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Literature summary for 6.1.1.6 extracted from
- Function of membranous lysyl-tRNA synthetase and its implication for tumorigenesis (2016), Biochim. Biophys. Acta, 1864, 1707-1713 .
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | KRS is released from the multi-tRNA synthetase complex (MSC) and translocates to the plasma membrane, where it binds to p67LR, resulting in cell migration and metastasis. Modulation of KRS-67LR interaction by an inhibitor BC-KYH16899 may offer a strategy with which to control metastasis | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 2-(2-([4-(methyl)-benzoyl]imino)benzothiazol-3-yl)butanoic acid | i.e. BC-K01 | Homo sapiens |  |
| 2-(5,6-difluoro-2-([3-(trifluoromethyl)benzoyl]imino)benzo[d]thiazol-3(2H)-yl)butanoic acid | i.e. BC-K-YH16899, shows three to sixfold better inhibition of KRS as BC-K01 in most of the assays and better volume of distribution in vivo | Homo sapiens | |
| YH16899 | KRS is the main target of YH16899. YH16899 inhibits enzyme KRS and KRS-mediated metastasis, it also reduces pulmonary nodule formation by approximately 70% without any effects on bodyweight. While YH16899 does not affect cancer cell viability, it inhibits the H226 cell migration with an IC50 of 0.0085 mM | Homo sapiens | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytosol | KRS is normally located in the cytosol as a component of the multitRNA synthetase complex (MSC) that consists of nine different ARSs and three auxiliary factors named AIMP1, 2 and 3 | Homo sapiens | 5829 | - |
| extracellular | the enzyme is secreted | Homo sapiens | - |
- |
| membrane | KRS is released fromMSC and translocates to the cell membrane, where it binds to p67LR | Homo sapiens | 16020 | - |
| plasma membrane | KRS binds p67LR at the plasma membranes | Homo sapiens | 5886 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | required | Homo sapiens | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + L-lysine + tRNALys | Homo sapiens | - |
AMP + diphosphate + L-lysyl-tRNALys | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | - |
- |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| phosphoprotein | phosphorylated KRS is released from multitRNA synthetase complex (MSC) and transölocates to the plasma membrane | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| colon cancer cell | - |
Homo sapiens | - |
| colonic cancer cell | among human ARSs, cytosolic lysyl-tRNA synthetase (KRS) is often highly expressed in cancer cells and tissues, and facilitates cancer cell migration and invasion through the interaction with the 67 kDa laminin receptor on the plasma membrane. KRS is often highly expressed in cancer cells | Homo sapiens | - |
| epithelial cell | - |
Homo sapiens | - |
| HCT-116 cell | - |
Homo sapiens | - |
| mesenchyme | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + L-lysine + tRNALys | - |
Homo sapiens | AMP + diphosphate + L-lysyl-tRNALys | - |
? | |
| additional information | enzyme KRS accomplishes catalysis in two steps. The first reaction involves the activation of lysine, where KRS selectively binds lysine by using one molecule of ATP. The second reaction involves the transfer of the activated lysine (lysine-AMP) to the acceptor end of tRNALys | Homo sapiens | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| More | KRS is normally located in the cytosol as a component of the multitRNA synthetase complex (MSC) that consists of nine different ARSs and three auxiliary factors named AIMP1, 2 and 3. A homodimer of KRS is linked to the N-terminal peptide of AIMP2, and the MSC contains two units of the KRS homodimer-AIMP2 monomer complex. This suggests that KRS exists in the MSC as a tetramer that is present at a relatively higher stoichiometry, compared to other components that are bound to the MSC as monomers or dimers | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| KRS | - |
Homo sapiens |
| Lysyl-tRNA synthetase | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Homo sapiens | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | cytosolic KRS is released from MSC and translocates to the cell membrane, where it binds to p67LR. BC-K01 and YH16899 to KRS abolishes the KRS-LR interaction | Homo sapiens |
| metabolism | the pro-metastatic functions of enzyme KRS and their pathophysiological implications, overview. KRS is released from the multi-tRNA synthetase complex (MSC) and translocates to the cell membrane, where it binds to p67LR, resulting in cell migration and metastasis. Since KRS plays a key role in the structural stability of the MSC. dissociation of KRS from the MSC may affect the cellular levels of other synthetase components within the MSC. KRS/p67LR/integrin alpha6beta1 complex formation correlates with transduction of intracellular signaling for ERK1/2 activation and paxillin expression/activation | Homo sapiens |
| additional information | KRS is normally located in the cytosol as a component of the multi-tRNA synthetase complex (MSC) that consists of nine different ARSs and three auxiliary factors named AIMP1, 2 and 3 | Homo sapiens |
| physiological function | aminoacyl-tRNA synthetases (ARSs) are essential enzymes that conjugate specific amino acids to their cognate tRNAs for protein synthesis. Among human ARSs, cytosolic lysyl-tRNA synthetase (KRS) is often highly expressed in cancer cells and tissues, and facilitates cancer cell migration and invasion through the interaction with the 67 kDa laminin receptor on the plasma membrane. Human KRS interacts with the laminin receptor (LR/RPSA) and enhances cell migration upon laminin stimulation. KRS positively regulates the membrane stability of p67LR, leading to efficient signaling for cell migration during cancer metastasis. Model for the pro-metastatic function of KRS via 67LR and integrin in the plasma membrane. Laminin binds to the integrin resulting in the activation of PI3K and p38 MAPK. Then, p38MAPK phosphorylates the KRS that is bound to the N-terminus of AIMP2 in the MSC. The phosphorylated KRS is released from MSC and translocates to the plasma membrane, where it forms the KRS/p67LR/integrin complex. KRS binding to the p67LR prevents Nedd4-mediated ubiquitination resulting in stabilization of p67LR. The KRS/p67LR/integrin complex also transduces intracellular signaling favorable for cell migration, through ERKs/c-Jun./paxillin expression and paxillin activation, leading to cancer cell dissemination and migration. KRS-mediated regulation of epithelial-mesenchymal transition, overview | Homo sapiens |
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