phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2 (SH2 domain-containing inositol-5'-phosphatase 2, SHIP-2, inositol polyphosphate phosphatase-like protein 1, INPPL-1, protein 51C, INPPL1, SHIP2)
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Function
- phosphatidylinositol (PtdIns) phosphatase
- specifically hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 to produce PtdIns(3,4)P2, thus negatively regulating PI3K pathways
- role in regulation of PI3K-dependent insulin signaling, molecular mechanisms & signaling pathways unclear
- overexpression reduces both insulin-stimulated MAP kinase & 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
- component of signaling pathway that regulates actin cytoskeleton remodeling
- required for maintenance & dynamic remodeling of actin structures
- role in receptor endocytosis, thus facilitating ligand- induced EGFR internalization & degradation
- role in regulation of cortical & submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thus regulating membrane ruffling
- regulates cell adhesion & cell spreading
- required for HGF-mediated lamellipodium formation, cell scattering & spreading
- acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation
- regulates neuritogenesis by regulating PtdIns(3,4,5)P3 level
- required to form an initial protrusive pattern, & later, maintain proper neurite outgrowth
- negative regulator of the FC-gamma-RIIA receptor (FCGR2A)
- mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), thus plays a role in terminating signal transduction from activating immune/hematopoietic cell receptor systems
- role in EGF signaling pathway
- upon stimulation by EGF, it is recruited by EGFR & dephosphorylates PtdIns(3,4,5)P3
- 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 hydrolyze PtdIns(1,3,4,5)P4, & could thus affect 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
- enzymatic activity is enhanced in the presence of phosphatidylserine
- interacts with tyrosine phosphorylated form of SHC1
- interacts with EGFR
- upon stimulation by the EGF signaling pathway, forms a complex with SHC1 & 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 & 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 & CAP/SORBS1
- interacts with activated EPHA2 receptor
- interacts with receptors FCGR2A & FCGR2B
- interacts with tyrosine kinases ABL1 & TEC
- interacts with CSF1R
- tyrosine phosphorylated by the members of the SRC family after exposure to a diverse array of extracellular stimuli including insulin, growth factors such as EGF or PDGF, chemokines, integrin ligands & hypertonic & oxidative stress
- may be phosphorylated upon IgG receptor FCGR2B-binding
- phosphorylated at Tyr-986 following cell attachment & spreading
- phosphorylated at Tyr-1162 following EGF signaling pathway stimulation
- phosphorylated at Thr-958 in response to PDGF
phosphatidylinositol 3,4,5-trisphosphate + H2O <--> phosphatidylinositol 3,4-bisphosphate + phosphate
Structure
- SH2 domain interacts with tyrosine phosphorylated forms of proteins including SHC1 or FCGR2A
- mediates interaction with p130Cas/BCAR1
- NPXY sequence motif found in many tyrosine- phosphorylated proteins required for the specific binding of PID domain (putative)
- belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family
- contains 1 SAM (sterile alpha motif) domain
- contains 1 SH2 domain
Compartment
- cytoplasm, cytosol, cytoskeleton, actin patch
- membrane, peripheral membrane protein
- translocates to membrane ruffles when activated,
- translocation is probably due to different mechanisms depending on stimulus & cell type
- partly translocated via its SH2 domain which mediates interaction with tyrosine phosphorylated receptors including the FC-gamma-RIIB receptor (FCGR2B)
- tyrosine phosphorylation may also play a role in membrane localization
- insulin specifically stimulates its redistribution from the cytosol to the plasma membrane
- recruited to the membrane following M-CSF stimulation
Alternative splicing
named isoforms=2
Expression
- widely expressed
- most prominent in skeletal muscle, heart & brain
- present in platelets
- expressed in transformed myeloid cells & in primary macrophages, but not in peripheral blood monocytes
- induced by treatment with bacterial lipopolysaccharide
Pathology
- defects in INPPL1 may be a cause of susceptibility to type 2 diabetes mellitus non-insulin dependent (NIDDM)
- genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome