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 update: 11 Mar, 2019
Cytoplasm Cell membrane Membrane raft Cytoplasm, cytoskeleton Membrane Note=Translocates to the plasmamembrane when activated, translocation is probably due todifferent mechanisms depending on the stimulus and cell typeTranslocates from the cytoplasm to membrane ruffles in aFCGR3/CD16-dependent manner Colocalizes with FC-gamma-RIIBreceptor (FCGR2B) or FCGR3/CD16 at membrane ruffles Tyrosinephosphorylation may also participate in membrane localization
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 Acts as a negative regulator of B-cell antigen receptorsignaling Mediates signaling from the FC-gamma-RIIB receptor(FCGR2B), playing a central role in terminating signaltransduction from activating immune/hematopoietic cell receptorsystems Acts as a negative regulator of myeloid cellproliferation/survival and chemotaxis, mast cell degranulation,immune cells homeostasis, integrin alpha-IIb/beta-3 signaling inplatelets and JNK signaling in B-cells Regulates proliferation ofosteoclast precursors, macrophage programming, phagocytosis andactivation and is required for endotoxin tolerance Involved inthe control of cell-cell junctions, CD32a signaling in neutrophilsand modulation of EGF-induced phospholipase C activity Keyregulator of neutrophil migration, by governing the formation ofthe leading edge and polarization required for chemotaxisModulates FCGR3/CD16-mediated cytotoxicity in NK cells Mediatesthe activin/TGF-beta-induced apoptosis through its Smad-dependentexpression May also hydrolyze PtdIns(1,3,4,5)P4, and could thusaffect the levels of the higher inositol polyphosphates likeInsP6
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.
Fc epsilon RI-mediated signaling pathways in mast cells are initiated by the interaction of antigen (Ag) with IgE bound to the extracellular domain of the alpha chain of Fc epsilon RI. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. Mast cells that are thus activated release preformed granules which contain biogenic amines (especially histamines) and proteoglycans (especially heparin). The activation of phospholipase A2 causes the release of membrane lipids followed by development of lipid mediators such as leukotrienes (LTC4, LTD4 and LTE4) and prostaglandins (especially PDG2). There is also secretion of cytokines, the most important of which are TNF-alpha, IL-4 and IL-5. These mediators and cytokines contribute to inflammatory responses.
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.
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)
Changes in gene expression are required for the T cell to gain full proliferative competence and to produce effector cytokines. Three transcription factors in particular have been found to play a key role in TCR-stimulated changes in gene expression, namely NF-kB, NFAT and AP-1.
A key step in NF-kB activation is the stimulation and translocation of PKC theta. The critical element that effects PKC theta activation is PI3K. This enzyme complex translocates to the plasma membrane by interacting with phospho-tyrosines on CD28 via its two SH2 domains located in p85 subunit. The p110 subunit of PI3K phosphorylates the inositol ring of PIP2 to generate PIP3 (steps 17-18). PIP3 may also be dephosphorylated by the phosphatase SHIP to generate PI-3,4-P2.
PIP3 and PI-3,4-P2 acts as binding sites to the PH domain of PKB/Akt and PDK1 (steps 19, 21 and 22). PKB is activated in response to PI3K stimulation by PDK1 (step 23). PDK1 has an essential role in regulating the activation of PKC theta and recruitment of CBM complex to the immune synapse. PKC theta is a member of novel class (DAG dependent, Ca++ independent) of PKC and the only member known to translocate to this synapse. Prior to TCR stimulation PKC theta exists in an inactive closed conformation. Upon release of DAG, it binds to PKC theta via the C1 domain and undergoes phosphorylation on tyrosine 90 by Lck to attain an open conformation. PKC theta is further phosphorylated by PDK1 on threonine 538. This step is critical for PKC activity (steps 24-26).
CARMA1 translocates to the plasma membrane following the interaction of its SH3 domain with the 'PxxP' motif on PDK1. CARMA1 is phosphorylated by PKC-theta on residue S552, leading to the oligomerization of CARMA1. This complex acts as a scaffold, recruiting Bcl10 to the synapse by interacting with their CARD domains.
Bcl10 undergoes phosphorylation mediated by the enzyme RIP2. Activated Bcl10 then mediates the ubiquitination of NEMO by recruiting MALT1 and TRAF6. MALT1 binds to Bcl10 with its Ig-like domains and undergoes oligomerization. TRAF6 binds to the oligomerized MALT1 and also undergoes oligomerization.
Oligomerized TRAF6 acts as a ubiquitin-protein ligase, catalyzing auto-K63-linked polyubiquitination (steps 27-33). This K-63 ubiquitinated TRAF6 activates TAK1 kinase bound to TAB2 and also ubiquitinates NEMO/IKK-gamma in the IKK complex. TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 kinase phosphorylates IKK-beta on residues S177 and S181 in the activation loop and activates the IKK kinase activity. IKK-beta phosphorylates the IkB-alpha bound to the NF-kB heterodimer, on residues S19 and S23 and directs IkB-beta to 26S proteasome degradation (step 34-38 & 40).
The NF-kB heterodimer with a free NTS sequence finally migrates to the nucleus to regulate gene transcription (step 39)
PECAM-1/CD31 is a member of the immunoglobulin superfamily (IgSF) and has been implicated to mediate the adhesion and trans-endothelial migration of T-lymphocytes into the vascular wall, T cell activation and angiogenesis. It has six Ig homology domains within its extracellularly and an ITIM motif within its cytoplasmic region. PECAM-1 mediates cellular interactions by both homophilic and heterophilic interactions. The cytoplasmic domain of PECAM-1 contains tyrosine residues which serves as docking sites for recruitment of cytosolic signaling molecules. Under conditions of platelet activation, PECAM-1 is phosphorylated by Src kinase members. The tyrosine residues 663 and 686 are required for recruitment of the SH2 domain containing PTPs
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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