Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

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

Gene

Inppl1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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 (By similarity). 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 (By similarity).By similarity6 Publications

Catalytic activityi

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

Activity 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 (By similarity).By similarity

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActin-binding, Hydrolase
Biological processCell adhesion, Immunity

Enzyme and pathway databases

BRENDAi3.1.3.36 3474
ReactomeiR-MMU-1660499 Synthesis of PIPs at the plasma membrane
R-MMU-1855204 Synthesis of IP3 and IP4 in the cytosol
R-MMU-912526 Interleukin receptor SHC signaling

Names & Taxonomyi

Protein namesi
Recommended name:
Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 (EC:3.1.3.86)
Alternative name(s):
AblSH3-binding protein
Inositol polyphosphate phosphatase-like protein 1
Short name:
INPPL-1
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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 7

Organism-specific databases

MGIiMGI:1333787 Inppl1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell projection, Cytoplasm, Cytoskeleton, Membrane

Pathology & Biotechi

Disruption phenotypei

Mice are viable, have normal glucose and insulin levels, and normal insulin and glucose tolerance. They are however highly resistant to weight gain when placed on a high-fat diet, suggesting that inhibition of Inppl1 would be useful in the effort to ameliorate diet-induced obesity. According to preliminary results from PubMed:11343120, mice display increased sensitivity to insulin, characterized by severe neonatal hypoglycemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. They display increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the Slc2a4/Glut4 glucose transporter and increased glycogen synthesis in skeletal muscles. However, these knockout mice also contain a deletion of the last exon of Phox2a gene. It is therefore unknown whether the insulin sensitivity observed in these mice result from inactivation of either Inppl1 or Phox2a.2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi47R → A: Does not affect the ability to inhibit PKB activity. 1 Publication1
Mutagenesisi608D → A: Abolishes both enzyme activity and ability to inhibit PKB activity. 1 Publication1
Mutagenesisi690C → A: Induces little effect. 1 Publication1
Mutagenesisi692R → A: Still partially active. 1 Publication1
Mutagenesisi987Y → F: Does not affect the ability to inhibit PKB activity. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL2331063

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003028711 – 1257Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2Add BLAST1257

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei132PhosphoserineCombined sources1
Modified residuei165PhosphothreonineBy similarity1
Modified residuei241PhosphoserineBy similarity1
Modified residuei353PhosphoserineBy similarity1
Modified residuei887PhosphotyrosineBy similarity1
Modified residuei891PhosphoserineBy similarity1
Modified residuei987PhosphotyrosineBy similarity1
Modified residuei1132PhosphoserineBy similarity1
Modified residuei1136PhosphotyrosineBy similarity1
Modified residuei1161PhosphotyrosineBy similarity1
Modified residuei1256PhosphoserineBy similarity1

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-987 following cell attachment and spreading. Phosphorylated at Tyr-1161 following EGF signaling pathway stimulation (By similarity).By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ6P549
MaxQBiQ6P549
PaxDbiQ6P549
PeptideAtlasiQ6P549
PRIDEiQ6P549

PTM databases

iPTMnetiQ6P549
PhosphoSitePlusiQ6P549

Expressioni

Tissue specificityi

Widely expressed.1 Publication

Developmental stagei

In E15.5 embryos, it is strongly expressed in the liver, specific regions of the central nervous system, the thymus, the lung, and the cartilage perichondrium. In adult it is markedly present in the brain and the thymus and at different stages of spermatozoa maturation in the seminiferous tubules.1 Publication

Inductioni

Overexpressed in diabetic db/db mice.1 Publication

Gene expression databases

BgeeiENSMUSG00000032737 Expressed in 299 organ(s), highest expression level in heart
CleanExiMM_INPPL1
ExpressionAtlasiQ6P549 baseline and differential
GenevisibleiQ6P549 MM

Interactioni

Subunit structurei

Interacts with tyrosine phosphorylated form of SHC1 (By similarity). Interacts with EGFR (By similarity). Upon stimulation by the EGF signaling pathway, it forms a complex with SHC1 and EGFR (By similarity). Interacts with cytoskeletal protein SORBS3/vinexin, promoting its localization to the periphery of cells (By similarity). Forms a complex with filamin (FLNA or FLNB), actin, GPIb (GP1BA or GP1BB) that regulates cortical and submembraneous actin (By similarity). Interacts with c-Met/MET, when c-Met/MET is phosphorylated on 'Tyr-1356' (By similarity). Interacts with p130Cas/BCAR1 (By similarity). Interacts with CENTD3/ARAP3 via its SAM domain (By similarity). Interacts with c-Cbl/CBL and CAP/SORBS1 (By similarity). Interacts with activated EPHA2 receptor (By similarity). Interacts with receptors FCGR2A (By similarity). Interacts with FCGR2B (PubMed:10789675, PubMed:15456754). Interacts with tyrosine kinase ABL1 (By similarity). Interacts with tyrosine kinase TEC (PubMed:15492005). Interacts with CSF1R (PubMed:15557176). Interacts (via N-terminus) with SH3YL1 (via SH3 domain) (PubMed:21624956).By similarity5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Itsn1Q9Z0R4-22EBI-2642932,EBI-8052786

GO - Molecular functioni

Protein-protein interaction databases

BioGridi200770, 5 interactors
IntActiQ6P549, 6 interactors
MINTiQ6P549
STRINGi10090.ENSMUSP00000048057

Structurei

Secondary structure

11257
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ6P549
SMRiQ6P549
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini21 – 117SH2PROSITE-ProRule annotationAdd BLAST97
Domaini1195 – 1257SAMPROSITE-ProRule annotationAdd BLAST63

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi945 – 950SH3-binding6
Motifi984 – 987NPXY motif4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi936 – 1170Pro-richAdd BLAST235

Domaini

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

Sequence similaritiesi

Keywords - Domaini

SH2 domain, SH3-binding

Phylogenomic databases

eggNOGiKOG0565 Eukaryota
KOG4384 Eukaryota
COG5411 LUCA
GeneTreeiENSGT00760000119075
HOGENOMiHOG000004836
HOVERGENiHBG106726
InParanoidiQ6P549
KOiK15909
OMAiVKSMDGY
OrthoDBiEOG091G00P6
PhylomeDBiQ6P549
TreeFamiTF323475

Family and domain databases

Gene3Di3.30.505.10, 1 hit
3.60.10.10, 1 hit
InterProiView protein in InterPro
IPR036691 Endo/exonu/phosph_ase_sf
IPR005135 Endo/exonuclease/phosphatase
IPR000300 IPPc
IPR001660 SAM
IPR013761 SAM/pointed_sf
IPR000980 SH2
IPR036860 SH2_dom_sf
PfamiView protein in Pfam
PF03372 Exo_endo_phos, 1 hit
PF00536 SAM_1, 1 hit
PF00017 SH2, 1 hit
PRINTSiPR00401 SH2DOMAIN
SMARTiView protein in SMART
SM00128 IPPc, 1 hit
SM00454 SAM, 1 hit
SM00252 SH2, 1 hit
SUPFAMiSSF47769 SSF47769, 1 hit
SSF55550 SSF55550, 1 hit
SSF56219 SSF56219, 1 hit
PROSITEiView protein in PROSITE
PS50105 SAM_DOMAIN, 1 hit
PS50001 SH2, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 3 potential isoforms that are computationally mapped.Show allAlign All

Q6P549-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MASVCGTPSP GGALGSPAPA WYHRDLSRAA AEELLARAGR DGSFLVRDSE
60 70 80 90 100
SVAGAFALCV LYQKHVHTYR ILPDGEDFLA VQTSQGVPVR RFQTLGELIG
110 120 130 140 150
LYAQPNQGLV CALLLPVEGE REPDPPDDRD ASDVEDEKPP LPPRSGSTSI
160 170 180 190 200
SAPVGPSSPL PTPETPTTPA AESTPNGLST VSHEYLKGSY GLDLEAVRGG
210 220 230 240 250
ASNLPHLTRT LVTSCRRLHS EVDKVLSGLE ILSKVFDQQS SPMVTRLLQQ
260 270 280 290 300
QSLPQTGEQE LESLVLKLSV LKDFLSGIQK KALKALQDMS STAPPAPLQP
310 320 330 340 350
SIRKAKTIPV QAFEVKLDVT LGDLTKIGKS QKFTLSVDVE GGRLVLLRRQ
360 370 380 390 400
RDSQEDWTTF THDRIRQLIK SQRVQNKLGV VFEKEKDRTQ RKDFIFVSAR
410 420 430 440 450
KREAFCQLLQ LMKNRHSKQD EPDMISVFIG TWNMGSVPPP KNVTSWFTSK
460 470 480 490 500
GLGKALDEVT VTIPHDIYVF GTQENSVGDR EWLDLLRGGL KELTDLDYRP
510 520 530 540 550
IAMQSLWNIK VAVLVKPEHE NRISHVSTSS VKTGIANTLG NKGAVGVSFM
560 570 580 590 600
FNGTSFGFVN CHLTSGNEKT TRRNQNYLDI LRLLSLGDRQ LSAFDISLRF
610 620 630 640 650
THLFWFGDLN YRLDMDIQEI LNYISRREFE PLLRVDQLNL EREKHKVFLR
660 670 680 690 700
FSEEEISFPP TYRYERGSRD TYAWHKQKPT GVRTNVPSWC DRILWKSYPE
710 720 730 740 750
THIICNSYGC TDDIVTSDHS PVFGTFEVGV TSQFISKKGL SKTSDQAYIE
760 770 780 790 800
FESIEAIVKT ASRTKFFIEF YSTCLEEYKK SFENDAQSSD NINFLKVQWS
810 820 830 840 850
SRQLPTLKPI LADIEYLQDQ HLLLTVKSMD GYESYGECVV ALKSMIGSTA
860 870 880 890 900
QQFLTFLSHR GEETGNIRGS MKVRVPTERL GTRERLYEWI SIDKDDTGAK
910 920 930 940 950
SKVPSVSRGS QEHRSGSRKP ASTETSCPLS KLFEEPEKPP PTGRPPAPPR
960 970 980 990 1000
AVPREEPLNP RLKSEGTSEQ EGVAAPPPKN SFNNPAYYVL EGVPHQLLPL
1010 1020 1030 1040 1050
EPPSLARAPL PPATKNKVAI TVPAPQLGRH RTPRVGEGSS SDEDSGGTLP
1060 1070 1080 1090 1100
PPDFPPPPLP DSAIFLPPNL DPLSMPVVRG RSGGEARGPP PPKAHPRPPL
1110 1120 1130 1140 1150
PPGTSPASTF LGEVASGDDR SCSVLQMAKT LSEVDYAPGP GRSALLPNPL
1160 1170 1180 1190 1200
ELQPPRGPSD YGRPLSFPPP RIRESIQEDL AEEAPCPQGG RASGLGEAGM
1210 1220 1230 1240 1250
GAWLRAIGLE RYEEGLVHNG WDDLEFLSDI TEEDLEEAGV QDPAHKRLLL

DTLQLSK
Length:1,257
Mass (Da):138,973
Last modified:July 5, 2004 - v1
Checksum:iB66DF96BEF22F01E
GO

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A087WPT7A0A087WPT7_MOUSE
Phosphatidylinositol 3,4,5-trisphos...
Inppl1
1,166Annotation score:
A0A1B0GST7A0A1B0GST7_MOUSE
Phosphatidylinositol 3,4,5-trisphos...
Inppl1
276Annotation score:
A0A1B0GR64A0A1B0GR64_MOUSE
Phosphatidylinositol 3,4,5-trisphos...
Inppl1
603Annotation score:

Sequence cautioni

The sequence AAI19454 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti412M → I in AAF28187 (PubMed:10610720).Curated1
Sequence conflicti506L → I in AAF28187 (PubMed:10610720).Curated1
Sequence conflicti705C → S in AAB82337 (PubMed:9126384).Curated1
Sequence conflicti972G → V in AAF28187 (PubMed:10610720).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF162781 mRNA Translation: AAF28187.1
BC049961 mRNA Translation: AAH49961.1
BC063080 mRNA Translation: AAH63080.1
BC119453 mRNA Translation: AAI19454.1 Different initiation.
U92477 mRNA Translation: AAB82337.1
CCDSiCCDS21515.1
RefSeqiNP_001116211.1, NM_001122739.1
NP_034697.2, NM_010567.2
XP_006507454.1, XM_006507391.3
XP_011239984.1, XM_011241682.2
XP_017177480.1, XM_017321991.1
UniGeneiMm.476000

Genome annotation databases

EnsembliENSMUST00000035836; ENSMUSP00000048057; ENSMUSG00000032737
ENSMUST00000165052; ENSMUSP00000132883; ENSMUSG00000032737
GeneIDi16332
KEGGimmu:16332
UCSCiuc009ipg.2 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF162781 mRNA Translation: AAF28187.1
BC049961 mRNA Translation: AAH49961.1
BC063080 mRNA Translation: AAH63080.1
BC119453 mRNA Translation: AAI19454.1 Different initiation.
U92477 mRNA Translation: AAB82337.1
CCDSiCCDS21515.1
RefSeqiNP_001116211.1, NM_001122739.1
NP_034697.2, NM_010567.2
XP_006507454.1, XM_006507391.3
XP_011239984.1, XM_011241682.2
XP_017177480.1, XM_017321991.1
UniGeneiMm.476000

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5ZRXX-ray1.50A/B1200-1257[»]
ProteinModelPortaliQ6P549
SMRiQ6P549
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi200770, 5 interactors
IntActiQ6P549, 6 interactors
MINTiQ6P549
STRINGi10090.ENSMUSP00000048057

Chemistry databases

ChEMBLiCHEMBL2331063

PTM databases

iPTMnetiQ6P549
PhosphoSitePlusiQ6P549

Proteomic databases

EPDiQ6P549
MaxQBiQ6P549
PaxDbiQ6P549
PeptideAtlasiQ6P549
PRIDEiQ6P549

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000035836; ENSMUSP00000048057; ENSMUSG00000032737
ENSMUST00000165052; ENSMUSP00000132883; ENSMUSG00000032737
GeneIDi16332
KEGGimmu:16332
UCSCiuc009ipg.2 mouse

Organism-specific databases

CTDi3636
MGIiMGI:1333787 Inppl1

Phylogenomic databases

eggNOGiKOG0565 Eukaryota
KOG4384 Eukaryota
COG5411 LUCA
GeneTreeiENSGT00760000119075
HOGENOMiHOG000004836
HOVERGENiHBG106726
InParanoidiQ6P549
KOiK15909
OMAiVKSMDGY
OrthoDBiEOG091G00P6
PhylomeDBiQ6P549
TreeFamiTF323475

Enzyme and pathway databases

BRENDAi3.1.3.36 3474
ReactomeiR-MMU-1660499 Synthesis of PIPs at the plasma membrane
R-MMU-1855204 Synthesis of IP3 and IP4 in the cytosol
R-MMU-912526 Interleukin receptor SHC signaling

Miscellaneous databases

ChiTaRSiInppl1 mouse
PROiPR:Q6P549
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000032737 Expressed in 299 organ(s), highest expression level in heart
CleanExiMM_INPPL1
ExpressionAtlasiQ6P549 baseline and differential
GenevisibleiQ6P549 MM

Family and domain databases

Gene3Di3.30.505.10, 1 hit
3.60.10.10, 1 hit
InterProiView protein in InterPro
IPR036691 Endo/exonu/phosph_ase_sf
IPR005135 Endo/exonuclease/phosphatase
IPR000300 IPPc
IPR001660 SAM
IPR013761 SAM/pointed_sf
IPR000980 SH2
IPR036860 SH2_dom_sf
PfamiView protein in Pfam
PF03372 Exo_endo_phos, 1 hit
PF00536 SAM_1, 1 hit
PF00017 SH2, 1 hit
PRINTSiPR00401 SH2DOMAIN
SMARTiView protein in SMART
SM00128 IPPc, 1 hit
SM00454 SAM, 1 hit
SM00252 SH2, 1 hit
SUPFAMiSSF47769 SSF47769, 1 hit
SSF55550 SSF55550, 1 hit
SSF56219 SSF56219, 1 hit
PROSITEiView protein in PROSITE
PS50105 SAM_DOMAIN, 1 hit
PS50001 SH2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiSHIP2_MOUSE
AccessioniPrimary (citable) accession number: Q6P549
Secondary accession number(s): O08611
, Q0VDX5, Q80YB9, Q9JLL7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 11, 2007
Last sequence update: July 5, 2004
Last modified: September 12, 2018
This is version 122 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

Do not show this banner again