241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
299 KEGG pathways;
876 Reactome pathways;
last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
S-adenosylhomocysteine hydrolase-like protein 1;DC-expressed AHCY-like molecule;IP(3)Rs binding protein released with IP(3);IRBIT;Putative adenosylhomocysteinase 2;S-adenosyl-L-homocysteine hydrolase 2;AdoHcyase 2;
Endoplasmic reticulum Cytoplasm, cytosol Microsome Apical cell membrane Note=Associates with membraneswhen phosphorylated, probably through interaction with ITPR1
Function (UniProt annotation)
Multifaceted cellular regulator which coordinatesseveral essential cellular functions including regulation ofepithelial HCO3(-) and fluid secretion, mRNA processing and DNAreplication Regulates ITPR1 sensitivity to inositol 1,4,5-trisphosphate competing for the common binding site and acting asendogenous 'pseudoligand' whose inhibitory activity can bemodulated by its phosphorylation status In the pancreatic andsalivary ducts, at resting state, attenuates inositol 1,4,5-trisphosphate-induced calcium release by interacting with ITPR1(PubMed:16793548) When extracellular stimuli induce ITPR1phosphorylation or inositol 1,4,5-trisphosphate production,dissociates of ITPR1 to interact with CFTR and SLC26A6 mediatingtheir synergistic activation by calcium and cAMP that stimulatesthe epithelial secretion of electrolytes and fluid (Bysimilarity) Also activates basolateral SLC4A4 isoform 1 tocoordinate fluid and HCO3(-) secretion (PubMed:16769890) Inhibitsthe effect of STK39 on SLC4A4 and CFTR by recruiting PP1phosphatase which activates SLC4A4, SLC26A6 and CFTR throughdephosphorylation (By similarity) Mediates the induction ofSLC9A3 surface expression produced by Angiotensin-2(PubMed:20584908) Depending on the cell type, activates SLC9A3 inresponse to calcium or reverses SLC9A3R2-dependent calciuminhibition (PubMed:18829453) May modulate the polyadenylationstate of specific mRNAs, both by controlling the subcellularlocation of FIP1L1 and by inhibiting PAPOLA activity, in responseto a stimulus that alters its phosphorylation state(PubMed:19224921) Acts as a (dATP)-dependent inhibitor ofribonucleotide reductase large subunit RRM1, controlling theendogenous dNTP pool and ensuring normal cell cycle progression(PubMed:25237103) In vitro does not exhibit any S-adenosyl-L-homocysteine hydrolase activity (By similarity)
Cysteine and methionine are sulfur-containing amino acids. Cysteine is synthesized from serine through different pathways in different organism groups. In bacteria and plants, cysteine is converted from serine (via acetylserine) by transfer of hydrogen sulfide [MD:M00021]. In animals, methionine-derived homocysteine is used as sulfur source and its condensation product with serine (cystathionine) is converted to cysteine [MD:M00338]. Cysteine is metabolized to pyruvate in multiple routes. Methionine is an essential amino acid, which animals cannot synthesize. In bacteria and plants, methionine is synthesized from aspartate [MD:M00017]. S-Adenosylmethionine (SAM), synthesized from methionine and ATP, is a methyl group donor in many important transfer reactions including DNA methylation for regulation of gene expression. SAM may also be used to regenerate methionine in the methionine salvage pathway [MD:M00034].
The phospholipase C (PLC) family of enzymes is both diverse and complex. The isoforms beta, gamma and delta (each have subtypes) make up the members of this family. PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2) into two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores while DAG activates protein kinase C isoforms which are involved in regulatory functions
Phospholipases play an integral role in phagocytosis by generating essential second messengers. An early step in phagocytic signaling is the association of PIP2 and IP3 with the phagocytic cup. These are formed by the activity of phosphoinositol kinases and phospholipases. PI3K is has been shown to accumulate at phagocytic cups and converts PI (4,5)P2 to PI (3,4,5)P3. These phosphoinositides are capable of binding and increasing the activity of proteins that regulate the actin cytoskeleton. Phospholipases are lipid modifying enzymes that produce lipid mediators such as diacylglycerol (DAG), arachidonic acid (AA) and IP3. Phopsholipases PLA, PLC and PLD have been shown to be involved in antibody (IgG) mediated phagocytosis. The PLC product IP3 stimulates release of calcium from the endoplasmic reticulum. This Ca+2 concentration increase is greatest in the cytoplasm surrounding the phagocytic cup. Calcium is involved in the various stages of phagosome formation, including phagocytic ingestion and phagosome maturation
Increase of intracellular calcium in mast cells is most crucial for mast cell degranulation. Elevation of intracellular calcium is achieved by activation of PLC-gamma. Mast cells express both PLC-gamma1 and PLC-gamma2 isoforms and activation of these enzymes leads to conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). The production of IP3 leads to mobilization of intracellular Ca+2, which later results in a sustained Ca+2 flux response that is maintained by an influx of extracellular Ca+2. In addition to degranulation, an increase in intracellular calcium concentration also activates the Ca2+/calmodulin-dependent serine phosphatase calcineurin. Calcineurin dephosphorylates the nuclear factor for T cell activation (NFAT) which exposes nuclear-localization signal sequence triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Once in the nucleus, NFAT regulates the transcription of several cytokine genes (Kambayashi et al. 2007, Hoth & Penner 1992, Ebinu et al. 2000, Siraganian et al)
Pancreatic beta cells integrate signals from several metabolites and hormones to control the secretion of insulin. In general, glucose triggers insulin secretion while other factors can amplify or inhibit the amount of insulin secreted in response to glucose. Factors which increase insulin secretion include the incretin hormones Glucose-dependent insulinotropic polypeptide (GIP and glucagon-like peptide-1 (GLP-1), acetylcholine, and fatty acids. Factors which inhibit insulin secretion include adrenaline and noradrenaline.
Increased blood glucose levels from dietary carbohydrate play a dominant role in insulin release from the beta cells of the pancreas. Glucose catabolism in the beta cell is the transducer that links increased glucose levels to insulin release. Glucose uptake and glycolysis generate cytosolic pyruvate; pyruvate is transported to mitochondria and converted both to oxaloacetate which increases levels of TCA cycle intermediates, and to acetyl-CoA which is oxidized to CO2 via the TCA cycle. The rates of ATP synthesis and transport to the cytosol increase, plasma membrane ATP-sensitive inward rectifying potassium channels (KATP channels) close, the membrane depolarizes, and voltage-gated calcium channels in the membrane open (Muoio and Newgard 2008; Wiederkehr and Wollheim 2006).
Elevated calcium concentrations near the plasma membrane cause insulin secretion in two phases: an initial high rate within minutes of glucose stimulation and a slow, sustained release lasting longer than 30 minutes. In the initial phase, 50-100 insulin granules already docked at the membrane are exocytosed. Exocytosis is rendered calcium-dependent by Synaptotagmin V/IX, a calcium-binding membrane protein located in the membrane of the docked granule, although the exact action of Synapototagmin in response to calcium is unknown. Calcium also causes a translocation of reserve granules within the cell towards the plasma membrane for release in the second, sustained phase of secretion. Human cells contain L-type (continually reopening), P/Q-type (long burst), R-type (long burst), and T-type (short burst) calcium channels and these partly account for differences between the two phases of secretion. Other factors that distinguish the two phases are not yet fully known (Bratanova-Tochkova et al. 2002; Henquin 2000; MacDonald et al. 2005)
VEGFR2 stimulates ERK not via GRB2-SOS-RAS, but via pY1175-dependent phosphorylation of PLC gamma and subsequent activation of PKCs. PKC plays an important mediatory role in the proliferative Ras/Raf/MEK/ERK pathway. PKC alpha can intersect the Ras/Raf/MEK/ERK cascade at the level of Ras (Clark et al. 2004) or downstream of Ras through direct phosphorylation of Raf (Kolch et al. 1993). VEGF stimulation leads to Ras activation in a Ras-guanine nucleotide exchange factor (GEF) independent mechanism. It rather relies on modulating the regulation of Ras-GTPase activating protein (GAP) than regulation of Ras-GEFS (Wu et al. 2003)
CLEC7A (Dectin-1) signals through the classic calcineurin/NFAT pathway through Syk activation phospholipase C-gamma 2 (PLCG2) leading to increased soluble IP3 (inositol trisphosphate). IP3 is able to bind endoplasmic Ca2+ channels, resulting in an influx of Ca2+ into the cytoplasm. This increase in calcium concentration induces calcineurin activation and consequently, dephosphorylation of NFAT and its translocation into the nucleus, triggering gene transcription and extracellular release of Interleukin-2 (Plato et al. 2013, Goodridge et al. 2007, Mourao-Sa et al. 2011)
Mature B cells express IgM and IgD immunoglobulins which are complexed with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesal et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010). The protein kinase SYK may also be involved in phosphorylating the ITAMs.The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Irish et al. 2006, Baldock et al. 2008, Tsang et al. 2008, reviewed in Bradshaw 2010).Activated SYK and other kinases phosphorylate BLNK (SLP-65, BASH) and BCAP. LYN and FYN phosphorylate CD19. Phosphorylated BLNK, BCAP, and CD19 serve as scaffolds which recruit effectors to the plasma membrane and assemble large complexes, the signalosomes. BCAP and CD19 recruit phosphoinositol 3-kinase (PI3K). BLNK recruits phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.Phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). Phosphorylated CD19 likewise recruits PIP3K. PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) to the plasma membrane via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates PLC-gamma2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004). Phosphorylated BLNK recruits PLC-gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002).PLC-gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of Ca2+ ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels (and possibly other TRP channels) in the plasma membrane, resulting in an influx of extracellular calcium ions (Mori et al. 2002, Muik et al. 2008, Luik et al. 2008, Park et al. 2009)