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| Protein Domain |
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Conserved_site |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].A number of growth factors stimulate mitogenesis by interacting with a familyof cell surface receptors which possess an intrinsic, ligand-sensitive,protein tyrosine kinase activity []. These receptor tyrosine kinases (RTK)all share the same topology: an extracellular ligand-binding domain, a singletransmembrane region and a cytoplasmic kinase domain. However they can beclassified into at least five groups. The prototype for class II RTK's is theinsulin receptor, a heterotetramer of two alpha and two beta chains linked bydisulphide bonds. The alpha and beta chains are cleavage products of aprecursor molecule. The alpha chain contains the ligand binding site, the betachain transverses the membrane and contains the tyrosine protein kinasedomain.While only the insulin and the insulin growth factor I receptors are known toexist in the tetrameric conformation specific to class II RTK's, all the aboveproteins share extensive homologies in their kinase domain, especially aroundthe putative site of autophosphorylation. |
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Family |
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This entry represents tryptophan-tRNA ligase (TrpRS; also known as tryptophanyl-tRNA synthetase) (). The enzyme is widely distributed, being found in archaea, bacteria and eukaryotes. TrpRS is a homodimer which attaches Tyr to the appropriate tRNA. TrpRS is a class I tRNA synthetase, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases [].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [, ]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [, , ]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c []. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) () are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase [].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [, ]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [, , ]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases []. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) () are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase [].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [, ]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [, , ]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].Two groups can be distinguished among tyrosyl-tRNA synthetases. One group contains bacterial andorganellar eukaryotic examples. The other contains archaeal and cytosolic eukaryotic examples. This entry represents the archaeal and cytosolic eukaryotic tyrosyl-tRNA synthetases. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) () are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase [].Two main groups can be distinguished among tyrosine-tRNA ligases: one group contains bacterial and organellar eukaryotic proteins and the other archaeal and cytosolic eukaryotic proteins. This entry represents the bacterial and organellar eukaryotic tyrosine-tRNA ligases.The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [, ]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [, , ]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases []. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) () are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase [].Two main groups can be distinguished among tyrosine-tRNA ligase: one group contains bacterial and organellar eukaryotic proteins and the other archaeal and cytosolic eukaryotic proteins. This entry belongs to the first group and contains tyrosein-tRNA ligase classified as type 2.The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [, ]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [, , ]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases []. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) () are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase [].Twomain groups can be distinguished among tyrosine-tRNA ligases: one group contains bacterial and organellar eukaryotic proteins and the other archaeal and cytosolic eukaryotic proteins. This entry represents contains bacterial and organellar eukaryotic tyrosine-tRNA ligases classified as type 1.The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [, ]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [, , ]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases []. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].In the absence of cAMP, protein kinase A (PKA) exists as an equimolar tetramer of regulatory (R) and catalytic (C) subunits. In addition to its role as an inhibitor of the C subunit, the R subunit anchors the holoenzyme to specific intracellular locations and prevents the C subunit from entering the nucleus. Typical R subunits have a conserved domain structure, consisting of the N-terminal dimerisation domain, inhibitory region, cAMP-binding domain A and cAMP-binding domain B. R subunits interact with C subunits primarily through the inhibitory site. The cAMP-binding domains show extensive sequence similarity and bind cAMP cooperatively.On the basis of phylogenetic trees generated from multiple sequence alignment of complete sequences, this family was divided into four sub-families, types I to IV []. Types I and II, found in animals, differ in molecular weight, sequence, autophosphorylation capability, cellular location and tissue distribution. Types I and II are further sub-divided into alpha and beta subtypes, based mainly on sequence similarity. Type III are from fungi and type IV are from alveolates. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Protein kinases are a group of enzymes that possess a catalytic subunit, which transfers the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues (such as serine, threonine, or tyrosine) in a substrate protein's side chain, resulting in a conformational change affecting protein function. Protein kinase function has been evolutionarily conserved from Escherichia coli to Homo sapiens (Human), where they play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation [].The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Anti-Mullerian hormone (AMH), also called Mullerian inhibiting substance, is a member of the transforming growth factor beta (TGF-beta) family that represses the development and function of reproductive organs []. Anti-Mullerian hormone is thought to exert its effects through two membrane-bound serine/threonine kinase receptors, type 2 and type 1. Upon ligand binding, these drive receptor-specific cytoplasmic substrates, the Smad molecules, into the nucleus where they act as transcription factors. A type 2 receptor specific for AMH was cloned through its homology with receptors of TGF-beta family members. Components of the AMH signalling pathway have been identified in gonads and gonadal cell lines. The AMH type II receptor is highly specific. In contrast, the identity of the AMH type I receptor is not clear. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This entry represents the non-receptor tyrosine kinases SYK and ZAP-70 [, , ]:SYK is a positive effector of BCR-stimulated responses. It couples the B-cell antigen receptor (BCR) to the mobilisation of calcium ion, either through a phosphoinositide 3-kinase-dependent pathway (when not phosphorylated on tyrosines of the linker region), or through a phospholipase C-gamma-dependent pathway (when phosphorylated on Tyr-342 and Tyr-346). Therefore, the differential phosphorylation of Syk can determine the pathway by which BCR is coupled to the regulation of intracellular calcium ion [, ].ZAP70 plays a role in T-cell development and lymphocyte activation. It is essential for TCR-mediated IL-2 production. Isoform 1 of ZAP70 induces TCR-mediated signal transduction, isoform 2 does not [, ]. |
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Family |
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Peptidase family A1, also known as the pepsin family, contains peptidases with bilobed structures [, ]. The two domains most probably evolved from the duplication of an ancestral gene encoding a primordial domain []. The active site is formed from an aspartic acid residue from each domain. Each aspartic acid occurs within a motif with the sequence D(T/S)G(T/S). Exceptionally, in the histoaspactic peptidase from Plasmodium falciparum, one of the Asp residues is replaced by His []. A third essential residue, Tyr or Phe, is found on the N-terminal domain only in a β-hairpin loop known as the "flap"; this residue is important for substrate binding, and most members of the family have a preference for a hydrophobic residue in the S1 substrate binding pocket. Most members of the family are active at acidic pH, but renin is unusually active at neutral pH. Family A1 peptidases are found predominantly in eukaryotes (but examples are known from bacteria [, ]). Currently known eukaryotic aspartyl peptidases and homologues include the following:Vertebrate gastric pepsins A (), gastricsin (, also known pepsin C), chymosin (; formerly known as rennin), and cathepsin E (). Pepsin A is widely used in protein sequencing because of its limited and predictable specificity. Chymosin is used to clot milk for cheese making.Lysosomal cathepsin D ().Renin () which functions in control of blood pressure by generating angiotensin I from angiotensinogen in the plasma.Memapsins 1 (; also known as BACE 2) and 2 (; also known as BACE) are membrane-bound and are able to perform one of the two cleavages (the beta-cleavage, hence they are also known as beta-secretases) in the beta-amyloid precursor to release the the amyloid-beta peptide, which accumulates in the plaques of Alzheimer's disease patients.Fungal peptidases such as aspergillopepsin A (), candidapepsin (), mucorpepsin (; also known as Mucorrennin), endothiapepsin (), polyporopepsin (), and rhizopuspepsin () are secreted for sapprophytic protein digestion.Fungal saccharopepsin () (proteinase A) (gene PEP4) is implicated in post-translational regulation of vacuolar hydrolases.Yeast barrierpepsin () (gene BAR1); a protease that cleaves alpha-factor and thus acts as an antagonist of the mating pheromone.Fission yeast Sxa1 may be involved in degrading or processing the mating pheromones [].In plants, phytepsin () degrades seed storage proteins and nepenthesin (EC 3.4.23.12) from a pitcher plant digests insect proteins. Also are included Aspartic proteinase 36 and Aspartic proteinase 39, which contribute to pollen and ovule development and have an important role in plant development in Arabidopsis [].Plasmepsins (and ) from Plasmodium species are important for the degradation of host haemoglobin.Non-peptidase homologues where one or more active site residues have been replaced, include mammalian pregnancy-associated glycoproteins, an allergen from a cockroach, and a xylanase inhibitor []. |
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| Protein Domain |
| Type: |
Domain |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].The AGC (cAMP-dependent, cGMP-dependent and protein kinase C) protein kinase family embraces a collection of protein kinases that display a high degree of sequence similarity within their respective kinase domains. AGC kinase proteins are characterised by three conserved phosphorylation sites that critically regulate their function. The first one is located in an activation loop in the centre of the kinase domain. The two other phosphorylation sites are located outside the kinase domain in a conserved region on its C-terminal side, the AGC-kinase C-terminal domain. These sites serves as phosphorylation-regulated switches to control both intra- and inter-molecular interactions. Without these priming phosphorylations, the kinases are catalytically inactive [, , ].Several structures of the AGC-kinase C-terminal domain have been solved. The first phosphorylation site is located in a turn motif, the second one at the end of the domain in an hydrophobic pocket. In PKB the phosphorylated hydrophobic motif engages a hydrophobic groove within the N-lobe of the kinase domain which orders alpha helices close to the active site []. |
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Family |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].The proteins in this family are homologues of the EpsG protein found in Methylobacillus sp. 12S and are generally found in operons with other Eps homologues. The protein is believed to function as the protein tyrosine kinase component of the chain length regulator (along with the transmembrane component EpsF). |
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| Protein Domain |
| Type: |
Domain |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].In the absence of cAMP, Protein Kinase A (PKA) exists as an equimolar tetramer of regulatory (R) and catalytic (C) subunits []. In addition to its role as an inhibitor of the C subunit, the R subunit anchors the holoenzyme to specific intracellular locations and prevents the C subunit from entering the nucleus. All R subunits have a conserved domain structure consisting of the N-terminal dimerization domain, inhibitory region, cAMP-binding domain A and cAMP-binding domain B. R subunits interact with C subunits primarily through the inhibitory site. The cAMP-binding domains show extensive sequence similarity and bind cAMP cooperatively.Two types of regulatory (R) subunits exist - types I and II - which differ in molecular weight, sequence, autophosphorylation capability, cellular location and tissue distribution. Types I and II were further sub-divided into alpha and beta subtypes, based mainly on sequence similarity. This entry represents the dimerization-anchoring domain of types I-alpha, I-beta, II-alpha and II-beta regulatory subunits of PKA proteins.The dimerization-anchoring domain is located within the first 45 residues of each regulatory subunit, and forms a high affinity binding site for A-kinase-anchoring proteins (AKAPs) []. |
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| Protein Domain |
| Type: |
Conserved_site |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Eukaryotic serine-threonine mitogen-activated protein (MAP) kinases are key regulators of cellular signal transduction systems and are conserved from Saccharomyces cerevisiae (Baker's yeast) to human beings. MAPK pathways are signalling cascades differentially regulated by growth factors, mitogens, hormones and stress which mediate cell growth, differentiation and survival. MAPK activity is regulated through a (usually) three-tiered cascade composed of a MAPK, a MAPK kinase (MAPKK, MEK) and a MAPK kinase kinase (MAPKK, MEKK). Substrates for the MAPKs include other kinases and transcription factors []. Mammals express at least four distinctly related groups of MAPKs, extracellularly-regulated kinases (ERKs), c-jun N-terminal kinases (JNKs), p38 proteins and ERK5. Plant MAPK pathways have attracted increasing interest, resulting in the isolation of a large number of different components of MAPK cascades. MAPKs play important roles in the signalling of most plant hormones and in developmental processes []. In the budding yeast S. cerevisiae, four separate but structurally related mitogen-activated protein kinase (MAPK)activation pathways are known, regulating mating, cell integrity and osmosity [].Enzymes in this family are characterised by two domains separated by a deep channel where potential substrates might bind. The N-terminal domain creates a binding pocket for the adenine ring of ATP, and the C-terminal domain contains the catalytic base, magnesium binding sites and phosphorylation lip []. Almost all MAPKs possess a conserved TXY motif in which both the threonine andtyrosine residues are phosphorylated during activation of the enzyme byupstream dual-specificity MAP kinase kinases (MAPKKs). |
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| Protein Domain |
| Type: |
Conserved_site |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].A number of growth factors stimulate mitogenesis by interacting with a familyof cell surface receptors which possess an intrinsic, ligand-sensitive,protein tyrosine kinase activity []. These receptor tyrosine kinases (RTK)all share the same topology: an extracellular ligand-binding domain, a singletransmembrane region and a cytoplasmic kinase domain and have beenclassified into at least five groups on the basis of sequence similarities.The extracellular domain of class V RTK's has 16 conserved cysteine residues that are probably involved indisulphide bonds; this region is followed by two copies of a fibronectin typeIII domain. The ligands for these receptors are proteins known as ephrins. The EPHA subtype receptors bind to GPI-anchored ephrins while the EPHB subtypereceptors bind to type-I membrane ephrins. |
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| Protein Domain |
| Type: |
Homologous_superfamily |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].SYK is a positive effector of B-cell antigen receptor (BCR) stimulated responses [, ]. ZAP-70 plays a role in T-cell development and lymphocyte activation. It is essential for TCR-mediated IL-2 production [, ].The N-terminal region of ZAP-70 consists of two SH2 domains that are connected by an helical region. The overall fold is Y shaped, with the intervening residues forming the stem []. This superfamily represents the inter-SH2 domain found in ZAP-70 and SYK kinases. |
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| Protein Domain |
| Type: |
Family |
| Description: |
The group of proteins in this entry are tyrosine-tRNA ligases from archaea, and they belong to tyrosine-tRNA ligases type 4.Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) () are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase [].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [, ]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [, , ]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases []. |
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| Protein Domain |
| Type: |
Family |
| Description: |
The group of proteins in this entry are tyrosine-tRNA ligases from archaea, and they belong to tyrosine-tRNA ligases type 3.Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) () are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase [].The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction [, ]. These proteins differ widely in size and oligomeric state, and have limited sequence homology []. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric []. Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices [], and are mostly dimeric or multimeric, containing at least three conserved regions [, , ]. However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c [].The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases []. |
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| Protein Domain |
| Type: |
Active_site |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This entry represents the tyrosine protein kinase active site. It also matches a number of proteins belonging to the atypical serine/threonine protein kinase BUD32 family, which lack the conventional structural elements necessary for the substrate recognition and also lack the lysine residue that in all other serine/threonine kinases participates in the catalytic event. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Eukaryotic serine-threonine mitogen-activated protein (MAP) kinases are key regulators of cellular signal transduction systems and are conserved from Saccharomyces cerevisiae (Baker's yeast) to human beings. MAPK pathways are signalling cascades differentially regulated by growth factors, mitogens, hormones and stress which mediate cell growth, differentiation and survival. MAPK activity is regulated through a (usually) three-tiered cascade composed of a MAPK, a MAPK kinase (MAPKK, MEK) and a MAPK kinase kinase (MAPKK, MEKK). Substrates for the MAPKs include other kinases and transcription factors []. Mammals express at least four distinctly related groups of MAPKs, extracellularly-regulated kinases (ERKs), c-jun N-terminal kinases (JNKs), p38 proteins and ERK5. Plant MAPK pathways have attracted increasing interest,resulting in the isolation of a large number of different components of MAPK cascades. MAPKs play important roles in the signalling of most plant hormones and in developmental processes []. In the budding yeast S. cerevisiae, four separate but structurally related mitogen-activated protein kinase (MAPK)activation pathways are known, regulating mating, cell integrity and osmosity [].Enzymes in this family are characterised by two domains separated by a deep channel where potential substrates might bind. The N-terminal domain creates a binding pocket for the adenine ring of ATP, and the C-terminal domain contains the catalytic base, magnesium binding sites and phosphorylation lip []. Almost all MAPKs possess a conserved TXY motif in which both the threonine andtyrosine residues are phosphorylated during activation of the enzyme byupstream dual-specificity MAP kinase kinases (MAPKKs).This group represents a mitogen-activated protein kinase kinase kinase kinase, which may play a role in the response to environmental stress. It appears to act upstream of the JUN N-terminal pathway []. |
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| Protein Domain |
| Type: |
Family |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].MAP (Mitogen Activated Protein) kinases participate in kinase cascades,whereby at least 3 protein kinases act in series, culminating in activationof MAP kinase [, ]. MAP kinases are activated by dual phosphorylation on both tyrosine and threonine residues of a conserved TXY motif.ERKs (Extracellularly Regulated Kinases) belong to the family of MAPkinases. ERK1 (also known as MAPK3) and ERK2 (also known as MAPK1) are proteins of 43 and 41kDa respectively. They are ~85% identical, even higher levels of similarity being seen in substrate bindingregions. Both are ubiquitously expressed, although levels vary fromtissue to tissue. They are activated, for example, by serum, growth factorsand cytokines. They phosphorylate both cytoskeletal proteins andtranscription factors, resulting ultimately in cell growth. Substrates carrya PX(T/S)P motif; other such "docking domains"also exist within ERK, whichinteract with specific motifs in the substrate: e.g., ERK1 and ERK2 possess2 DXXD docking sites capable of interaction with a Kinase Interaction Motif(KIM), which can be found on activators (MAPKK), inhibitors (PTP-SL and dualspecificity phosphatases) and substrates (Elk-1). |
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| Protein Domain |
| Type: |
Family |
| Description: |
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].MAP (Mitogen Activated Protein) kinases participate in kinase cascades,whereby at least 3 protein kinases act in series, culminating in activationof MAP kinase []. MAP kinases are activated by dual phosphorylationon both tyrosine and threonine residues of a conserved TXY motif.ERKs (Extracellularly Regulated Kinases) belong to the family of MAPkinases. ERK 3 (also known as MAPK6) and ERK 4 (also known as MAPK4), however, have no more similarity to ERK 1 and 2 thando the other major classes of MAP kinase, JNK and p38. ERK3 isconstitutively located in the nucleus, despite the lack of a traditionalnuclear localisation signal []. It is unique among MAP kinases incontaining in its activation loop only a single phosphorylation site (serine189) - other MAP kinases have the sequence TXY in this loop, but ERK3contains SEG, with glycine in place of tyrosine.ERK3 has no homologues in nematode or yeast genomes, indicating that it mayhave arisen from a relatively late gene duplication. Its structure,based on similarity to ERK2, contains segregated alpha and beta regions. |
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| Publication |
| First Author: |
Olvedy M |
| Year: |
2017 |
| Journal: |
J Clin Invest |
| Title: |
Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma. |
| Volume: |
127 |
| Issue: |
6 |
| Pages: |
2310-2325 |
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| Publication |
| First Author: |
Rice RH |
| Year: |
2012 |
| Journal: |
PLoS One |
| Title: |
Differentiating inbred mouse strains from each other and those with single gene mutations using hair proteomics. |
| Volume: |
7 |
| Issue: |
12 |
| Pages: |
e51956 |
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| Publication |
| First Author: |
Sundberg JP |
| Year: |
2014 |
| Journal: |
Exp Mol Pathol |
| Title: |
Crisp1 and alopecia areata in C3H/HeJ mice. |
| Volume: |
97 |
| Issue: |
3 |
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| First Author: |
Kobiita A |
| Year: |
2020 |
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Cell Rep |
| Title: |
The Diabetes Gene JAZF1 Is Essential for the Homeostatic Control of Ribosome Biogenesis and Function in Metabolic Stress. |
| Volume: |
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| Issue: |
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107846 |
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| First Author: |
Durnin L |
| Year: |
2017 |
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Am J Physiol Gastrointest Liver Physiol |
| Title: |
Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal. |
| Volume: |
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| Issue: |
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Joshi SS |
| Year: |
2019 |
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PLoS Genet |
| Title: |
CD34 defines melanocyte stem cell subpopulations with distinct regenerative properties. |
| Volume: |
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| Issue: |
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e1008034 |
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Zingg D |
| Year: |
2018 |
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Cancer Cell |
| Title: |
EZH2-Mediated Primary Cilium Deconstruction Drives Metastatic Melanoma Formation. |
| Volume: |
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| Issue: |
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Knight DA |
| Year: |
2013 |
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J Clin Invest |
| Title: |
Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. |
| Volume: |
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| Issue: |
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| Pages: |
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| First Author: |
Sullivan MR |
| Year: |
2019 |
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Cell Metab |
| Title: |
Increased Serine Synthesis Provides an Advantage for Tumors Arising in Tissues Where Serine Levels Are Limiting. |
| Volume: |
29 |
| Issue: |
6 |
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| First Author: |
Mann MB |
| Year: |
2015 |
| Journal: |
Nat Genet |
| Title: |
Transposon mutagenesis identifies genetic drivers of Braf(V600E) melanoma. |
| Volume: |
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| Issue: |
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| Pages: |
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Grinberg-Bleyer Y |
| Year: |
2017 |
| Journal: |
Cell |
| Title: |
NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer. |
| Volume: |
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| Year: |
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Nat Immunol |
| Title: |
CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. |
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Nat Metab |
| Title: |
The endothelial Dll4-muscular Notch2 axis regulates skeletal muscle mass. |
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Gribben C |
| Year: |
2021 |
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Cell Stem Cell |
| Title: |
Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas. |
| Volume: |
28 |
| Issue: |
11 |
| Pages: |
2000-2008.e4 |
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Urtatiz1 O |
| Year: |
2021 |
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bioRxiv |
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Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma. |
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Varum S |
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2019 |
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Cell Stem Cell |
| Title: |
Yin Yang 1 Orchestrates a Metabolic Program Required for Both Neural Crest Development and Melanoma Formation. |
| Volume: |
24 |
| Issue: |
4 |
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637-653.e9 |
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Adorno M |
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2018 |
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Sci Rep |
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Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation. |
| Volume: |
8 |
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Burd CE |
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2013 |
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Cell |
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Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. |
| Volume: |
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Chryplewicz A |
| Year: |
2022 |
| Journal: |
Cancer Cell |
| Title: |
Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity. |
| Volume: |
40 |
| Issue: |
10 |
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1111-1127.e9 |
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| First Author: |
Sun Q |
| Year: |
2019 |
| Journal: |
Nat Commun |
| Title: |
A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease. |
| Volume: |
10 |
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5023 |
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Hari L |
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2012 |
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Development |
| Title: |
Temporal control of neural crest lineage generation by Wnt/β-catenin signaling. |
| Volume: |
139 |
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12 |
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| First Author: |
Sun Q |
| Year: |
2023 |
| Journal: |
Nature |
| Title: |
Dedifferentiation maintains melanocyte stem cells in a dynamic niche. |
| Volume: |
616 |
| Issue: |
7958 |
| Pages: |
774-782 |
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| First Author: |
Rabbani P |
| Year: |
2011 |
| Journal: |
Cell |
| Title: |
Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. |
| Volume: |
145 |
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6 |
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941-955 |
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| First Author: |
Spranger S |
| Year: |
2017 |
| Journal: |
Cancer Cell |
| Title: |
Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. |
| Volume: |
31 |
| Issue: |
5 |
| Pages: |
711-723.e4 |
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| First Author: |
Urtatiz O |
| Year: |
2021 |
| Journal: |
Elife |
| Title: |
Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma. |
| Volume: |
10 |
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| First Author: |
Li MY |
| Year: |
2021 |
| Journal: |
Dev Cell |
| Title: |
UV-induced reduction in Polycomb repression promotes epidermal pigmentation. |
| Volume: |
56 |
| Issue: |
18 |
| Pages: |
2547-2561.e8 |
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| First Author: |
Jacquelot N |
| Year: |
2021 |
| Journal: |
Nat Immunol |
| Title: |
Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma. |
| Volume: |
22 |
| Issue: |
7 |
| Pages: |
851-864 |
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| First Author: |
Lionarons DA |
| Year: |
2019 |
| Journal: |
Cancer Cell |
| Title: |
RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance. |
| Volume: |
36 |
| Issue: |
1 |
| Pages: |
68-83.e9 |
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An L |
| Year: |
2024 |
| Journal: |
Nat Commun |
| Title: |
Sexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation. |
| Volume: |
15 |
| Issue: |
1 |
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796 |
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| First Author: |
Das SK |
| Year: |
2016 |
| Journal: |
Oncotarget |
| Title: |
Knockout of MDA-9/Syntenin (SDCBP) expression in the microenvironment dampens tumor-supporting inflammation and inhibits melanoma metastasis. |
| Volume: |
7 |
| Issue: |
30 |
| Pages: |
46848-46861 |
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| First Author: |
Arumi-Planas M |
| Year: |
2023 |
| Journal: |
Oncogene |
| Title: |
Microenvironmental Snail1-induced immunosuppression promotes melanoma growth. |
| Volume: |
42 |
| Issue: |
36 |
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2659-2672 |
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Kohlhapp FJ |
| Year: |
2016 |
| Journal: |
Cell Rep |
| Title: |
Non-oncogenic Acute Viral Infections Disrupt Anti-cancer Responses and Lead to Accelerated Cancer-Specific Host Death. |
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4 |
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Köhler C |
| Year: |
2017 |
| Journal: |
Cell Stem Cell |
| Title: |
Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes. |
| Volume: |
21 |
| Issue: |
5 |
| Pages: |
679-693.e6 |
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Moon H |
| Year: |
2017 |
| Journal: |
Cell Stem Cell |
| Title: |
Melanocyte Stem Cell Activation and Translocation Initiate Cutaneous Melanoma in Response to UV Exposure. |
| Volume: |
21 |
| Issue: |
5 |
| Pages: |
665-678.e6 |
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| First Author: |
Erkes DA |
| Year: |
2017 |
| Journal: |
J Immunol |
| Title: |
Virus-Specific CD8+ T Cells Infiltrate Melanoma Lesions and Retain Function Independently of PD-1 Expression. |
| Volume: |
198 |
| Issue: |
7 |
| Pages: |
2979-2988 |
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| First Author: |
Cain-Hom C |
| Year: |
2017 |
| Journal: |
Nucleic Acids Res |
| Title: |
Efficient mapping of transgene integration sites and local structural changes in Cre transgenic mice using targeted locus amplification. |
| Volume: |
45 |
| Issue: |
8 |
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| First Author: |
Jordan PW |
| Year: |
2017 |
| Journal: |
Chromosome Res |
| Title: |
Sororin is enriched at the central region of synapsed meiotic chromosomes. |
| Volume: |
25 |
| Issue: |
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Karras P |
| Year: |
2022 |
| Journal: |
Nature |
| Title: |
A cellular hierarchy in melanoma uncouples growth and metastasis. |
| Volume: |
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| Issue: |
7930 |
| Pages: |
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Hopkins J |
| Year: |
2014 |
| Journal: |
PLoS Genet |
| Title: |
Meiosis-specific cohesin component, Stag3 is essential for maintaining centromere chromatid cohesion, and required for DNA repair and synapsis between homologous chromosomes. |
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10 |
| Issue: |
7 |
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Ward A |
| Year: |
2016 |
| Journal: |
G3 (Bethesda) |
| Title: |
Genetic Interactions Between the Meiosis-Specific Cohesin Components, STAG3, REC8, and RAD21L. |
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| Issue: |
6 |
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| First Author: |
Etzerodt A |
| Year: |
2019 |
| Journal: |
J Exp Med |
| Title: |
Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression. |
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| Issue: |
10 |
| Pages: |
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|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
372
 |
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1114
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1138
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
717
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
754
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
473
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
443
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
648
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
467
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
628
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
619
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
535
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1735
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
278
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
472
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
757
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1007
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
527
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
959
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
784
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
519
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
431
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
435
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
504
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
426
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
244
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
556
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
729
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
268
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
499
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
416
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1243
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
503
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
567
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
1757
|
| Fragment?: |
false |
|
•
•
•
•
•
|
| Protein |
| Organism: |
Mus musculus/domesticus |
| Length: |
497
|
| Fragment?: |
false |
|
•
•
•
•
•
|
