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O15357

- SHIP2_HUMAN

UniProt

O15357 - SHIP2_HUMAN

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Protein

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

Gene
INPPL1, SHIP2
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

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
Complete GO annotation...

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.3 Publications

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
Complete GO annotation...

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.
Note: Disease susceptibility may be associated with variations affecting the gene represented in this entry.2 Publications
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.
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.1 Publication
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 – 1321Phosphoserine By 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.8 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).2 Publications

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.

Miscellaneous databases

EvolutionaryTraceiO15357.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini21 – 11797SH2Add
BLAST
Domaini1196 – 125863SAMAdd
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 SH2 domain.

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.

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. VSP_027985Add
BLAST

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti307 – 3071I → M in AAA96658. 1 Publication
Sequence conflicti1142 – 11421R → A in AAA50503. 1 Publication
Sequence conflicti1142 – 11421R → A in AAA96658. 1 Publication

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

« Hide 'large scale' publications
  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: September 3, 2014
This is version 110 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

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