SHIP2_PIG
ID SHIP2_PIG Reviewed; 1260 AA.
AC D7PF45; F1SUW7;
DT 03-JUL-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-JUL-2019, sequence version 2.
DT 03-AUG-2022, entry version 59.
DE RecName: Full=Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2;
DE EC=3.1.3.86 {ECO:0000269|PubMed:12847108};
DE AltName: Full=Inositol polyphosphate phosphatase-like protein 1;
DE Short=INPPL-1;
DE AltName: Full=Protein 51C;
DE AltName: Full=SH2 domain-containing inositol 5'-phosphatase 2;
DE Short=SH2 domain-containing inositol phosphatase 2;
DE Short=SHIP-2;
GN Name=INPPL1; Synonyms=SHIP2;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=21935613; DOI=10.1007/s11010-011-1060-6;
RA Xiong Q., Chai J., Deng C., Jiang S., Li X., Suo X., Zhang N., Yang Q.,
RA Liu Y., Zheng R., Chen M.;
RT "Molecular characterization, expression pattern, and association analysis
RT with carcass traits of the porcine SHIP2 gene.";
RL Mol. Cell. Biochem. 360:225-233(2012).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Duroc;
RG Porcine genome sequencing project;
RL Submitted (NOV-2009) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=12847108; DOI=10.1074/jbc.m300816200;
RA Deleris P., Bacqueville D., Gayral S., Carrez L., Salles J.P., Perret B.,
RA Breton-Douillon M.;
RT "SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell
RT nuclei, but only SHIP-2 is associated with nuclear speckles.";
RL J. Biol. Chem. 278:38884-38891(2003).
CC -!- FUNCTION: Phosphatidylinositol (PtdIns) phosphatase that specifically
CC hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate
CC (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively
CC regulating the PI3K (phosphoinositide 3-kinase) pathways
CC (PubMed:12847108). Plays a central role in regulation of PI3K-dependent
CC insulin signaling, although the precise molecular mechanisms and
CC signaling pathways remain unclear. While overexpression reduces both
CC insulin-stimulated MAP kinase and Akt activation, its absence does not
CC affect insulin signaling or GLUT4 trafficking. Confers resistance to
CC dietary obesity. May act by regulating AKT2, but not AKT1,
CC phosphorylation at the plasma membrane. Part of a signaling pathway
CC that regulates actin cytoskeleton remodeling. Required for the
CC maintenance and dynamic remodeling of actin structures as well as in
CC endocytosis, having a major impact on ligand-induced EGFR
CC internalization and degradation. Participates in regulation of cortical
CC and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby
CC regulating membrane ruffling. Regulates cell adhesion and cell
CC spreading. Required for HGF-mediated lamellipodium formation, cell
CC scattering and spreading. Acts as a negative regulator of EPHA2
CC receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation.
CC Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3
CC level and is required to form an initial protrusive pattern, and later,
CC maintain proper neurite outgrowth. Acts as a negative regulator of the
CC FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-
CC RIIB receptor (FCGR2B), playing a central role in terminating signal
CC transduction from activating immune/hematopoietic cell receptor
CC systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it
CC is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a
CC negative role in regulating the PI3K-PKB pathway, possibly by
CC inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated
CC phagocytosis in macrophages independently of INPP5D/SHIP1. In
CC macrophages, down-regulates NF-kappa-B-dependent gene transcription by
CC regulating macrophage colony-stimulating factor (M-CSF)-induced
CC signaling. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect
CC the levels of the higher inositol polyphosphates like InsP6. Involved
CC in endochondral ossification (By similarity).
CC {ECO:0000250|UniProtKB:O15357, ECO:0000269|PubMed:12847108}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-
CC trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3,4-bisphosphate) + phosphate; Xref=Rhea:RHEA:25528,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57658,
CC ChEBI:CHEBI:57836; EC=3.1.3.86;
CC Evidence={ECO:0000269|PubMed:12847108};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25529;
CC Evidence={ECO:0000305|PubMed:12847108};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-
CC trisphosphate) + H2O = 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3,4-bisphosphate) + phosphate; Xref=Rhea:RHEA:43548,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:83416,
CC ChEBI:CHEBI:83417; Evidence={ECO:0000250|UniProtKB:O15357};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43549;
CC Evidence={ECO:0000250|UniProtKB:O15357};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-
CC 3,4,5-trisphosphate) + H2O = 1,2-dihexadecanoyl-sn-glycero-3-phospho-
CC (1D-myo-inositol-3,4-bisphosphate) + phosphate; Xref=Rhea:RHEA:43556,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:83420,
CC ChEBI:CHEBI:83422; Evidence={ECO:0000250|UniProtKB:O15357};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43557;
CC Evidence={ECO:0000250|UniProtKB:O15357};
CC -!- ACTIVITY REGULATION: Activated upon translocation to the sites of
CC synthesis of PtdIns(3,4,5)P3 in the membrane. Enzymatic activity is
CC enhanced in the presence of phosphatidylserine.
CC {ECO:0000250|UniProtKB:O15357}.
CC -!- SUBUNIT: Interacts with tyrosine phosphorylated form of SHC1. Interacts
CC with EGFR. Upon stimulation by the EGF signaling pathway, it forms a
CC complex with SHC1 and EGFR. Interacts with cytoskeletal protein
CC SORBS3/vinexin, promoting its localization to the periphery of cells.
CC Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or
CC GP1BB) that regulates cortical and submembraneous actin. Interacts with
CC c-Met/MET, when c-Met/MET is phosphorylated on 'Tyr-1356'. Interacts
CC with p130Cas/BCAR1. Interacts with CENTD3/ARAP3 via its SAM domain.
CC Interacts with c-Cbl/CBL and CAP/SORBS1. Interacts with activated EPHA2
CC receptor. Interacts with receptor FCGR2A. Interacts with receptor
CC FCGR2B. Interacts with tyrosine kinase ABL1 (By similarity). Interacts
CC with tyrosine kinase TEC (By similarity). Interacts with CSF1R (By
CC similarity). Interacts (via N-terminus) with SH3YL1 (via SH3 domain).
CC Interacts with FCRL6 (tyrosine phosphorylated form) (By similarity).
CC Interacts (via SH2 domain) with tyrosine phosphorylated KLRC1 (via
CC ITIM). {ECO:0000250|UniProtKB:O15357, ECO:0000250|UniProtKB:Q6P549}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:O15357}. Cytoplasm, cytoskeleton. Membrane
CC {ECO:0000250|UniProtKB:O15357}; Peripheral membrane protein. Cell
CC projection, filopodium {ECO:0000250|UniProtKB:O15357}. Cell projection,
CC lamellipodium {ECO:0000250|UniProtKB:O15357}. Nucleus
CC {ECO:0000269|PubMed:12847108}. Nucleus speckle
CC {ECO:0000269|PubMed:12847108}. Note=Translocates to membrane ruffles
CC when activated, translocation is probably due to different mechanisms
CC depending on the stimulus and cell type. Partly translocated via its
CC SH2 domain which mediates interaction with tyrosine phosphorylated
CC receptors such as the FC-gamma-RIIB receptor (FCGR2B). Tyrosine
CC phosphorylation may also participate in membrane localization. Insulin
CC specifically stimulates its redistribution from the cytosol to the
CC plasma membrane. Recruited to the membrane following M-CSF stimulation.
CC In activated spreading platelets, localizes with actin at filopodia,
CC lamellipodia and the central actin ring.
CC {ECO:0000250|UniProtKB:O15357}.
CC -!- TISSUE SPECIFICITY: Expressed abundantly in skeletal muscle tissue.
CC {ECO:0000269|PubMed:21935613}.
CC -!- DOMAIN: The SH2 domain interacts with tyrosine phosphorylated forms of
CC proteins such as SHC1 or FCGR2A. It also mediates the interaction with
CC p130Cas/BCAR1. {ECO:0000250|UniProtKB:O15357}.
CC -!- DOMAIN: The NPXY sequence motif found in many tyrosine-phosphorylated
CC proteins is required for the specific binding of the PID domain.
CC {ECO:0000250}.
CC -!- PTM: Tyrosine phosphorylated by the members of the SRC family after
CC exposure to a diverse array of extracellular stimuli such as insulin,
CC growth factors such as EGF or PDGF, chemokines, integrin ligands and
CC hypertonic and oxidative stress. May be phosphorylated upon IgG
CC receptor FCGR2B-binding. Phosphorylated at Tyr-988 following cell
CC attachment and spreading. Phosphorylated at Tyr-1164 following EGF
CC signaling pathway stimulation. {ECO:0000250|UniProtKB:O15357}.
CC -!- SIMILARITY: Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase
CC family. {ECO:0000305}.
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DR EMBL; GU391030; ADG23056.1; -; mRNA.
DR EMBL; AEMK02000070; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001177208.1; NM_001190279.1.
DR AlphaFoldDB; D7PF45; -.
DR SMR; D7PF45; -.
DR STRING; 9823.ENSSSCP00000015729; -.
DR SwissLipids; SLP:000000861; -.
DR GeneID; 100462718; -.
DR KEGG; ssc:100462718; -.
DR CTD; 3636; -.
DR eggNOG; KOG0565; Eukaryota.
DR eggNOG; KOG4384; Eukaryota.
DR HOGENOM; CLU_007493_1_1_1; -.
DR OMA; EWISVDQ; -.
DR OrthoDB; 311217at2759; -.
DR TreeFam; TF323475; -.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR Genevisible; D7PF45; SS.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0030175; C:filopodium; IEA:UniProtKB-SubCell.
DR GO; GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0004445; F:inositol-polyphosphate 5-phosphatase activity; IBA:GO_Central.
DR GO; GO:0034485; F:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity; IEA:RHEA.
DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR GO; GO:0043569; P:negative regulation of insulin-like growth factor receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IEA:InterPro.
DR GO; GO:0050776; P:regulation of immune response; IBA:GO_Central.
DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR InterPro; IPR000300; IPPc.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR Pfam; PF00536; SAM_1; 1.
DR Pfam; PF00017; SH2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00128; IPPc; 1.
DR SMART; SM00454; SAM; 1.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR SUPFAM; SSF56219; SSF56219; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW Cell projection; Cytoplasm; Cytoskeleton; Hydrolase; Immunity;
KW Lipid metabolism; Membrane; Nucleus; Phosphoprotein; Reference proteome;
KW SH2 domain; SH3-binding.
FT CHAIN 1..1260
FT /note="Phosphatidylinositol 3,4,5-trisphosphate 5-
FT phosphatase 2"
FT /id="PRO_0000447605"
FT DOMAIN 25..121
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 1198..1260
FT /note="SAM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT REGION 126..178
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 899..1120
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1181..1200
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 946..951
FT /note="SH3-binding"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOTIF 985..988
FT /note="NPXY motif"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT COMPBIAS 126..144
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 159..173
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 940..956
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 997..1011
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1050..1075
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1092..1109
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 136
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 243
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 355
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 888
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 892
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 960
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 988
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 1133
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 1164
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 1259
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT CONFLICT 11
FT /note="G -> GG (in Ref. 1; ADG23056)"
FT /evidence="ECO:0000305"
FT CONFLICT 150
FT /note="G -> GS (in Ref. 1; ADG23056)"
FT /evidence="ECO:0000305"
FT CONFLICT 167
FT /note="E -> ET (in Ref. 1; ADG23056)"
FT /evidence="ECO:0000305"
FT CONFLICT 813
FT /note="L -> LA (in Ref. 1; ADG23056)"
FT /evidence="ECO:0000305"
FT CONFLICT 943
FT /note="T -> N (in Ref. 1; ADG23056)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1260 AA; 138538 MW; ED57E0C2F7A68145 CRC64;
MASACGAPGP GAGPGAALGS PAPAWYHRDL SRAAAEELLA RAGRDGSFLV RDSESVAGAF
ALCVLYQKHV HTYRILPDGE DFLAVQTSQG VPVRRFQTLG ELIGLYAQPN QGLVCALLLP
VERERELDPP DERDASDGED EKPPLPPRSG TSVSAPLGPS SPPAAPEPPT PAVESAPNGL
STVSHEYLKG SYGLDLEAVR GGASNLPHLT RTLAASCRRL HSEVDKVLSG LEILSKVFDQ
QSSPMVTRLL QQQNPPQTGE QELESLVLKL SVLKDFLSGI QKKALKALQD MSSTAPPAPV
QPSTRKAKTI PVQAFEVKLD VTLGDLTKIG KSQKFTLSVD VEGGRLVLLR RQRDSQEDWT
TFTHDRIRQL IKSQRVQNKL GVVFEKEKER TQRKDFIFVS ARKREAFCQL LQLMKNKHSK
QDEPDMISVF IGTWNMGSVP PPRNVTSWFT SKGLGKTLDE VTVTIPHDIY VFGTQENSVG
DREWLDLLRG GLKELTDLDY RPIAMQSLWN IKVAVLVKPE HENRISHVST SSVKTGIANT
LGNKGAVGVS FMFNGTSFGF VNCHLTSGNE KTARRNQNYL DILRLLSLGD RQLGAFDISL
RFTHLFWFGD LNYRLDMDIQ EILNYISRKE FEPLLRVDQL NLEREKHKVF LRFSEEEISF
PPTYRYERGS RDTYAWHKQK PTGVRTNVPS WCDRILWKSH PETHIICNSY GCTDDIVTSD
HSPVFGTFEV GVTSQFISKK GLSKTADQAY IEFESIEAIV KTASRTKFFI EFYSTCLEEY
KKSFENDAQS SDNVNFLKVQ WSSRQLPTLK PILDIEYLQD QHLLLTVKSM DGYESYGECV
VALKSMIGST AQQFLTFLSH RGEETGNIRG SMKVRVPTER LGTRERLYEW ISIDKDEAGA
KSKAPSVSRG SQEPRSGSRK PAPAEASCPL SKLFEEPEKP PPTGRPPAPP RAAPREEPLT
PRLKPEGAPE PEGVAAPPPK NSFNNPAYYV LEGVPHQLLP PEPPSPARAP VPPATKNKVA
ITVPAPQLGR HRPPRVGEGS SSDEESGGTL PPPDFPPPPL PDSAIFLPPS REPLPGPGVR
GRSGGEARAL PPPKAHPRPP LPPGPLPPGT FLGEAAGGDD RSCSVLQVAK KLSEVDSAPP
GPGRCLLLPG PLELQPARAL PSDYGRPLSF PPPRIRESVQ EDLAEEAPCP QAGRTGGLGE
AGMGAWLRAI GLERYEEGLV HNGWDDLEFL SDITEEDLEE AGVQDPAHKR LLLDTLQLSK
