Q9WVR3 (SHIP2_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified May 1, 2013. Version 81. History...
Names and origin
|Protein names||Recommended name:|
Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2
Inositol polyphosphate phosphatase-like protein 1
SH2 domain-containing inositol 5'-phosphatase 2
Short name=SH2 domain-containing inositol phosphatase 2
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||1257 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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. Ref.1 Ref.3 Ref.4 Ref.5
1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate + H2O = 1-phosphatidyl-1D-myo-inositol 3,4-diphosphate + phosphate.
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.
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 By similarity.
Cytoplasm › cytosol. Cytoplasm › cytoskeleton By similarity. Membrane; Peripheral membrane protein. Cell projection › filopodium By similarity. Cell projection › lamellipodium By similarity. Note: Translocates to membrane ruffles when activated, translocation is probably due to different mechanisms depending on the stimulus and cell type. Partly translocated via its SH2 domain which mediates interaction with tyrosine phosphorylated receptors such as the FC-gamma-RIIB receptor (FCGR2B). Tyrosine phosphorylation may also participate in membrane localization. Insulin specifically stimulates its redistribution from the cytosol to the plasma membrane. Recruited to the membrane following M-CSF stimulation. In activated spreading platelets, localizes with actin at filopodia, lamellipodia and the central actin ring. Ref.4
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.
The NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain By similarity.
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. Ref.1
Variant Cys-1142 found in diabetic GK strain may be a cause of diabete in this strain. Genetic variations in Inppl1 may also be a cause of susceptibility to hypertension.
Belongs to the inositol 1,4,5-trisphosphate 5-phosphatase family.
Contains 1 SAM (sterile alpha motif) domain.
Contains 1 SH2 domain.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: Q9WVR3-1) |
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: Q9WVR3-2) |
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 1257||1257||Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2||PRO_0000302872|
|Domain||21 – 117||97||SH2|
|Domain||1195 – 1257||63||SAM|
|Motif||945 – 950||6||SH3-binding|
|Motif||984 – 987||4||NPXY motif|
|Compositional bias||936 – 1106||171||Pro-rich|
Amino acid modifications
|Modified residue||165||1||Phosphothreonine By similarity|
|Modified residue||241||1||Phosphoserine By similarity|
|Modified residue||987||1||Phosphotyrosine By similarity|
|Modified residue||1136||1||Phosphotyrosine By similarity|
|Modified residue||1161||1||Phosphotyrosine By similarity|
|Alternative sequence||1184 – 1257||74||Missing in isoform 2.||VSP_027986|
|Natural variant||1142||1||R → C in strain: GK. Ref.6|
|Mutagenesis||987||1||Y → F: Loss of phosphorylation following insulin stimulation. Ref.4|
|Sequence conflict||910||1||S → N in BAA81818. Ref.1|
|Sequence conflict||1009||1||P → L in BAA81818. Ref.1|
|||"Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin signaling."|
Ishihara H., Sasaoka T., Hori H., Wada T., Hirai H., Haruta T., Kobayashi M.
Biochem. Biophys. Res. Commun. 260:265-272(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, PHOSPHORYLATION.
|||"Localization of mRNA for SHIP2, SH2 domain-containing inositol polyphosphate 5-phosphatase, in the brain of developing and mature rats."|
Kudo M., Saito S., Owada Y., Suzaki H., Kondo H.
Brain Res. Mol. Brain Res. 75:172-177(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
|||"Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5'-phosphatase catalytic activity."|
Wada T., Sasaoka T., Funaki M., Hori H., Murakami S., Ishiki M., Haruta T., Asano T., Ogawa W., Ishihara H., Kobayashi M.
Mol. Cell. Biol. 21:1633-1646(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"Membrane localization of Src homology 2-containing inositol 5'-phosphatase 2 via Shc association is required for the negative regulation of insulin signaling in Rat1 fibroblasts overexpressing insulin receptors."|
Ishihara H., Sasaoka T., Ishiki M., Wada T., Hori H., Kagawa S., Kobayashi M.
Mol. Endocrinol. 16:2371-2381(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF TYR-987.
|||"An essential role for the SHIP2-dependent negative feedback loop in neuritogenesis of nerve growth factor-stimulated PC12 cells."|
Aoki K., Nakamura T., Inoue T., Meyer T., Matsuda M.
J. Cell Biol. 177:817-827(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"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: VARIANT CYS-1142.
|+||Additional computationally mapped references.|
|AB011439 mRNA. Translation: BAA81818.1.|
AB025794 mRNA. Translation: BAA82308.1.
|RefSeq||NP_001257772.1. NM_001270843.1. |
3D structure databases
|HSSP||HSSP built from PDB template 1D1Z based on UniProtKB O60880. |
|SMR||Q9WVR3. Positions 18-119. |
Protein-protein interaction databases
|IntAct||Q9WVR3. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|UCSC||RGD:68396. rat. |
|RGD||68396. Inppl1. |
Gene expression databases
Family and domain databases
|Gene3D||220.127.116.11. 1 hit. |
3.30.505.10. 1 hit.
|InterPro||IPR005135. Endo/exonuclease/phosphatase. |
|Pfam||PF03372. Exo_endo_phos. 1 hit. |
PF07647. SAM_2. 1 hit.
PF00017. SH2. 1 hit.
|PRINTS||PR00401. SH2DOMAIN. |
|SMART||SM00128. IPPc. 1 hit. |
SM00454. SAM. 1 hit.
SM00252. SH2. 1 hit.
|SUPFAM||SSF56219. Exo_endo_phos. 1 hit. |
SSF47769. SAM_homology. 1 hit.
|PROSITE||PS50105. SAM_DOMAIN. 1 hit. |
PS50001. SH2. 1 hit.
|Accession||Primary (citable) accession number: Q9WVR3|
Secondary accession number(s): Q9R1V2
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families