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O15357 (SHIP2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 109. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:INPPL1
Synonyms:SHIP2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1258 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.6 Ref.9 Ref.10 Ref.13 Ref.15 Ref.16 Ref.21 Ref.24 Ref.34

Catalytic activity

1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate + H2O = 1-phosphatidyl-1D-myo-inositol 3,4-diphosphate + phosphate. Ref.6 Ref.7

Enzyme regulation

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. Ref.19

Subunit structure

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. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.14 Ref.15 Ref.16 Ref.20 Ref.22 Ref.23 Ref.24

Subcellular location

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. Ref.9 Ref.10 Ref.15

Tissue specificity

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. Ref.1 Ref.2 Ref.6 Ref.15 Ref.16

Induction

By bacterial lipopolysaccharides (LPS). Ref.16 Ref.19

Domain

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.

Post-translational modification

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. Ref.6 Ref.7 Ref.9 Ref.11 Ref.12 Ref.13 Ref.16 Ref.25

Involvement in disease

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.
Note: Disease susceptibility may be associated with variations affecting the gene represented in this entry. Ref.26 Ref.28

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.

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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.34

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.

Sequence similarities

Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.

Contains 1 SAM (sterile alpha motif) domain.

Contains 1 SH2 domain.

Sequence caution

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.

Ontologies

Keywords
   Biological processCell adhesion
Immunity
   Cellular componentCell projection
Cytoplasm
Cytoskeleton
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDiabetes mellitus
Disease mutation
   DomainSH2 domain
SH3-binding
   LigandActin-binding
   Molecular functionHydrolase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactin filament organization

Inferred from mutant phenotype Ref.21. Source: UniProtKB

cell adhesion

Traceable author statement Ref.21. Source: UniProtKB

endochondral ossification

Inferred from mutant phenotype Ref.34. Source: UniProtKB

endocytosis

Inferred from mutant phenotype Ref.21. Source: UniProtKB

glucose metabolic process

Inferred from electronic annotation. Source: Ensembl

immune system process

Inferred from electronic annotation. Source: UniProtKB-KW

inositol phosphate metabolic process

Traceable author statement. Source: Reactome

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

negative regulation of gene expression

Inferred from electronic annotation. Source: Ensembl

phosphatidylinositol biosynthetic process

Traceable author statement. Source: Reactome

phosphatidylinositol dephosphorylation

Inferred from electronic annotation. Source: InterPro

phospholipid metabolic process

Traceable author statement. Source: Reactome

post-embryonic development

Inferred from electronic annotation. Source: Ensembl

response to insulin

Inferred from electronic annotation. Source: Ensembl

ruffle assembly

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentGolgi apparatus

Inferred from direct assay. Source: HPA

cytoplasm

Inferred from direct assay. Source: HPA

cytoskeleton

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytosol

Traceable author statement. Source: Reactome

filopodium

Inferred from electronic annotation. Source: UniProtKB-SubCell

lamellipodium

Inferred from electronic annotation. Source: UniProtKB-SubCell

plasma membrane

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionSH2 domain binding

Inferred from physical interaction PubMed 5668240. Source: UniProtKB

hydrolase activity

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction PubMed 21712384. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O15357-1)

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.
Isoform 2 (identifier: O15357-2)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 12581258Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2
PRO_0000302870

Regions

Domain21 – 11797SH2
Domain1196 – 125863SAM
Motif944 – 9496SH3-binding
Motif983 – 9864NPXY motif
Compositional bias935 – 1105171Pro-rich

Amino acid modifications

Modified residue1321Phosphoserine By similarity
Modified residue1651Phosphothreonine Ref.31
Modified residue2411Phosphoserine Ref.31 Ref.32
Modified residue9581Phosphothreonine Ref.25
Modified residue9861Phosphotyrosine; by SRC Ref.9 Ref.13
Modified residue11351Phosphotyrosine Ref.18
Modified residue11621Phosphotyrosine Ref.12

Natural variations

Alternative sequence1 – 242242Missing in isoform 2.
VSP_027985
Natural variant4011R → W in OPSMD. Ref.34
VAR_069586
Natural variant6321L → I Associated with susceptibility to NIDDM. Ref.28
Corresponds to variant rs61749195 [ dbSNP | Ensembl ].
VAR_034980
Natural variant6591P → S in OPSMD. Ref.34
VAR_069587
Natural variant6881W → C in OPSMD. Ref.34
VAR_069588
Natural variant7211V → M. Ref.28
Corresponds to variant rs116848359 [ dbSNP | Ensembl ].
VAR_034981
Natural variant7221F → I in OPSMD. Ref.34
VAR_069589
Natural variant9821N → S Associated with susceptibility to NIDDM. Ref.28
Corresponds to variant rs70940821 [ dbSNP | Ensembl ].
VAR_034982
Natural variant10831A → G. Ref.28
Corresponds to variant rs11548491 [ dbSNP | Ensembl ].
VAR_034983
Natural variant11141A → G. Ref.2 Ref.4 Ref.5
Corresponds to variant rs1049472 [ dbSNP | Ensembl ].
VAR_034984

Experimental info

Mutagenesis471R → G: Abolishes interaction with p130Cas/BCAR1 and its ability to induce increased adhesion. Abolishes phosphorylation upon FCGR2A clustering. Ref.11 Ref.13 Ref.16
Mutagenesis6071D → A: Abolishes enzyme activity but not phosphorylation upon FCGR2A clustering. Ref.13 Ref.16
Mutagenesis9581T → A: Reduces PDGF-stimulated tyrosine phosphorylation and association with SHC1. Ref.13 Ref.25
Mutagenesis986 – 9872YY → FF: Inducer a strong reduction of phosphorylation upon re-plating on collagen I. Ref.13
Sequence conflict3071I → M in AAA96658. Ref.1
Sequence conflict11421R → A in AAA50503. Ref.1
Sequence conflict11421R → A in AAA96658. Ref.1

Secondary structure

................................................................................. 1258
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 24, 2009. Version 2.
Checksum: D76B5AA8ACDE8CBA

FASTA1,258138,599
        10         20         30         40         50         60 
MASACGAPGP GGALGSQAPS WYHRDLSRAA AEELLARAGR DGSFLVRDSE SVAGAFALCV 

        70         80         90        100        110        120 
LYQKHVHTYR ILPDGEDFLA VQTSQGVPVR RFQTLGELIG LYAQPNQGLV CALLLPVEGE 

       130        140        150        160        170        180 
REPDPPDDRD ASDGEDEKPP LPPRSGSTSI SAPTGPSSPL PAPETPTAPA AESAPNGLST 

       190        200        210        220        230        240 
VSHDYLKGSY GLDLEAVRGG ASHLPHLTRT LATSCRRLHS EVDKVLSGLE ILSKVFDQQS 

       250        260        270        280        290        300 
SPMVTRLLQQ QNLPQTGEQE LESLVLKLSV LKDFLSGIQK KALKALQDMS STAPPAPQPS 

       310        320        330        340        350        360 
TRKAKTIPVQ AFEVKLDVTL GDLTKIGKSQ KFTLSVDVEG GRLVLLRRQR DSQEDWTTFT 

       370        380        390        400        410        420 
HDRIRQLIKS QRVQNKLGVV FEKEKDRTQR KDFIFVSARK REAFCQLLQL MKNKHSKQDE 

       430        440        450        460        470        480 
PDMISVFIGT WNMGSVPPPK NVTSWFTSKG LGKTLDEVTV TIPHDIYVFG TQENSVGDRE 

       490        500        510        520        530        540 
WLDLLRGGLK ELTDLDYRPI AMQSLWNIKV AVLVKPEHEN RISHVSTSSV KTGIANTLGN 

       550        560        570        580        590        600 
KGAVGVSFMF NGTSFGFVNC HLTSGNEKTA RRNQNYLDIL RLLSLGDRQL NAFDISLRFT 

       610        620        630        640        650        660 
HLFWFGDLNY RLDMDIQEIL NYISRKEFEP LLRVDQLNLE REKHKVFLRF SEEEISFPPT 

       670        680        690        700        710        720 
YRYERGSRDT YAWHKQKPTG VRTNVPSWCD RILWKSYPET HIICNSYGCT DDIVTSDHSP 

       730        740        750        760        770        780 
VFGTFEVGVT SQFISKKGLS KTSDQAYIEF ESIEAIVKTA SRTKFFIEFY STCLEEYKKS 

       790        800        810        820        830        840 
FENDAQSSDN INFLKVQWSS RQLPTLKPIL ADIEYLQDQH LLLTVKSMDG YESYGECVVA 

       850        860        870        880        890        900 
LKSMIGSTAQ QFLTFLSHRG EETGNIRGSM KVRVPTERLG TRERLYEWIS IDKDEAGAKS 

       910        920        930        940        950        960 
KAPSVSRGSQ EPRSGSRKPA FTEASCPLSR LFEEPEKPPP TGRPPAPPRA APREEPLTPR 

       970        980        990       1000       1010       1020 
LKPEGAPEPE GVAAPPPKNS FNNPAYYVLE GVPHQLLPPE PPSPARAPVP SATKNKVAIT 

      1030       1040       1050       1060       1070       1080 
VPAPQLGHHR HPRVGEGSSS DEESGGTLPP PDFPPPPLPD SAIFLPPSLD PLPGPVVRGR 

      1090       1100       1110       1120       1130       1140 
GGAEARGPPP PKAHPRPPLP PGPSPASTFL GEVASGDDRS CSVLQMAKTL SEVDYAPAGP 

      1150       1160       1170       1180       1190       1200 
ARSALLPGPL ELQPPRGLPS DYGRPLSFPP PRIRESIQED LAEEAPCLQG GRASGLGEAG 

      1210       1220       1230       1240       1250 
MSAWLRAIGL ERYEEGLVHN GWDDLEFLSD ITEEDLEEAG VQDPAHKRLL LDTLQLSK 

« Hide

Isoform 2 [UniParc].

Checksum: F99D2FBEDA102C1F
Show »

FASTA1,016113,176

References

« Hide 'large scale' references
[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]"Human chromosome 11 DNA sequence and analysis including novel gene identification."
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. expand/collapse author list , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y.
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
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]"SHIP2 interaction with the cytoskeletal protein Vinexin."
Paternotte N., Zhang J., Vandenbroere I., Backers K., Blero D., Kioka N., Vanderwinden J.-M., Pirson I., Erneux C.
FEBS J. 272:6052-6066(2005) [PubMed] [Europe PMC] [Abstract]
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]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
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]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[34]"Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia."
Huber C., Faqeih E.A., Bartholdi D., Bole-Feysot C., Borochowitz Z., Cavalcanti D.P., Frigo A., Nitschke P., Roume J., Santos H.G., Shalev S.A., Superti-Furga A., Delezoide A.L., Le Merrer M., Munnich A., Cormier-Daire V.
Am. J. Hum. Genet. 92:144-149(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, VARIANTS OPSMD TRP-401; SER-659; CYS-688 AND ILE-722.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS8213.1. [O15357-1]
PIRJC5765.
RefSeqNP_001558.3. NM_001567.3. [O15357-1]
XP_006718597.1. XM_006718534.1. [O15357-1]
UniGeneHs.523875.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2K4PNMR-A1194-1258[»]
2KSONMR-B1200-1258[»]
2MK2NMR-A20-117[»]
3NR8X-ray2.80A/B419-732[»]
4A9CX-ray2.10A/B419-732[»]
ProteinModelPortalO15357.
SMRO15357. Positions 17-186, 422-731, 1194-1258.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109848. 77 interactions.
DIPDIP-39733N.
IntActO15357. 23 interactions.
MINTMINT-137208.
STRING9606.ENSP00000298229.

Chemistry

ChEMBLCHEMBL2331064.

PTM databases

PhosphoSiteO15357.

Proteomic databases

MaxQBO15357.
PaxDbO15357.
PRIDEO15357.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000298229; ENSP00000298229; ENSG00000165458. [O15357-1]
ENST00000538751; ENSP00000444619; ENSG00000165458. [O15357-2]
ENST00000541756; ENSP00000446360; ENSG00000165458. [O15357-2]
GeneID3636.
KEGGhsa:3636.
UCSCuc001osf.3. human. [O15357-1]

Organism-specific databases

CTD3636.
GeneCardsGC11P071935.
H-InvDBHIX0201720.
HGNCHGNC:6080. INPPL1.
HPAHPA037601.
MIM125853. phenotype.
258480. phenotype.
600829. gene.
neXtProtNX_O15357.
Orphanet2746. Opsismodysplasia.
PharmGKBPA29888.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5411.
HOGENOMHOG000004836.
HOVERGENHBG106726.
InParanoidO15357.
KOK15909.
OMAYQKHVHT.
OrthoDBEOG75F4CD.
PhylomeDBO15357.
TreeFamTF323475.

Enzyme and pathway databases

BioCycMetaCyc:HS09233-MONOMER.
ReactomeREACT_111217. Metabolism.
REACT_6900. Immune System.
SABIO-RKO15357.
SignaLinkO15357.

Gene expression databases

ArrayExpressO15357.
BgeeO15357.
CleanExHS_INPPL1.
GenevestigatorO15357.

Family and domain databases

Gene3D1.10.150.50. 1 hit.
3.30.505.10. 1 hit.
3.60.10.10. 1 hit.
InterProIPR005135. Endo/exonuclease/phosphatase.
IPR000300. IPPc.
IPR001660. SAM.
IPR013761. SAM/pointed.
IPR021129. SAM_type1.
IPR000980. SH2.
[Graphical view]
PfamPF03372. Exo_endo_phos. 1 hit.
PF00536. SAM_1. 1 hit.
PF00017. SH2. 1 hit.
[Graphical view]
PRINTSPR00401. SH2DOMAIN.
SMARTSM00128. IPPc. 1 hit.
SM00454. SAM. 1 hit.
SM00252. SH2. 1 hit.
[Graphical view]
SUPFAMSSF47769. SSF47769. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56219. SSF56219. 1 hit.
PROSITEPS50105. SAM_DOMAIN. 1 hit.
PS50001. SH2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSINPPL1. human.
EvolutionaryTraceO15357.
GeneWikiINPPL1.
GenomeRNAi3636.
NextBio14233.
PROO15357.
SOURCESearch...

Entry information

Entry nameSHIP2_HUMAN
AccessionPrimary (citable) accession number: O15357
Secondary accession number(s): B2RTX5, Q13577, Q13578
Entry history
Integrated into UniProtKB/Swiss-Prot: September 11, 2007
Last sequence update: November 24, 2009
Last modified: July 9, 2014
This is version 109 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM