phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 (SH2 domain-containing inositol-5'-phosphatase 1, SH2 domain-containing inositol phosphatase 1, SHIP-1, inositol polyphosphate-5-phosphatase of 145 kD, SIP-145, p150Ship, hp51CN, INPP5D, SHIP, SHIP1)
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Function
- phosphatidylinositol (PtdIns) phosphatase
- specifically hydrolyzes 5-phosphate of PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thus negatively regulating PI3K pathways
- acts as a negative regulator of B-cell antigen receptor signaling
- mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), thus role in terminating signal transduction from activating immune/hematopoietic cell receptor
- negative regulator of myeloid cell proliferation/survival & chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets & JNK signaling in B-cells
- regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis & activation & is required for endotoxin tolerance
- involved in control of cell-cell junctions, CD32a signaling in neutrophils & modulation of EGF-induced phospholipase C activity
- key regulator of neutrophil migration, by governing formation of the leading edge & polarization required for chemotaxis
- modulates FCGR3/CD16-mediated cytotoxicity in NK cells
- mediates activin/TGF-beta-induced apoptosis through its Smad-dependent expression
- may also hydrolyze PtdIns(1,3,4,5)P4, & could thus affect the levels of the higher inositol polyphosphates including InsP6
- activated upon translocation to the sites of synthesis of PtdIns(3,4,5)P3 in the membrane (putative)
- interacts with tyrosine phosphorylated forms of SHC1, DOK1, DOK3, PTPN11/SHP-2, SLAMF1/CD150
- interacts with PTPN11 in response to IL-3
- interacts with receptors EPOR, MS4A2/FCER1B & FCER1G, FCGR2A, FCGR2B & FCGR3
- interacts with GRB2 & PLCG1
- interacts with tyrosine kinases SRC & TEC
- interacts with FCGR2A, leading to regulate gene expression during the phagocytic process
- interacts with c-Met/MET (putative)
- tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli such as cytokines, growth factors, antibodies, chemokines, integrin ligands & hypertonic & oxidative stress
- phosphorylated upon IgG receptor FCGR2B-binding
phosphatidylinositol 3,4,5-trisphosphate + H2O <--> phosphatidylinositol 3,4-bisphosphate + phosphate
Structure
- SH2 domain interacts with tyrosine phosphorylated forms of proteins such as SHC1 or PTPN11/SHP- it competes with that of GRB2 for binding to phosphorylated SHC1 to inhibit the Ras pathway it is also required for tyrosine phosphorylation
- NPXY sequence motif found in many tyrosine-phosphorylated proteins is required for the specific binding of the PID domain (putative)
- belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family
- contains 1 SH2 domain
Compartment
- cytoplasm, membrane, peripheral membrane
- translocates to the plasma membrane when activated, translocation is probably due to different mechanisms depending on the stimulus & cell type partly translocated via its SH2 domain which mediates interaction with tyrosine phosphorylated receptors including FC-gamma-RIIB receptor (FCGR2B) or CD16/FCGR3
- tyrosine phosphorylation may also participate to membrane localization (putative)
Alternative splicing
named isoforms=3
Expression
- specifically expressed in immune & hematopoietic cells
- expressed in bone marrow & blood cells
- levels vary considerably within this compartment
- present in at least 74% of immature CD34+ cells, whereas within the more mature population of CD33+ cells, it is present in only 10% of cells
- present in the majority of T-cells, while it is present in a minority of B-cells (at protein level)