241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update: 11 Mar, 2019
Cytoplasm, cytosol Cytoplasm, cytoskeletonMembrane; Peripheral membrane protein Cell projection,filopodium Cell projection, lamellipodium Note=Translocates tomembrane ruffles when activated, translocation is probably due todifferent mechanisms depending on the stimulus and cell typePartly translocated via its SH2 domain which mediates interactionwith tyrosine phosphorylated receptors such as the FC-gamma-RIIBreceptor (FCGR2B) Tyrosine phosphorylation may also participatein membrane localization Insulin specifically stimulates itsredistribution from the cytosol to the plasma membrane Recruitedto the membrane following M-CSF stimulation In activatedspreading platelets, localizes with actin at filopodia,lamellipodia and the central actin ring
Function (UniProt annotation)
Phosphatidylinositol (PtdIns) phosphatase thatspecifically 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-dependentinsulin signaling, although the precise molecular mechanisms andsignaling pathways remain unclear While overexpression reducesboth insulin-stimulated MAP kinase and Akt activation, its absencedoes not affect insulin signaling or GLUT4 trafficking Confersresistance to dietary obesity May act by regulating AKT2, but notAKT1, phosphorylation at the plasma membrane Part of a signalingpathway that regulates actin cytoskeleton remodeling Required forthe maintenance and dynamic remodeling of actin structures as wellas in endocytosis, having a major impact on ligand-induced EGFRinternalization and degradation Participates in regulation ofcortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3thereby regulating membrane ruffling (PubMed:21624956) Regulatescell adhesion and cell spreading Required for HGF-mediatedlamellipodium formation, cell scattering and spreading Acts as anegative regulator of EPHA2 receptor endocytosis by inhibiting viaPI3K-dependent Rac1 activation Acts as a regulator ofneuritogenesis by regulating PtdIns(3,4,5)P3 level and is requiredto form an initial protrusive pattern, and later, maintain properneurite outgrowth Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A) Mediates signaling from the FC-gamma-RIIBreceptor (FCGR2B), playing a central role in terminating signaltransduction from activating immune/hematopoietic cell receptorsystems Involved in EGF signaling pathway Upon stimulation byEGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3Plays a negative role in regulating the PI3K-PKB pathway, possiblyby inhibiting PKB activity Down-regulates Fc-gamma-R-mediatedphagocytosis in macrophages independently of INPP5D/SHIP1 Inmacrophages, down-regulates NF-kappa-B-dependent genetranscription 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 inositolpolyphosphates like InsP6 Involved in endochondral ossification
B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes.
Phagocytosis plays an essential role in host-defense mechanisms through the uptake and destruction of infectious pathogens. Specialized cell types including macrophages, neutrophils, and monocytes take part in this process in higher organisms. After opsonization with antibodies (IgG), foreign extracellular materials are recognized by Fc gamma receptors. Cross-linking of Fc gamma receptors initiates a variety of signals mediated by tyrosine phosphorylation of multiple proteins, which lead through the actin cytoskeleton rearrangements and membrane remodeling to the formation of phagosomes. Nascent phagosomes undergo a process of maturation that involves fusion with lysosomes. The acquisition of lysosomal proteases and release of reactive oxygen species are crucial for digestion of engulfed materials in phagosomes.
Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.
At the plasma membrane, subsequent phosphorylation of phosphatidylinositol 4-phosphate (PI4P) produces phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) while the actions of various other kinases and phosphatases produces phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 5-phosphate (PI5P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (Zhang et al. 1997, Gurung et al. 2003, Guo et al. 1999, Vanhaesebroeck et al. 1997, Tolias et al. 1998, Schaletzky et al. 2003, Kim et al. 2002, Clarke et al. 2010). Many of the phosphatidylinositol phosphatases that act at the plasma membrane belong to the myotubularin family. Enzymatically inactive myotubularin family members can heterodimerize with catalytically active mytotubularins to regulate their stability, activity and/or substrate specificity (Berger et al. 2006, Zou et al. 2012)
An array of inositol trisphosphate (IP3) and tetrakisphosphate (IP4) molecules are synthesised by the action of various kinases and phosphatases in the cytosol (Irvine & Schell 2001, Bunney & Katan 2010)
Phosphorylation of Shc at three tyrosine residues, 239, 240 (Gotoh et al. 1996) and 317 (Salcini et al. 1994) involves unidentified tyrosine kinases presumed to be part of the activated receptor complex. These phosphorylated tyrosines subsequently bind SH2 signaling proteins such as Grb2, Gab2 and SHIP that are involved in the regulation of different signaling pathways. Grb2 can associate with the guanosine diphosphate-guanosine triphosphate exchange factor Sos1, leading to Ras activation and regulation of cell proliferation. Downstream signals are mediated via the Raf-MEK-Erk pathway.Grb2 can also associate through Gab2 with PI3K and with SHIP.Figure reproduced from Gu, H. et al. 2000. Mol. Cell. Biol. 20(19):7109-7120Copyright American Society for Microbiology. All Rights Reserved
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