SHIP2_MOUSE
ID SHIP2_MOUSE Reviewed; 1257 AA.
AC Q6P549; O08611; Q0VDX5; Q80YB9; Q9JLL7;
DT 11-SEP-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2;
DE EC=3.1.3.86 {ECO:0000269|PubMed:10958682};
DE AltName: Full=AblSH3-binding protein;
DE AltName: Full=Inositol polyphosphate phosphatase-like protein 1;
DE Short=INPPL-1;
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 Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=10610720; DOI=10.1006/geno.1999.5995;
RA Schurmans S., Carrio R., Behrends J., Pouillon V., Merino J., Clement S.;
RT "The mouse SHIP2 (Inppl1) gene: complementary DNA, genomic structure,
RT promoter analysis, and gene expression in the embryo and adult mouse.";
RL Genomics 62:260-271(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and FVB/N; TISSUE=Brain, and Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 705-1183.
RX PubMed=9126384; DOI=10.1006/abio.1997.2040;
RA Yamabhai M., Kay B.K.;
RT "Examining the specificity of Src homology 3 domain -- ligand interactions
RT with alkaline phosphatase fusion proteins.";
RL Anal. Biochem. 247:143-151(1997).
RN [4]
RP INTERACTION WITH KLRC1.
RX PubMed=9485206;
RX DOI=10.1002/(sici)1521-4141(199801)28:01<264::aid-immu264>3.0.co;2-o;
RA Le Drean E., Vely F., Olcese L., Cambiaggi A., Guia S., Krystal G.,
RA Gervois N., Moretta A., Jotereau F., Vivier E.;
RT "Inhibition of antigen-induced T cell response and antibody-induced NK cell
RT cytotoxicity by NKG2A: association of NKG2A with SHP-1 and SHP-2 protein-
RT tyrosine phosphatases.";
RL Eur. J. Immunol. 28:264-276(1998).
RN [5]
RP INTERACTION WITH FCGR2B, AND PHOSPHORYLATION.
RX PubMed=10789675; DOI=10.1016/s0165-2478(00)00162-0;
RA Muraille E., Bruhns P., Pesesse X., Daeeron M., Erneux C.;
RT "The SH2 domain containing inositol 5-phosphatase SHIP2 associates to the
RT immunoreceptor tyrosine-based inhibition motif of Fc gammaRIIB in B cells
RT under negative signaling.";
RL Immunol. Lett. 72:7-15(2000).
RN [6]
RP FUNCTION, MUTAGENESIS OF ARG-47; ASP-608; CYS-690; ARG-692 AND TYR-987, AND
RP CATALYTIC ACTIVITY.
RX PubMed=10958682; DOI=10.1128/mcb.20.18.6860-6871.2000;
RA Taylor V., Wong M., Brandts C., Reilly L., Dean N.M., Cowsert L.M.,
RA Moodie S., Stokoe D.;
RT "5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation
RT and cell cycle arrest in glioblastoma cells.";
RL Mol. Cell. Biol. 20:6860-6871(2000).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=11343120; DOI=10.1038/35051094;
RA Clement S., Krause U., Desmedt F., Tanti J.-F., Behrends J., Pesesse X.,
RA Sasaki T., Penninger J., Doherty M., Malaisse W., Dumont J.E.,
RA Le Marchand-Brustel Y., Erneux C., Hue L., Schurmans S.;
RT "The lipid phosphatase SHIP2 controls insulin sensitivity.";
RL Nature 409:92-97(2001).
RN [8]
RP ERRATUM OF PUBMED:11343120.
RA Clement S., Krause U., Desmedt F., Tanti J.-F., Behrends J., Pesesse X.,
RA Sasaki T., Penninger J., Doherty M., Malaisse W., Dumont J.E.,
RA Le Marchand-Brustel Y., Erneux C., Hue L., Schurmans S.;
RL Nature 431:878-878(2004).
RN [9]
RP INDUCTION.
RX PubMed=12145149; DOI=10.2337/diabetes.51.8.2387;
RA Hori H., Sasaoka T., Ishihara H., Wada T., Murakami S., Ishiki M.,
RA Kobayashi M.;
RT "Association of SH2-containing inositol phosphatase 2 with the insulin
RT resistance of diabetic db/db mice.";
RL Diabetes 51:2387-2394(2002).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=14744864; DOI=10.1074/jbc.m311534200;
RA Sasaoka T., Wada T., Fukui K., Murakami S., Ishihara H., Suzuki R.,
RA Tobe K., Kadowaki T., Kobayashi M.;
RT "SH2-containing inositol phosphatase 2 predominantly regulates Akt2, and
RT not Akt1, phosphorylation at the plasma membrane in response to insulin in
RT 3T3-L1 adipocytes.";
RL J. Biol. Chem. 279:14835-14843(2004).
RN [11]
RP INTERACTION WITH FCGR2B.
RX PubMed=15456754; DOI=10.1074/jbc.m410261200;
RA Isnardi I., Lesourne R., Bruhns P., Fridman W.H., Cambier J.C., Daeeron M.;
RT "Two distinct tyrosine-based motifs enable the inhibitory receptor
RT FcgammaRIIB to cooperatively recruit the inositol phosphatases SHIP1/2 and
RT the adapters Grb2/Grap.";
RL J. Biol. Chem. 279:51931-51938(2004).
RN [12]
RP INTERACTION WITH TEC.
RX PubMed=15492005; DOI=10.1074/jbc.m408141200;
RA Tomlinson M.G., Heath V.L., Turck C.W., Watson S.P., Weiss A.;
RT "SHIP family inositol phosphatases interact with and negatively regulate
RT the Tec tyrosine kinase.";
RL J. Biol. Chem. 279:55089-55096(2004).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION, AND INTERACTION WITH
RP CSF1R.
RX PubMed=15557176; DOI=10.4049/jimmunol.173.11.6820;
RA Wang Y., Keogh R.J., Hunter M.G., Mitchell C.A., Frey R.S., Javaid K.,
RA Malik A.B., Schurmans S., Tridandapani S., Marsh C.B.;
RT "SHIP2 is recruited to the cell membrane upon macrophage colony-stimulating
RT factor (M-CSF) stimulation and regulates M-CSF-induced signaling.";
RL J. Immunol. 173:6820-6830(2004).
RN [14]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15654325; DOI=10.1038/nm1178;
RA Sleeman M.W., Wortley K.E., Lai K.-M.V., Gowen L.C., Kintner J.,
RA Kline W.O., Garcia K., Stitt T.N., Yancopoulos G.D., Wiegand S.J.,
RA Glass D.J.;
RT "Absence of the lipid phosphatase SHIP2 confers resistance to dietary
RT obesity.";
RL Nat. Med. 11:199-205(2005).
RN [15]
RP FUNCTION.
RX PubMed=16179375; DOI=10.1182/blood-2005-05-1841;
RA Ai J., Maturu A., Johnson W., Wang Y., Marsh C.B., Tridandapani S.;
RT "The inositol phosphatase SHIP-2 down-regulates FcgammaR-mediated
RT phagocytosis in murine macrophages independently of SHIP-1.";
RL Blood 107:813-820(2006).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-132, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [18]
RP INTERACTION WITH SH3YL1.
RX PubMed=21624956; DOI=10.1083/jcb.201012161;
RA Hasegawa J., Tokuda E., Tenno T., Tsujita K., Sawai H., Hiroaki H.,
RA Takenawa T., Itoh T.;
RT "SH3YL1 regulates dorsal ruffle formation by a novel phosphoinositide-
RT binding domain.";
RL J. Cell Biol. 193:901-916(2011).
RN [19] {ECO:0007744|PDB:5ZRX}
RP X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) OF 1200-1257 IN COMPLEX WITH EPHA2,
RP FUNCTION, AND MUTAGENESIS OF ASP-1222 AND PHE-1226.
RX PubMed=29749928; DOI=10.7554/elife.35677;
RA Wang Y., Shang Y., Li J., Chen W., Li G., Wan J., Liu W., Zhang M.;
RT "Specific Eph receptor-cytoplasmic effector signaling mediated by SAM-SAM
RT domain interactions.";
RL Elife 7:0-0(2018).
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:10958682). 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 (By similarity). Regulates cell adhesion
CC and cell spreading (PubMed:29749928). Required for HGF-mediated
CC lamellipodium formation, cell scattering and spreading. Acts as a
CC negative regulator of EPHA2 receptor endocytosis by inhibiting via
CC PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis
CC by regulating PtdIns(3,4,5)P3 level and is required to form an initial
CC protrusive pattern, and later, maintain proper neurite outgrowth. Acts
CC as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A).
CC Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a
CC central role in terminating signal transduction from activating
CC immune/hematopoietic cell receptor systems. Involved in EGF signaling
CC pathway. Upon stimulation by EGF, it is recruited by EGFR and
CC dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating
CC the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-
CC regulates Fc-gamma-R-mediated phagocytosis in macrophages independently
CC of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent
CC gene transcription by regulating macrophage colony-stimulating factor
CC (M-CSF)-induced signaling. May also hydrolyze PtdIns(1,3,4,5)P4, and
CC could thus affect the levels of the higher inositol polyphosphates like
CC InsP6. Involved in endochondral ossification (By similarity).
CC {ECO:0000250|UniProtKB:O15357, ECO:0000269|PubMed:10958682,
CC ECO:0000269|PubMed:11343120, ECO:0000269|PubMed:14744864,
CC ECO:0000269|PubMed:15557176, ECO:0000269|PubMed:15654325,
CC ECO:0000269|PubMed:16179375, ECO:0000269|PubMed:29749928}.
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:10958682};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25529;
CC Evidence={ECO:0000305|PubMed:10958682};
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 (By similarity).
CC {ECO:0000250}.
CC -!- SUBUNIT: Interacts with tyrosine phosphorylated form of SHC1 (By
CC similarity). Interacts with EGFR (By similarity). Upon stimulation by
CC the EGF signaling pathway, it forms a complex with SHC1 and EGFR (By
CC similarity). Interacts with cytoskeletal protein SORBS3/vinexin,
CC promoting its localization to the periphery of cells (By similarity).
CC Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or
CC GP1BB) that regulates cortical and submembraneous actin (By
CC similarity). Interacts with c-Met/MET, when c-Met/MET is phosphorylated
CC on 'Tyr-1356' (By similarity). Interacts with p130Cas/BCAR1 (By
CC similarity). Interacts with CENTD3/ARAP3 via its SAM domain (By
CC similarity). Interacts with c-Cbl/CBL and CAP/SORBS1 (By similarity).
CC Interacts with activated EPHA2 receptor (PubMed:29749928). Interacts
CC with receptors FCGR2A (By similarity). Interacts with FCGR2B
CC (PubMed:10789675, PubMed:15456754). Interacts with tyrosine kinase ABL1
CC (By similarity). Interacts with tyrosine kinase TEC (PubMed:15492005).
CC Interacts with CSF1R (PubMed:15557176). Interacts (via N-terminus) with
CC SH3YL1 (via SH3 domain) (PubMed:21624956). Interacts (via SH2 domain)
CC with tyrosine phosphorylated KLRC1 (via ITIM).
CC {ECO:0000250|UniProtKB:O15357, ECO:0000269|PubMed:10789675,
CC ECO:0000269|PubMed:15456754, ECO:0000269|PubMed:15492005,
CC ECO:0000269|PubMed:15557176, ECO:0000269|PubMed:21624956,
CC ECO:0000269|PubMed:29749928, ECO:0000269|PubMed:9485206}.
CC -!- INTERACTION:
CC Q6P549; Q9Z0R4-2: Itsn1; NbExp=2; IntAct=EBI-2642932, EBI-8052786;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9WVR3}. Cytoplasm, cytoskeleton {ECO:0000250}.
CC Membrane {ECO:0000250|UniProtKB:Q9WVR3}; Peripheral membrane protein.
CC Cell projection, filopodium {ECO:0000250|UniProtKB:O15357}. Cell
CC projection, lamellipodium {ECO:0000250|UniProtKB:O15357}. Nucleus
CC {ECO:0000250|UniProtKB:D7PF45}. Nucleus speckle
CC {ECO:0000250|UniProtKB:D7PF45}. 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 -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:10610720}.
CC -!- DEVELOPMENTAL STAGE: In 15.5 dpc embryos, it is strongly expressed in
CC the liver, specific regions of the central nervous system, the thymus,
CC the lung, and the cartilage perichondrium. In adult it is markedly
CC present in the brain and the thymus and at different stages of
CC spermatozoa maturation in the seminiferous tubules.
CC {ECO:0000269|PubMed:10610720}.
CC -!- INDUCTION: Overexpressed in diabetic db/db mice.
CC {ECO:0000269|PubMed:12145149}.
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 (By similarity). {ECO:0000250}.
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-987 following cell
CC attachment and spreading. Phosphorylated at Tyr-1161 following EGF
CC signaling pathway stimulation (By similarity). {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable, have normal glucose and insulin
CC levels, and normal insulin and glucose tolerance. They are however
CC highly resistant to weight gain when placed on a high-fat diet,
CC suggesting that inhibition of Inppl1 would be useful in the effort to
CC ameliorate diet-induced obesity. According to preliminary results from
CC PubMed:11343120, mice display increased sensitivity to insulin,
CC characterized by severe neonatal hypoglycemia, deregulated expression
CC of the genes involved in gluconeogenesis, and perinatal death. They
CC display increased glucose tolerance and insulin sensitivity associated
CC with an increased recruitment of the Slc2a4/Glut4 glucose transporter
CC and increased glycogen synthesis in skeletal muscles. However, these
CC knockout mice also contain a deletion of the last exon of Phox2a gene.
CC It is therefore unknown whether the insulin sensitivity observed in
CC these mice result from inactivation of either Inppl1 or Phox2a.
CC {ECO:0000269|PubMed:11343120, ECO:0000269|PubMed:15654325}.
CC -!- SIMILARITY: Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase
CC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAI19454.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF162781; AAF28187.1; -; mRNA.
DR EMBL; BC049961; AAH49961.1; -; mRNA.
DR EMBL; BC063080; AAH63080.1; -; mRNA.
DR EMBL; BC119453; AAI19454.1; ALT_INIT; mRNA.
DR EMBL; U92477; AAB82337.1; -; mRNA.
DR CCDS; CCDS21515.1; -.
DR RefSeq; NP_001116211.1; NM_001122739.1.
DR RefSeq; NP_034697.2; NM_010567.2.
DR RefSeq; XP_006507454.1; XM_006507391.3.
DR RefSeq; XP_011239984.1; XM_011241682.2.
DR RefSeq; XP_017177480.1; XM_017321991.1.
DR PDB; 5ZRX; X-ray; 1.50 A; A/B=1200-1257.
DR PDBsum; 5ZRX; -.
DR AlphaFoldDB; Q6P549; -.
DR BMRB; Q6P549; -.
DR SMR; Q6P549; -.
DR BioGRID; 200770; 16.
DR IntAct; Q6P549; 6.
DR MINT; Q6P549; -.
DR STRING; 10090.ENSMUSP00000048057; -.
DR ChEMBL; CHEMBL2331063; -.
DR iPTMnet; Q6P549; -.
DR PhosphoSitePlus; Q6P549; -.
DR EPD; Q6P549; -.
DR MaxQB; Q6P549; -.
DR PaxDb; Q6P549; -.
DR PeptideAtlas; Q6P549; -.
DR PRIDE; Q6P549; -.
DR ProteomicsDB; 257225; -.
DR Antibodypedia; 30825; 357 antibodies from 33 providers.
DR DNASU; 16332; -.
DR Ensembl; ENSMUST00000035836; ENSMUSP00000048057; ENSMUSG00000032737.
DR Ensembl; ENSMUST00000165052; ENSMUSP00000132883; ENSMUSG00000032737.
DR GeneID; 16332; -.
DR KEGG; mmu:16332; -.
DR UCSC; uc009ipg.2; mouse.
DR CTD; 3636; -.
DR MGI; MGI:1333787; Inppl1.
DR VEuPathDB; HostDB:ENSMUSG00000032737; -.
DR eggNOG; KOG0565; Eukaryota.
DR eggNOG; KOG4384; Eukaryota.
DR GeneTree; ENSGT00940000156576; -.
DR InParanoid; Q6P549; -.
DR OMA; EWISVDQ; -.
DR OrthoDB; 311217at2759; -.
DR PhylomeDB; Q6P549; -.
DR TreeFam; TF323475; -.
DR BRENDA; 3.1.3.36; 3474.
DR Reactome; R-MMU-1660499; Synthesis of PIPs at the plasma membrane.
DR Reactome; R-MMU-1855204; Synthesis of IP3 and IP4 in the cytosol.
DR Reactome; R-MMU-912526; Interleukin receptor SHC signaling.
DR BioGRID-ORCS; 16332; 4 hits in 79 CRISPR screens.
DR ChiTaRS; Inppl1; mouse.
DR PRO; PR:Q6P549; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q6P549; protein.
DR Bgee; ENSMUSG00000032737; Expressed in hindlimb stylopod muscle and 260 other tissues.
DR ExpressionAtlas; Q6P549; baseline and differential.
DR Genevisible; Q6P549; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0030175; C:filopodium; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0030027; C:lamellipodium; ISO:MGI.
DR GO; GO:0016607; C:nuclear speck; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0003779; F:actin binding; IEA:UniProtKB-KW.
DR GO; GO:0004445; F:inositol-polyphosphate 5-phosphatase activity; ISO:MGI.
DR GO; GO:0034485; F:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity; IEA:RHEA.
DR GO; GO:0005547; F:phosphatidylinositol-3,4,5-trisphosphate binding; ISO:MGI.
DR GO; GO:0042169; F:SH2 domain binding; ISO:MGI.
DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR GO; GO:0007015; P:actin filament organization; ISO:MGI.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0044255; P:cellular lipid metabolic process; IMP:MGI.
DR GO; GO:0001958; P:endochondral ossification; ISS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; ISO:MGI.
DR GO; GO:0006006; P:glucose metabolic process; IMP:MGI.
DR GO; GO:0002376; P:immune system process; IEA:UniProtKB-KW.
DR GO; GO:0032957; P:inositol trisphosphate metabolic process; ISO:MGI.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:MGI.
DR GO; GO:0008156; P:negative regulation of DNA replication; ISO:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:MGI.
DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISO:MGI.
DR GO; GO:0043569; P:negative regulation of insulin-like growth factor receptor signaling pathway; ISO:MGI.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; ISO:MGI.
DR GO; GO:0010977; P:negative regulation of neuron projection development; ISO:MGI.
DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; ISO:MGI.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; IMP:MGI.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IEA:InterPro.
DR GO; GO:0009791; P:post-embryonic development; IMP:MGI.
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 GO; GO:0032868; P:response to insulin; IMP:MGI.
DR GO; GO:0097178; P:ruffle assembly; IMP:MGI.
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 3D-structure; Actin-binding; Cell adhesion; Cell projection; Cytoplasm;
KW Cytoskeleton; Hydrolase; Immunity; Lipid metabolism; Membrane; Nucleus;
KW Phosphoprotein; Reference proteome; SH2 domain; SH3-binding.
FT CHAIN 1..1257
FT /note="Phosphatidylinositol 3,4,5-trisphosphate 5-
FT phosphatase 2"
FT /id="PRO_0000302871"
FT DOMAIN 21..117
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 1195..1257
FT /note="SAM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT REGION 119..181
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 897..986
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 999..1119
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1134..1196
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 945..950
FT /note="SH3-binding"
FT MOTIF 984..987
FT /note="NPXY motif"
FT COMPBIAS 120..140
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 939..955
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1049..1065
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1089..1105
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 132
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355"
FT MOD_RES 165
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 241
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 353
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 887
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 891
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 987
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 1132
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 1136
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 1161
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MOD_RES 1256
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15357"
FT MUTAGEN 47
FT /note="R->A: Does not affect the ability to inhibit PKB
FT activity."
FT /evidence="ECO:0000269|PubMed:10958682"
FT MUTAGEN 608
FT /note="D->A: Abolishes both enzyme activity and ability to
FT inhibit PKB activity."
FT /evidence="ECO:0000269|PubMed:10958682"
FT MUTAGEN 690
FT /note="C->A: Induces little effect."
FT /evidence="ECO:0000269|PubMed:10958682"
FT MUTAGEN 692
FT /note="R->A: Still partially active."
FT /evidence="ECO:0000269|PubMed:10958682"
FT MUTAGEN 987
FT /note="Y->F: Does not affect the ability to inhibit PKB
FT activity."
FT /evidence="ECO:0000269|PubMed:10958682"
FT MUTAGEN 1222
FT /note="D->A: Abolishes interaction with EPHA2 SAM domain."
FT /evidence="ECO:0000269|PubMed:29749928"
FT MUTAGEN 1226
FT /note="F->A,L: Abolishes interaction with EPHA2 SAM
FT domain."
FT /evidence="ECO:0000269|PubMed:29749928"
FT CONFLICT 412
FT /note="M -> I (in Ref. 1; AAF28187)"
FT /evidence="ECO:0000305"
FT CONFLICT 506
FT /note="L -> I (in Ref. 1; AAF28187)"
FT /evidence="ECO:0000305"
FT CONFLICT 705
FT /note="C -> S (in Ref. 3; AAB82337)"
FT /evidence="ECO:0000305"
FT CONFLICT 972
FT /note="G -> V (in Ref. 1; AAF28187)"
FT /evidence="ECO:0000305"
FT HELIX 1200..1206
FT /evidence="ECO:0007829|PDB:5ZRX"
FT HELIX 1210..1212
FT /evidence="ECO:0007829|PDB:5ZRX"
FT HELIX 1213..1218
FT /evidence="ECO:0007829|PDB:5ZRX"
FT HELIX 1224..1227
FT /evidence="ECO:0007829|PDB:5ZRX"
FT HELIX 1232..1237
FT /evidence="ECO:0007829|PDB:5ZRX"
FT HELIX 1243..1255
FT /evidence="ECO:0007829|PDB:5ZRX"
SQ SEQUENCE 1257 AA; 138973 MW; B66DF96BEF22F01E CRC64;
MASVCGTPSP GGALGSPAPA WYHRDLSRAA AEELLARAGR DGSFLVRDSE SVAGAFALCV
LYQKHVHTYR ILPDGEDFLA VQTSQGVPVR RFQTLGELIG LYAQPNQGLV CALLLPVEGE
REPDPPDDRD ASDVEDEKPP LPPRSGSTSI SAPVGPSSPL PTPETPTTPA AESTPNGLST
VSHEYLKGSY GLDLEAVRGG ASNLPHLTRT LVTSCRRLHS EVDKVLSGLE ILSKVFDQQS
SPMVTRLLQQ QSLPQTGEQE LESLVLKLSV LKDFLSGIQK KALKALQDMS STAPPAPLQP
SIRKAKTIPV QAFEVKLDVT LGDLTKIGKS QKFTLSVDVE GGRLVLLRRQ RDSQEDWTTF
THDRIRQLIK SQRVQNKLGV VFEKEKDRTQ RKDFIFVSAR KREAFCQLLQ LMKNRHSKQD
EPDMISVFIG TWNMGSVPPP KNVTSWFTSK GLGKALDEVT VTIPHDIYVF GTQENSVGDR
EWLDLLRGGL KELTDLDYRP IAMQSLWNIK VAVLVKPEHE NRISHVSTSS VKTGIANTLG
NKGAVGVSFM FNGTSFGFVN CHLTSGNEKT TRRNQNYLDI LRLLSLGDRQ LSAFDISLRF
THLFWFGDLN YRLDMDIQEI LNYISRREFE PLLRVDQLNL EREKHKVFLR FSEEEISFPP
TYRYERGSRD TYAWHKQKPT GVRTNVPSWC DRILWKSYPE THIICNSYGC TDDIVTSDHS
PVFGTFEVGV TSQFISKKGL SKTSDQAYIE FESIEAIVKT ASRTKFFIEF YSTCLEEYKK
SFENDAQSSD NINFLKVQWS SRQLPTLKPI LADIEYLQDQ HLLLTVKSMD GYESYGECVV
ALKSMIGSTA QQFLTFLSHR GEETGNIRGS MKVRVPTERL GTRERLYEWI SIDKDDTGAK
SKVPSVSRGS QEHRSGSRKP ASTETSCPLS KLFEEPEKPP PTGRPPAPPR AVPREEPLNP
RLKSEGTSEQ EGVAAPPPKN SFNNPAYYVL EGVPHQLLPL EPPSLARAPL PPATKNKVAI
TVPAPQLGRH RTPRVGEGSS SDEDSGGTLP PPDFPPPPLP DSAIFLPPNL DPLSMPVVRG
RSGGEARGPP PPKAHPRPPL PPGTSPASTF LGEVASGDDR SCSVLQMAKT LSEVDYAPGP
GRSALLPNPL ELQPPRGPSD YGRPLSFPPP RIRESIQEDL AEEAPCPQGG RASGLGEAGM
GAWLRAIGLE RYEEGLVHNG WDDLEFLSDI TEEDLEEAGV QDPAHKRLLL DTLQLSK
