  • inositol-1,4,5-trisphosphate 5-phosphatase family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton
    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
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS endocytosis transport
    PATHWAY
    metabolism
    signaling
    a component
  • BAG4 forms a complex with several 5-ptase family members, including INPPL1, INPP5D, INPP5K
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • 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
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) OPSMD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in diabetes and obesity
    Susceptibility
  • 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
    Marker
  • identified as a useful prognostic marker in Colorectal cancer (CRC)
  • Therapy target
    SystemTypeDisorderPubmed
    diabetetype 2 
    significant therapeutic target for the treatment of both obesity and type 2 diabetes
    cancer  
    inhibition of INPP5D and INPPL1 may have broad clinical application in the treatment of multiple tumor types
    metabolismlipidcholesterol
    its inhibition could be considered as a potential target for treatment of dyslipidemia
    cancerdigestivecolon
    targeting CRC may provide novel strategy for CRC treatment
    ANIMAL & CELL MODELS