Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Basket 0
(max 400 entries)x

Your basket is currently empty.

Select item(s) and click on "Add to basket" to create your own collection here
(400 entries max)

O15357

- SHIP2_HUMAN

UniProt

O15357 - SHIP2_HUMAN

Protein

Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2

Gene

INPPL1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
    • BLAST
    • Align
    • Format
    • Add to basket
    • History
      Entry version 111 (01 Oct 2014)
      Sequence version 2 (24 Nov 2009)
      Previous versions | rss
    • Help video
    • Feedback
    • Comment

    Functioni

    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. 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.9 Publications

    Catalytic activityi

    1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate + H2O = 1-phosphatidyl-1D-myo-inositol 3,4-diphosphate + phosphate.2 Publications

    Enzyme regulationi

    Activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane. Enzymatic activity is enhanced in the presence of phosphatidylserine.1 Publication

    GO - Molecular functioni

    1. hydrolase activity Source: UniProtKB-KW
    2. protein binding Source: UniProtKB
    3. SH2 domain binding Source: UniProtKB

    GO - Biological processi

    1. actin filament organization Source: UniProtKB
    2. cell adhesion Source: UniProtKB
    3. endochondral ossification Source: UniProtKB
    4. endocytosis Source: UniProtKB
    5. glucose metabolic process Source: Ensembl
    6. immune system process Source: UniProtKB-KW
    7. inositol phosphate metabolic process Source: Reactome
    8. negative regulation of cell proliferation Source: Ensembl
    9. negative regulation of gene expression Source: Ensembl
    10. phosphatidylinositol biosynthetic process Source: Reactome
    11. phosphatidylinositol dephosphorylation Source: InterPro
    12. phospholipid metabolic process Source: Reactome
    13. post-embryonic development Source: Ensembl
    14. response to insulin Source: Ensembl
    15. ruffle assembly Source: Ensembl
    16. small molecule metabolic process Source: Reactome

    Keywords - Molecular functioni

    Hydrolase

    Keywords - Biological processi

    Cell adhesion, Immunity

    Keywords - Ligandi

    Actin-binding

    Enzyme and pathway databases

    BioCyciMetaCyc:HS09233-MONOMER.
    ReactomeiREACT_121025. Synthesis of PIPs at the plasma membrane.
    REACT_150312. Synthesis of IP3 and IP4 in the cytosol.
    REACT_23891. Interleukin receptor SHC signaling.
    SABIO-RKO15357.
    SignaLinkiO15357.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (EC:3.1.3.86)
    Alternative name(s):
    Inositol polyphosphate phosphatase-like protein 1
    Short name:
    INPPL-1
    Protein 51C
    SH2 domain-containing inositol 5'-phosphatase 2
    Short name:
    SH2 domain-containing inositol phosphatase 2
    Short name:
    SHIP-2
    Gene namesi
    Name:INPPL1
    Synonyms:SHIP2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 11

    Organism-specific databases

    HGNCiHGNC:6080. INPPL1.

    Subcellular locationi

    Cytoplasmcytosol. Cytoplasmcytoskeleton. Membrane; Peripheral membrane protein. Cell projectionfilopodium. Cell projectionlamellipodium
    Note: Translocates to membrane ruffles when activated, translocation is probably due to different mechanisms depending on the stimulus and cell type. Partly translocated via its SH2 domain which mediates interaction with tyrosine phosphorylated receptors such as the FC-gamma-RIIB receptor (FCGR2B). Tyrosine phosphorylation may also participate in membrane localization. Insulin specifically stimulates its redistribution from the cytosol to the plasma membrane. Recruited to the membrane following M-CSF stimulation. In activated spreading platelets, localizes with actin at filopodia, lamellipodia and the central actin ring.

    GO - Cellular componenti

    1. cytoplasm Source: HPA
    2. cytoskeleton Source: UniProtKB-SubCell
    3. cytosol Source: Reactome
    4. filopodium Source: UniProtKB-SubCell
    5. Golgi apparatus Source: HPA
    6. lamellipodium Source: UniProtKB-SubCell
    7. plasma membrane Source: Ensembl

    Keywords - Cellular componenti

    Cell projection, Cytoplasm, Cytoskeleton, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.2 Publications
    Note: Disease susceptibility may be associated with variations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti632 – 6321L → I Associated with susceptibility to NIDDM. 1 Publication
    Corresponds to variant rs61749195 [ dbSNP | Ensembl ].
    VAR_034980
    Natural varianti982 – 9821N → S Associated with susceptibility to NIDDM. 1 Publication
    Corresponds to variant rs70940821 [ dbSNP | Ensembl ].
    VAR_034982
    Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent.2 Publications
    Opsismodysplasia (OPSMD) [MIM:258480]: A rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with very delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti401 – 4011R → W in OPSMD. 1 Publication
    VAR_069586
    Natural varianti659 – 6591P → S in OPSMD. 1 Publication
    VAR_069587
    Natural varianti688 – 6881W → C in OPSMD. 1 Publication
    VAR_069588
    Natural varianti722 – 7221F → I in OPSMD. 1 Publication
    VAR_069589

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi47 – 471R → G: Abolishes interaction with p130Cas/BCAR1 and its ability to induce increased adhesion. Abolishes phosphorylation upon FCGR2A clustering. 3 Publications
    Mutagenesisi607 – 6071D → A: Abolishes enzyme activity but not phosphorylation upon FCGR2A clustering. 2 Publications
    Mutagenesisi958 – 9581T → A: Reduces PDGF-stimulated tyrosine phosphorylation and association with SHC1. 2 Publications
    Mutagenesisi986 – 9872YY → FF: Inducer a strong reduction of phosphorylation upon re-plating on collagen I. 1 Publication

    Keywords - Diseasei

    Diabetes mellitus, Disease mutation

    Organism-specific databases

    MIMi125853. phenotype.
    258480. phenotype.
    Orphaneti2746. Opsismodysplasia.
    PharmGKBiPA29888.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 12581258Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2PRO_0000302870Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei132 – 1321PhosphoserineBy similarity
    Modified residuei165 – 1651Phosphothreonine1 Publication
    Modified residuei241 – 2411Phosphoserine2 Publications
    Modified residuei958 – 9581Phosphothreonine1 Publication
    Modified residuei986 – 9861Phosphotyrosine; by SRC2 Publications
    Modified residuei1135 – 11351Phosphotyrosine1 Publication
    Modified residuei1162 – 11621Phosphotyrosine1 Publication

    Post-translational modificationi

    Tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli such as insulin, growth factors such as EGF or PDGF, chemokines, integrin ligands and hypertonic and oxidative stress. May be phosphorylated upon IgG receptor FCGR2B-binding. Phosphorylated at Tyr-986 following cell attachment and spreading. Phosphorylated at Tyr-1162 following EGF signaling pathway stimulation. Phosphorylated at Thr-958 in response to PDGF.11 Publications

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    MaxQBiO15357.
    PaxDbiO15357.
    PRIDEiO15357.

    PTM databases

    PhosphoSiteiO15357.

    Expressioni

    Tissue specificityi

    Widely expressed, most prominently in skeletal muscle, heart and brain. Present in platelets. Expressed in transformed myeloid cells and in primary macrophages, but not in peripheral blood monocytes.5 Publications

    Inductioni

    By bacterial lipopolysaccharides (LPS).1 Publication

    Gene expression databases

    ArrayExpressiO15357.
    BgeeiO15357.
    CleanExiHS_INPPL1.
    GenevestigatoriO15357.

    Organism-specific databases

    HPAiHPA037601.

    Interactioni

    Subunit structurei

    Interacts with tyrosine phosphorylated form of SHC1, Interacts with EGFR. Upon stimulation by the EGF signaling pathway, it forms a complex with SHC1 and EGFR. Interacts with cytoskeletal protein SORBS3/vinexin, promoting its localization to the periphery of cells. Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or GP1BB) that regulates cortical and submembraneous actin. Interacts with c-Met/MET, when c-Met/MET is phosphorylated on 'Tyr-1356'. Interacts with p130Cas/BCAR1. Interacts with CENTD3/ARAP3 via its SAM domain. Interacts with c-Cbl/CBL and CAP/SORBS1. Interacts with activated EPHA2 receptor. Interacts with receptors FCGR2A and FCGR2B. Interacts with tyrosine kinases ABL1 and TEC. Interacts with CSF1R.13 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    ARP102753EBI-1384248,EBI-608057
    BCAR1P569452EBI-1384248,EBI-702093
    GAB1Q134802EBI-1384248,EBI-517684
    HID1Q8IV362EBI-1384248,EBI-743438
    ITSN1Q15811-29EBI-1384248,EBI-8052395
    METP085812EBI-1384248,EBI-1039152
    SORBS1Q9BX665EBI-1384248,EBI-433642
    SORBS3O60504-12EBI-1384248,EBI-1222953

    Protein-protein interaction databases

    BioGridi109848. 77 interactions.
    DIPiDIP-39733N.
    IntActiO15357. 23 interactions.
    MINTiMINT-137208.
    STRINGi9606.ENSP00000298229.

    Structurei

    Secondary structure

    1
    1258
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi21 – 233
    Helixi28 – 3811
    Beta strandi41 – 488
    Beta strandi56 – 616
    Beta strandi66 – 727
    Beta strandi75 – 773
    Beta strandi79 – 813
    Beta strandi85 – 873
    Beta strandi91 – 944
    Helixi95 – 1028
    Beta strandi423 – 43210
    Helixi443 – 4464
    Beta strandi450 – 4534
    Helixi459 – 4613
    Beta strandi465 – 4739
    Helixi478 – 49316
    Beta strandi498 – 5058
    Beta strandi508 – 5147
    Helixi516 – 5216
    Beta strandi522 – 53211
    Beta strandi541 – 55010
    Beta strandi553 – 5619
    Helixi569 – 58214
    Turni591 – 5933
    Turni595 – 5984
    Beta strandi599 – 6079
    Beta strandi612 – 6143
    Helixi616 – 6249
    Helixi629 – 6324
    Helixi636 – 6427
    Beta strandi645 – 6473
    Beta strandi690 – 6967
    Beta strandi702 – 7098
    Beta strandi715 – 7184
    Beta strandi721 – 7288
    Helixi1202 – 12065
    Turni1207 – 12093
    Helixi1211 – 12133
    Helixi1214 – 12185
    Turni1219 – 12213
    Helixi1225 – 12284
    Helixi1233 – 12386
    Helixi1244 – 125613

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2K4PNMR-A1194-1258[»]
    2KSONMR-B1200-1258[»]
    2MK2NMR-A20-117[»]
    3NR8X-ray2.80A/B419-732[»]
    4A9CX-ray2.10A/B419-732[»]
    ProteinModelPortaliO15357.
    SMRiO15357. Positions 17-186, 422-731, 1194-1258.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO15357.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini21 – 11797SH2PROSITE-ProRule annotationAdd
    BLAST
    Domaini1196 – 125863SAMPROSITE-ProRule annotationAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi944 – 9496SH3-binding
    Motifi983 – 9864NPXY motif

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi935 – 1105171Pro-richAdd
    BLAST

    Domaini

    The SH2 domain interacts with tyrosine phosphorylated forms of proteins such as SHC1 or FCGR2A. It also mediates the interaction with p130Cas/BCAR1.
    The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain.By similarity

    Sequence similaritiesi

    Contains 1 SAM (sterile alpha motif) domain.PROSITE-ProRule annotation
    Contains 1 SH2 domain.PROSITE-ProRule annotation

    Keywords - Domaini

    SH2 domain, SH3-binding

    Phylogenomic databases

    eggNOGiCOG5411.
    HOGENOMiHOG000004836.
    HOVERGENiHBG106726.
    InParanoidiO15357.
    KOiK15909.
    OMAiYQKHVHT.
    OrthoDBiEOG75F4CD.
    PhylomeDBiO15357.
    TreeFamiTF323475.

    Family and domain databases

    Gene3Di1.10.150.50. 1 hit.
    3.30.505.10. 1 hit.
    3.60.10.10. 1 hit.
    InterProiIPR005135. Endo/exonuclease/phosphatase.
    IPR000300. IPPc.
    IPR001660. SAM.
    IPR013761. SAM/pointed.
    IPR021129. SAM_type1.
    IPR000980. SH2.
    [Graphical view]
    PfamiPF03372. Exo_endo_phos. 1 hit.
    PF00536. SAM_1. 1 hit.
    PF00017. SH2. 1 hit.
    [Graphical view]
    PRINTSiPR00401. SH2DOMAIN.
    SMARTiSM00128. IPPc. 1 hit.
    SM00454. SAM. 1 hit.
    SM00252. SH2. 1 hit.
    [Graphical view]
    SUPFAMiSSF47769. SSF47769. 1 hit.
    SSF55550. SSF55550. 1 hit.
    SSF56219. SSF56219. 1 hit.
    PROSITEiPS50105. SAM_DOMAIN. 1 hit.
    PS50001. SH2. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: O15357-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MASACGAPGP GGALGSQAPS WYHRDLSRAA AEELLARAGR DGSFLVRDSE     50
    SVAGAFALCV LYQKHVHTYR ILPDGEDFLA VQTSQGVPVR RFQTLGELIG 100
    LYAQPNQGLV CALLLPVEGE REPDPPDDRD ASDGEDEKPP LPPRSGSTSI 150
    SAPTGPSSPL PAPETPTAPA AESAPNGLST VSHDYLKGSY GLDLEAVRGG 200
    ASHLPHLTRT LATSCRRLHS EVDKVLSGLE ILSKVFDQQS SPMVTRLLQQ 250
    QNLPQTGEQE LESLVLKLSV LKDFLSGIQK KALKALQDMS STAPPAPQPS 300
    TRKAKTIPVQ AFEVKLDVTL GDLTKIGKSQ KFTLSVDVEG GRLVLLRRQR 350
    DSQEDWTTFT HDRIRQLIKS QRVQNKLGVV FEKEKDRTQR KDFIFVSARK 400
    REAFCQLLQL MKNKHSKQDE PDMISVFIGT WNMGSVPPPK NVTSWFTSKG 450
    LGKTLDEVTV TIPHDIYVFG TQENSVGDRE WLDLLRGGLK ELTDLDYRPI 500
    AMQSLWNIKV AVLVKPEHEN RISHVSTSSV KTGIANTLGN KGAVGVSFMF 550
    NGTSFGFVNC HLTSGNEKTA RRNQNYLDIL RLLSLGDRQL NAFDISLRFT 600
    HLFWFGDLNY RLDMDIQEIL NYISRKEFEP LLRVDQLNLE REKHKVFLRF 650
    SEEEISFPPT YRYERGSRDT YAWHKQKPTG VRTNVPSWCD RILWKSYPET 700
    HIICNSYGCT DDIVTSDHSP VFGTFEVGVT SQFISKKGLS KTSDQAYIEF 750
    ESIEAIVKTA SRTKFFIEFY STCLEEYKKS FENDAQSSDN INFLKVQWSS 800
    RQLPTLKPIL ADIEYLQDQH LLLTVKSMDG YESYGECVVA LKSMIGSTAQ 850
    QFLTFLSHRG EETGNIRGSM KVRVPTERLG TRERLYEWIS IDKDEAGAKS 900
    KAPSVSRGSQ EPRSGSRKPA FTEASCPLSR LFEEPEKPPP TGRPPAPPRA 950
    APREEPLTPR LKPEGAPEPE GVAAPPPKNS FNNPAYYVLE GVPHQLLPPE 1000
    PPSPARAPVP SATKNKVAIT VPAPQLGHHR HPRVGEGSSS DEESGGTLPP 1050
    PDFPPPPLPD SAIFLPPSLD PLPGPVVRGR GGAEARGPPP PKAHPRPPLP 1100
    PGPSPASTFL GEVASGDDRS CSVLQMAKTL SEVDYAPAGP ARSALLPGPL 1150
    ELQPPRGLPS DYGRPLSFPP PRIRESIQED LAEEAPCLQG GRASGLGEAG 1200
    MSAWLRAIGL ERYEEGLVHN GWDDLEFLSD ITEEDLEEAG VQDPAHKRLL 1250
    LDTLQLSK 1258
    Length:1,258
    Mass (Da):138,599
    Last modified:November 24, 2009 - v2
    Checksum:iD76B5AA8ACDE8CBA
    GO
    Isoform 2 (identifier: O15357-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-242: Missing.

    Show »
    Length:1,016
    Mass (Da):113,176
    Checksum:iF99D2FBEDA102C1F
    GO

    Sequence cautioni

    The sequence AAA50503.1 differs from that shown. Reason: Frameshift at position 1153.
    The sequence AAA96658.1 differs from that shown. Reason: Frameshift at several positions.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti307 – 3071I → M in AAA96658. (PubMed:8530088)Curated
    Sequence conflicti1142 – 11421R → A in AAA50503. (PubMed:8530088)Curated
    Sequence conflicti1142 – 11421R → A in AAA96658. (PubMed:8530088)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti401 – 4011R → W in OPSMD. 1 Publication
    VAR_069586
    Natural varianti632 – 6321L → I Associated with susceptibility to NIDDM. 1 Publication
    Corresponds to variant rs61749195 [ dbSNP | Ensembl ].
    VAR_034980
    Natural varianti659 – 6591P → S in OPSMD. 1 Publication
    VAR_069587
    Natural varianti688 – 6881W → C in OPSMD. 1 Publication
    VAR_069588
    Natural varianti721 – 7211V → M.1 Publication
    Corresponds to variant rs116848359 [ dbSNP | Ensembl ].
    VAR_034981
    Natural varianti722 – 7221F → I in OPSMD. 1 Publication
    VAR_069589
    Natural varianti982 – 9821N → S Associated with susceptibility to NIDDM. 1 Publication
    Corresponds to variant rs70940821 [ dbSNP | Ensembl ].
    VAR_034982
    Natural varianti1083 – 10831A → G.1 Publication
    Corresponds to variant rs11548491 [ dbSNP | Ensembl ].
    VAR_034983
    Natural varianti1114 – 11141A → G.3 Publications
    Corresponds to variant rs1049472 [ dbSNP | Ensembl ].
    VAR_034984

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 242242Missing in isoform 2. 1 PublicationVSP_027985Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L24444 mRNA. Translation: AAA50503.1. Frameshift.
    L36818 mRNA. Translation: AAA96658.1. Frameshift.
    Y14385 mRNA. Translation: CAA74743.1.
    AP000593 Genomic DNA. No translation available.
    CH471076 Genomic DNA. Translation: EAW74855.1.
    BC140853 mRNA. Translation: AAI40854.1.
    CCDSiCCDS8213.1. [O15357-1]
    PIRiJC5765.
    RefSeqiNP_001558.3. NM_001567.3. [O15357-1]
    XP_006718597.1. XM_006718534.1. [O15357-1]
    UniGeneiHs.523875.

    Genome annotation databases

    EnsembliENST00000298229; ENSP00000298229; ENSG00000165458. [O15357-1]
    ENST00000538751; ENSP00000444619; ENSG00000165458. [O15357-2]
    ENST00000541756; ENSP00000446360; ENSG00000165458. [O15357-2]
    GeneIDi3636.
    KEGGihsa:3636.
    UCSCiuc001osf.3. human. [O15357-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    Atlas of Genetics and Cytogenetics in Oncology and Haematology

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L24444 mRNA. Translation: AAA50503.1 . Frameshift.
    L36818 mRNA. Translation: AAA96658.1 . Frameshift.
    Y14385 mRNA. Translation: CAA74743.1 .
    AP000593 Genomic DNA. No translation available.
    CH471076 Genomic DNA. Translation: EAW74855.1 .
    BC140853 mRNA. Translation: AAI40854.1 .
    CCDSi CCDS8213.1. [O15357-1 ]
    PIRi JC5765.
    RefSeqi NP_001558.3. NM_001567.3. [O15357-1 ]
    XP_006718597.1. XM_006718534.1. [O15357-1 ]
    UniGenei Hs.523875.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2K4P NMR - A 1194-1258 [» ]
    2KSO NMR - B 1200-1258 [» ]
    2MK2 NMR - A 20-117 [» ]
    3NR8 X-ray 2.80 A/B 419-732 [» ]
    4A9C X-ray 2.10 A/B 419-732 [» ]
    ProteinModelPortali O15357.
    SMRi O15357. Positions 17-186, 422-731, 1194-1258.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 109848. 77 interactions.
    DIPi DIP-39733N.
    IntActi O15357. 23 interactions.
    MINTi MINT-137208.
    STRINGi 9606.ENSP00000298229.

    Chemistry

    ChEMBLi CHEMBL2331064.

    PTM databases

    PhosphoSitei O15357.

    Proteomic databases

    MaxQBi O15357.
    PaxDbi O15357.
    PRIDEi O15357.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000298229 ; ENSP00000298229 ; ENSG00000165458 . [O15357-1 ]
    ENST00000538751 ; ENSP00000444619 ; ENSG00000165458 . [O15357-2 ]
    ENST00000541756 ; ENSP00000446360 ; ENSG00000165458 . [O15357-2 ]
    GeneIDi 3636.
    KEGGi hsa:3636.
    UCSCi uc001osf.3. human. [O15357-1 ]

    Organism-specific databases

    CTDi 3636.
    GeneCardsi GC11P071935.
    H-InvDB HIX0201720.
    HGNCi HGNC:6080. INPPL1.
    HPAi HPA037601.
    MIMi 125853. phenotype.
    258480. phenotype.
    600829. gene.
    neXtProti NX_O15357.
    Orphaneti 2746. Opsismodysplasia.
    PharmGKBi PA29888.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG5411.
    HOGENOMi HOG000004836.
    HOVERGENi HBG106726.
    InParanoidi O15357.
    KOi K15909.
    OMAi YQKHVHT.
    OrthoDBi EOG75F4CD.
    PhylomeDBi O15357.
    TreeFami TF323475.

    Enzyme and pathway databases

    BioCyci MetaCyc:HS09233-MONOMER.
    Reactomei REACT_121025. Synthesis of PIPs at the plasma membrane.
    REACT_150312. Synthesis of IP3 and IP4 in the cytosol.
    REACT_23891. Interleukin receptor SHC signaling.
    SABIO-RK O15357.
    SignaLinki O15357.

    Miscellaneous databases

    ChiTaRSi INPPL1. human.
    EvolutionaryTracei O15357.
    GeneWikii INPPL1.
    GenomeRNAii 3636.
    NextBioi 14233.
    PROi O15357.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O15357.
    Bgeei O15357.
    CleanExi HS_INPPL1.
    Genevestigatori O15357.

    Family and domain databases

    Gene3Di 1.10.150.50. 1 hit.
    3.30.505.10. 1 hit.
    3.60.10.10. 1 hit.
    InterProi IPR005135. Endo/exonuclease/phosphatase.
    IPR000300. IPPc.
    IPR001660. SAM.
    IPR013761. SAM/pointed.
    IPR021129. SAM_type1.
    IPR000980. SH2.
    [Graphical view ]
    Pfami PF03372. Exo_endo_phos. 1 hit.
    PF00536. SAM_1. 1 hit.
    PF00017. SH2. 1 hit.
    [Graphical view ]
    PRINTSi PR00401. SH2DOMAIN.
    SMARTi SM00128. IPPc. 1 hit.
    SM00454. SAM. 1 hit.
    SM00252. SH2. 1 hit.
    [Graphical view ]
    SUPFAMi SSF47769. SSF47769. 1 hit.
    SSF55550. SSF55550. 1 hit.
    SSF56219. SSF56219. 1 hit.
    PROSITEi PS50105. SAM_DOMAIN. 1 hit.
    PS50001. SH2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Cloning and characterization of a human cDNA (INPPL1) sharing homology with inositol polyphosphate phosphatases."
      Hejna J.A., Saito H., Merkens L.S., Tittle T.V., Jakobs P.M., Whitney M.A., Grompe M., Friedberg A.S., Moses R.E.
      Genomics 29:285-287(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY.
    2. "Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP."
      Pesesse X., Deleu S., De Smedt F., Drayer L., Erneux C.
      Biochem. Biophys. Res. Commun. 239:697-700(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, VARIANT GLY-1114.
      Tissue: Hippocampus.
    3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT GLY-1114.
    5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT GLY-1114.
    6. "Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein."
      Habib T., Hejna J.A., Moses R.E., Decker S.J.
      J. Biol. Chem. 273:18605-18609(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, ENZYME ACTIVITY, TISSUE SPECIFICITY, PHOSPHORYLATION, INTERACTION WITH SHC1.
    7. "A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells."
      Wisniewski D., Strife A., Swendeman S., Erdjument-Bromage H., Geromanos S., Kavanaugh W.M., Tempst P., Clarkson B.
      Blood 93:2707-2720(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY, ENZYME ACTIVITY, PHOSPHORYLATION, INTERACTION WITH SHC1 AND ABL1.
    8. "Molecular basis of the recruitment of the SH2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 by fcgamma RIIB."
      Bruhns P., Vely F., Malbec O., Fridman W.H., Vivier E., Daeeron M.
      J. Biol. Chem. 275:37357-37364(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH FCGR2B.
    9. "The Src homology 2 domain containing inositol 5-phosphatase SHIP2 is recruited to the epidermal growth factor (EGF) receptor and dephosphorylates phosphatidylinositol 3,4,5-trisphosphate in EGF-stimulated COS-7 cells."
      Pesesse X., Dewaste V., De Smedt F., Laffargue M., Giuriato S., Moreau C., Payrastre B., Erneux C.
      J. Biol. Chem. 276:28348-28355(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH EGFR AND SHC1, PHOSPHORYLATION AT TYR-986.
    10. "The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin."
      Dyson J.M., O'Malley C.J., Becanovic J., Munday A.D., Berndt M.C., Coghill I.D., Nandurkar H.H., Ooms L.M., Mitchell C.A.
      J. Cell Biol. 155:1065-1079(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH FLNA AND FLNB.
    11. "SH2-containing inositol 5'-phosphatase SHIP2 associates with the p130(Cas) adapter protein and regulates cellular adhesion and spreading."
      Prasad N., Topping R.S., Decker S.J.
      Mol. Cell. Biol. 21:1416-1428(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION, INTERACTION WITH BCAR1, MUTAGENESIS OF ARG-47.
    12. "Tyrosine phosphorylation mapping of the epidermal growth factor receptor signaling pathway."
      Steen H., Kuster B., Fernandez M., Pandey A., Mann M.
      J. Biol. Chem. 277:1031-1039(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT TYR-1162.
    13. "Src family tyrosine kinases regulate adhesion-dependent tyrosine phosphorylation of 5'-inositol phosphatase SHIP2 during cell attachment and spreading on collagen I."
      Prasad N., Topping R.S., Decker S.J.
      J. Cell Sci. 115:3807-3815(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT TYR-986, MUTAGENESIS OF 986-TYR-TYR-987.
    14. "The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2."
      Vandenbroere I., Paternotte N., Dumont J.E., Erneux C., Pirson I.
      Biochem. Biophys. Res. Commun. 300:494-500(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CBL AND SORBS1.
    15. "SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V: localization of SHIP-2 to the activated platelet actin cytoskeleton."
      Dyson J.M., Munday A.D., Kong A.M., Huysmans R.D., Matzaris M., Layton M.J., Nandurkar H.H., Berndt M.C., Mitchell C.A.
      Blood 102:940-948(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INTERACTION WITH ACTIN; FILAMIN AND GPIB.
    16. "SHIP-2 inositol phosphatase is inducibly expressed in human monocytes and serves to regulate Fcgamma receptor-mediated signaling."
      Pengal R.A., Ganesan L.P., Fang H., Marsh C.B., Anderson C.L., Tridandapani S.
      J. Biol. Chem. 278:22657-22663(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, TISSUE SPECIFICITY, INDUCTION, PHOSPHORYLATION, INTERACTION WITH FCGR2A, MUTAGENESIS OF ARG-47 AND ASP-607.
    17. "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."
      Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J.
      Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    18. "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
      Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
      Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1135, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    19. "The influence of anionic lipids on SHIP2 phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase activity."
      Vandeput F., Backers K., Villeret V., Pesesse X., Erneux C.
      Cell. Signal. 18:2193-2199(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: ENZYME REGULATION.
    20. Cited for: INTERACTION WITH SORBS3.
    21. "SH2-containing 5'-inositol phosphatase, SHIP2, regulates cytoskeleton organization and ligand-dependent down-regulation of the epidermal growth factor receptor."
      Prasad N.K., Decker S.J.
      J. Biol. Chem. 280:13129-13136(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    22. "The SH2-domain-containing inositol 5-phosphatase (SHIP)-2 binds to c-Met directly via tyrosine residue 1356 and involves hepatocyte growth factor (HGF)-induced lamellipodium formation, cell scattering and cell spreading."
      Koch A., Mancini A., El Bounkari O., Tamura T.
      Oncogene 24:3436-3447(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH MET.
    23. "The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner."
      Raaijmakers J.H., Deneubourg L., Rehmann H., de Koning J., Zhang Z., Krugmann S., Erneux C., Bos J.L.
      Cell. Signal. 19:1249-1257(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CENTD3.
    24. "Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation."
      Zhuang G., Hunter S., Hwang Y., Chen J.
      J. Biol. Chem. 282:2683-2694(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH EPHA2.
    25. "Regulation of PDGF-stimulated SHIP2 tyrosine phosphorylation and association with Shc in 3T3-L1 preadipocytes."
      Artemenko Y., Gagnon A., Ibrahim S., Sorisky A.
      J. Cell. Physiol. 211:598-607(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-958, MUTAGENESIS OF THR-958.
    26. "The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man."
      Marion E., Kaisaki P.J., Pouillon V., Gueydan C., Levy J.C., Bodson A., Krzentowski G., Daubresse J.-C., Mockel J., Behrends J., Servais G., Szpirer C., Kruys V., Gauguier D., Schurmans S.
      Diabetes 51:2012-2017(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INVOLVEMENT IN NIDDM.
    27. "Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome."
      Kaisaki P.J., Delepine M., Woon P.Y., Sebag-Montefiore L., Wilder S.P., Menzel S., Vionnet N., Marion E., Riveline J.-P., Charpentier G., Schurmans S., Levy J.C., Lathrop M., Farrall M., Gauguier D.
      Diabetes 53:1900-1904(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INVOLVEMENT IN METABOLIC SYNDROME.
    28. "Impact of SRC homology 2-containing inositol 5'-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling."
      Kagawa S., Sasaoka T., Yaguchi S., Ishihara H., Tsuneki H., Murakami S., Fukui K., Wada T., Kobayashi S., Kimura I., Kobayashi M.
      J. Clin. Endocrinol. Metab. 90:2911-2919(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INVOLVEMENT IN NIDDM, VARIANTS ILE-632; MET-721; SER-982 AND GLY-1083.
    29. "Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension."
      Braga Marcano A.C., Burke B., Gungadoo J., Wallace C., Kaisaki P.J., Woon P.Y., Farrall M., Clayton D., Brown M., Dominiczak A., Connell J.M., Webster J., Lathrop M., Caulfield M., Samani N., Gauguier D., Munroe P.B.
      J. Med. Genet. 44:603-605(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: INVOLVEMENT IN METABOLIC SYNDROME.
    30. "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
      Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
      Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    31. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-165 AND SER-241, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    32. "Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
      Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
      Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-241, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    33. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    34. Cited for: FUNCTION, VARIANTS OPSMD TRP-401; SER-659; CYS-688 AND ILE-722.

    Entry informationi

    Entry nameiSHIP2_HUMAN
    AccessioniPrimary (citable) accession number: O15357
    Secondary accession number(s): B2RTX5, Q13577, Q13578
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: September 11, 2007
    Last sequence update: November 24, 2009
    Last modified: October 1, 2014
    This is version 111 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    Its ability to confer resistance to dietary obesity suggests that it may serve as a possible therapeutic target in cases of type 2 diabetes and obesity.

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 11
      Human chromosome 11: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3