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 Endoplasmic reticulum NucleusCytoplasm, Stress granule Note=Present in the neuronal hyaline inclusion bodies specificallyfound in motor neurons from amyotrophic lateral sclerosis patients(PubMed:15456787) Present in the Lewy bodies specifically foundin neurons from Parkinson disease patients (PubMed:15456787)Recruited to the cytoplasmic surface of the endoplasmic reticulumvia interaction with AMFR/gp78 (PubMed:16168377) Following DNAdouble-strand breaks, recruited to the sites of damage(PubMed:22120668) Recruited to stalled replication forks viainteraction with SPRTN (PubMed:23042605) Recruited to damagedlysosomes decorated with K48-linked ubiquitin chains(PubMed:27753622) Colocalizes with TIA1, ZFAND1 and G3BP1 incytoplasmic stress granules (SGs) in response to arsenite-inducedstress treatment (PubMed:29804830)
Function (UniProt annotation)
Necessary for the fragmentation of Golgi stacks duringmitosis and for their reassembly after mitosis Involved in theformation of the transitional endoplasmic reticulum (tER) Thetransfer of membranes from the endoplasmic reticulum to the Golgiapparatus occurs via 50-70 nm transition vesicles which derivefrom part-rough, part-smooth transitional elements of theendoplasmic reticulum (tER) Vesicle budding from the tER is anATP-dependent process The ternary complex containing UFD1, VCPand NPLOC4 binds ubiquitinated proteins and is necessary for theexport of misfolded proteins from the ER to the cytoplasm, wherethey are degraded by the proteasome The NPLOC4-UFD1-VCP complexregulates spindle disassembly at the end of mitosis and isnecessary for the formation of a closed nuclear envelopeRegulates E3 ubiquitin-protein ligase activity of RNF19AComponent of the VCP/p97-AMFR/gp78 complex that participates inthe final step of the sterol-mediated ubiquitination andendoplasmic reticulum-associated degradation (ERAD) of HMGCRInvolved in endoplasmic reticulum stress-induced pre-emptivequality control, a mechanism that selectively attenuates thetranslocation of newly synthesized proteins into the endoplasmicreticulum and reroutes them to the cytosol for proteasomaldegradation (PubMed:26565908) Plays a role in the regulation ofstress granules (SGs) clearance process upon arsenite-inducedresponse (PubMed:29804830) Also involved in DNA damage response:recruited to double-strand breaks (DSBs) sites in a RNF8- andRNF168-dependent manner and promotes the recruitment of TP53BP1 atDNA damage sites (PubMed:22020440, PubMed:22120668) Recruited tostalled replication forks by SPRTN: may act by mediatingextraction of DNA polymerase eta (POLH) to prevent excessivetranslesion DNA synthesis and limit the incidence of mutationsinduced by DNA damage (PubMed:23042607, PubMed:23042605) Requiredfor cytoplasmic retrotranslocation of stressed/damagedmitochondrial outer-membrane proteins and their subsequentproteasomal degradation (PubMed:16186510, PubMed:21118995)Essential for the maturation of ubiquitin-containingautophagosomes and the clearance of ubiquitinated protein byautophagy (PubMed:20104022, PubMed:27753622) Acts as a negativeregulator of type I interferon production by interacting withDDX58/RIG-I: interaction takes place when DDX58/RIG-I isubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains,leading to recruit RNF125 and promote ubiquitination anddegradation of DDX58/RIG-I (PubMed:26471729) May play a role inthe ubiquitin-dependent sorting of membrane proteins to lysosomeswhere they undergo degradation (PubMed:21822278) May moreparticularly play a role in caveolins sorting in cells(PubMed:21822278, PubMed:23335559) By controlling the steady-state expression of the IGF1R receptor, indirectly regulates theinsulin-like growth factor receptor signaling pathway(PubMed:26692333)
The endoplasmic reticulum (ER) is a subcellular organelle where proteins are folded with the help of lumenal chaperones. Newly synthesized peptides enter the ER via the sec61 pore and are glycosylated. Correctly folded proteins are packaged into transport vesicles that shuttle them to the Golgi complex. Misfolded proteins are retained within the ER lumen in complex with molecular chaperones. Proteins that are terminally misfolded bind to BiP and are directed toward degradation through the proteasome in a process called ER-associated degradation (ERAD). Accumulation of misfolded proteins in the ER causes ER stress and activates a signaling pathway called the unfolded protein response (UPR). In certain severe situations, however, the protective mechanisms activated by the UPR are not sufficient to restore normal ER function and cells die by apoptosis.
Legionellosis is a potentially fatal infectious disease caused by the bacterium Legionella pneumophila and other legionella species. Two distinct clinical and epidemiological syndromes are associated with Legionella species: Legionnaires' disease is the more severe form of the infection, which may involve pneumonia, and Pontiac fever is a milder respiratory illness.The pathogenesis of L. pneumophila is derived from its growth within lung macrophages. One of the L. pneumophila's type IV secretion systems, the Dot/Icm secretion system, is of critical importance for its ability to replicate and to cause disease. The Dot/Icm substrates modulate multiple host cell processes and in particular, redirect trafficking of the L. pneumophila phagosome and mediate its conversion into an ER-derived organelle competent for intracellular bacterial replication. L. pneumophila also manipulates host cell death and survival pathways in a way that allows continued intracellular replication.
DNA polymerase eta (POLH) consists of 713 amino acids and can bypass thymidine-thymidine dimers, correctly adding two dAMPs opposite to the lesion. Mutations in the POLH gene result in the loss of this bypass activity and account for the XP variant phenotype (XPV) in human xeroderma pigmentosum disorder patients. POLH can carry out TLS past various UV and chemically induced lesions via two steps: (a) preferential incorporation of correct bases opposite to the lesion (b) conditional elongation only at the sites where such correct bases are inserted (Masutani et al. 1999, Masutani et al. 2000)
Heat shock factor 1 (HSF1) is a transcription factor that activates gene expression in response to a variety of stresses, including heat shock, oxidative stress, as well as inflammation and infection (Shamovsky I and Nudler E 2008; Akerfelt et al. 2010; Bjork and Sistonen 2010; Anckar and Sistonen 2011).
HSF1 is constitutively present in the cell. In the absence of stress HSF1 is found in both the cytoplasm and the nucleus as an inactive monomer (Sarge KD et al. 1993; Mercier PA et al. 1999; Vujanac M et al. 2005). A physical or chemical proteotoxic stress rapidly induces HSF1 activation, which occurs through a multi?step process, involving HSF1 monomer-to-homotrimer transition, nuclear accumulation, and binding to a promoter element, called the heat shock element (HSE), which leads to the increase in the stress-inducible gene expression (Sarge KD et al. 1993; Baler R et al. 1998; Sonna LA et al. 2002; Shamovsky I and Nudler E 2008; Sakurai H and Enoki Y 2010; Herbomel G et al. 2013). Depending on the type of stress stimulus, the multiple events associated with HSF1 activation might be affected differently (Holmberg CI et al 2000; Bjork and Sistonen 2010)
The ATP-binding cassette (ABC) superfamily of active transporters involves a large number of functionally diverse transmembrane proteins. They transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. These substrates include amino acids, lipids, inorganic ions, peptides, saccharides, peptides for antigen presentation, metals, drugs, and proteins. The ABC transporters not only move a variety of substrates into and out of the cell, but are also involved in intracellular compartmental transport. Energy derived from the hydrolysis of ATP is used to transport the substrate across the membrane against a concentration gradient. Human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease (Dean et al. 2001, Borst and Elferink 2002, Rees et al. 2009)
After being synthesized in the ER membrane the 14-sugars lipid-linked oligosaccharide is co-translationally transferred to an unfolded protein, as described in the previous steps. After this point the N-glycan is progressively trimmed of the three glucoses and some of the mannoses before the protein is transported to the cis-Golgi. The role of these trimming reactions is that the N-glycan attached to an unfolded glycoprotein in the ER assume the role of 'tags' that direct the interactions of the glycoprotein with different elements that mediate its folding. The removal of the two outer glucoses leads to an N-glycan with only one glucose, which is a signal for the binding of either one of two chaperone proteins, calnexin (CNX) and calreticulin (CRT). These chaperones provide an environment where the protein can fold more easily. The interaction with these proteins is not transient and is terminated by the trimming of the last remaining glucose, after which the glycoprotein is released from CNX or CRT and directed to the ER Quality Control compartment (ERQC) if it still has folding defects, or transported to the Golgi if the folding is correct. The involvement of N-glycans in the folding quality control of proteins in the ER explains why this form of glycosylation is so important, and why defects in the enzymes involved in these reactions are frequently associated with congenital diseases. However, there are many unknown points in this process, as it is known that even proteins without N-glycosylation sites can be folded properly (Caramelo JJ and Parodi AJ, 2008)
Mammalian genomes encode three Hedgehog ligands, Sonic Hedgehog (SHH), Indian Hedgehog (IHH) and Desert Hedgehog (DHH). These secreted morphogens can remain associated with lipid rafts on the surface of the secreting cell and affect developmental processes in adjacent cells. Alternatively, they can be released by proteolysis or packaging into vesicles or lipoprotein particles and dispersed to act on distant cells. SHH activity is required for organization of the limb bud, notochord and neural plate, IHH regulates bone and cartilage development and is partially redundant with SHH, and DHH contributes to germ cell development in the testis and formation of the peripheral nerve sheath (reviewed in Pan et al, 2013). Despite divergent biological roles, all Hh ligands are subject to proteolytic processing and lipid modification during transit to the surface of the secreting cell (reviewed in Gallet, 2011). Precursor Hh undergoes autoproteolytic cleavage mediated by the C-terminal region to yield an amino-terminal peptide Hh-Np (also referred to as Hh-N) (Chen et al, 2011). No other well defined role for the C-terminal region of Hh has been identified, and the secreted Hh-Np is responsible for all Hh signaling activity. Hh-Np is modified with cholesterol and palmitic acid during transit through the secretory system, and both modifications contribute to the activity of the ligand (Porter et al, 1996; Pepinsky et al, 1998; Chamoun et al, 2001). At the cell surface, Hh-Np remains associated with the secreting cell membrane by virtue of its lipid modifications, which promote clustering of Hh-Np into lipid rafts (Callejo et al, 2006; Peters et al, 2004). Long range dispersal of Hh-Np depends on the untethering of the ligand from the membrane through a variety of mechanisms. These include release of monomers through the combined activity of the transmembrane protein Dispatched (DISP2) and the secreted protein SCUBE2, assembly into soluble multimers or apolipoprotein particles or release on the surface of exovesicles (Vyas et al, 2008; Tukachinsky et al, 2012; Chen 2004; Zeng et al, 2001; reviewed in Briscoe and Therond, 2013)
Hh signaling is required for a number of developmental processes, and mutations that disrupt the normal processing and biogenesis of Hh ligand can result in neonatal abnormalities. SHH is one of a number of genes that have been associated with the congenital disorder holoprosencephaly, which causes abnormalities in brain and craniofacial development (Roessler et al, 2009; reviewed in Roessler and Muenke, 2011). SHH variants associated with the condition affect the autocatalytic processing of the precursor and dramatically impair the production of the secreted active Hh-Np, abrogating signaling (reviewed in Pan et al, 2013)
Cystic fibrosis transmembrane conductance regulator (CFTR) is a low conductance chloride-selective channel that mediates the transport of chloride ions in human airway epithelial cells. Chloride ions plays a key role in maintaining homoeostasis of epithelial secretions in the lungs. Defects in CFTR can cause cystic fibrosis (CF; MIM:602421), a common generalised disorder in Caucasians affecting the exocrine glands. CF results in an ionic imbalance that impairs clearance of secretions, not only in the lung, but also in the pancreas, gastrointestinal tract and liver. Wide-ranging manifestations of the disease include chronic lung disease, exocrine pancreatic insufficiency, blockage of the terminal ileum, male infertility and salty sweat. The median survival of CF patients in North America and Western Europe is around 40 years (Davis 2006, Radlovic 2012)
The Josephin domain is present in four human DUBs: Ataxin-3 (ATXN3), ATXN3L, Josephin-1 (JOSD1) and JOSD2. All have been shown to possess DUB activity (Tzveltkov & Breuer 2007, Weeks et al. 2011). Josephin domain DUBs may specialize in distinguishing between polyubiquitin chains of different lengths (Eletr & Wilkinson 2014)
Humans have 16 Overian tumour domain (OTU) family DUBs that can be evolutionally divided into three classes, the OTUs, the Otubains (OTUBs), and the A20-like OTUs (Komander et al. 2009). OTU family DUBs can be highly selective in the type of ubiquitin crosslinks they cleave. OTUB1 is specific for K48-linked chains, whereas OTUB2 can cleave K11, K63 and K48-linked poly-Ub (Wang et al. 2009, Edelmann et al. 2009, Mevissen et al. 2013). A20 prefers K48-linked chains, Cezanne is specific for K11-linked chains, and TRABID acts on both K29, K33 and K63-linked poly-Ub (Licchesi et al. 2011, Komander & Barford 2008, Bremm et al. 2010, Mevissen et al. 2013). The active site of the OTU domain contains an unusual loop not seen in other thiol-DUBs and can lack an obvious catalytic Asp/Asn (Komander & Barford 2009, Messick et al. 2008, Lin et al. 2008). A20 and OTUB1 have an unusual mode of activity, binding directly to E2 enzymes (Nakada et al. 2010, Wertz et al. 2004)
Neutrophils are the most abundant leukocytes (white blood cells), indispensable in defending the body against invading microorganisms. In response to infection, neutrophils leave the circulation and migrate towards the inflammatory focus. They contain several subsets of granules that are mobilized to fuse with the cell membrane or phagosomal membrane, resulting in the exocytosis or exposure of membrane proteins. Traditionally, neutrophil granule constituents are described as antimicrobial or proteolytic, but granules also introduce membrane proteins to the cell surface, changing how the neutrophil responds to its environment (Borregaard et al. 2007). Primed neutrophils actively secrete cytokines and other inflammatory mediators and can present antigens via MHC II, stimulating T-cells (Wright et al. 2010).Granules form during neutrophil differentiation. Granule subtypes can be distinguished by their content but overlap in structure and composition. The differences are believed to be a consequence of changing protein expression and differential timing of granule formation during the terminal processes of neutrophil differentiation, rather than sorting (Le Cabec et al. 1996). The classical granule subsets are Azurophil or primary granules (AG), secondary granules (SG) and gelatinase granules (GG). Neutrophils also contain exocytosable storage cell organelles, storage vesicles (SV), formed by endocytosis they contain many cell-surface markers and extracellular, plasma proteins (Borregaard et al. 1992). Ficolin-1-rich granules (FG) are like GGs highly exocytosable but gelatinase-poor (Rorvig et al. 2009)
E3 ubiquitin ligases catalyze the transfer of an ubiquitin from an E2-ubiquitin conjugate to a target protein. Generally, ubiquitin is transferred via formation of an amide bond to a particular lysine residue of the target protein, but ubiquitylation of cysteine, serine and threonine residues in a few targeted proteins has also been demonstrated (reviewed in McDowell and Philpott 2013, Berndsen and Wolberger 2014). Based on protein homologies, families of E3 ubiquitin ligases have been identified that include RING-type ligases (reviewed in Deshaies et al. 2009, Metzger et al. 2012, Metzger et al. 2014), HECT-type ligases (reviewed in Rotin et al. 2009, Metzger et al. 2012), and RBR-type ligases (reviewed in Dove et al. 2016). A subset of the RING-type ligases participate in CULLIN-RING ligase complexes (CRLs which include SCF complexes, reviewed in Lee and Zhou 2007, Genschik et al. 2013, Skaar et al. 2013, Lee et al. 2014).Some E3-E2 combinations catalyze mono-ubiquitination of the target protein (reviewed in Nakagawa and Nakayama 2015). Other E3-E2 combinations catalyze conjugation of further ubiquitin monomers to the initial ubiquitin, forming polyubiquitin chains. (It may also be possible for some E3-E2 combinations to preassemble polyubiquitin and transfer it as a unit to the target protein.) Ubiquitin contains several lysine (K) residues and a free alpha amino group to which further ubiquitin can be conjugated. Thus different types of polyubiquitin are possible: K11 linked polyubiquitin is observed in endoplasmic reticulum-associated degradation (ERAD), K29 linked polyubiquitin is observed in lysosomal degradation, K48 linked polyubiquitin directs target proteins to the proteasome for degradation, whereas K63 linked polyubiquitin generally acts as a scaffold to recruit other proteins in several cellular processes, notably DNA repair (reviewed in Komander et al. 2009)
Methylation of lysine (Lys) and arginine (Arg) residues on non-histone proteins is a prevalent post-translational modification and important regulator of cellular signal transduction pathways including MAPK, WNT, BMP, Hippo and JAK–STAT. Crosstalk between methylation and other types of post-translational modifications and between histone and non-histone protein methylation is frequent, affecting cellular functions such as chromatin remodelling, gene transcription, protein synthesis, signal transduction and DNA repair (Biggar & Li 2015)
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