Note | Enzyme number (IUBMB): EC 2.7.11.1. |
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| Isoforms of human VRK2 protein. They share identical sequence until aminoacid 394. |
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Description | VRK2 protein has two isoforms: VRK2A isoform is a 508 amino acid 58.141 KDa protein and VRK2B isoform, a 397 amino acid 45.030 KDa protein (Blanco et al., 2006). Both isoforms present a serine-threonine kinase domain (residues 29-266) with an ATP-binding site (residues 36-61) and three active kinase motifs (residues 164-168, 184-188 and 218-220). Protein autophosphorylated in several residues (Nichols and Traktman, 2004). |
Expression | VRK2A is widely expressed in normal and tumoral cells and all human cell lines tested expressed this isoform. VRK2B is expressed only in some cell lines (Blanco et al., 2006; Fernandez et al., 2010). VRK2A expression positively correlated with estrogen and progesterone receptors and inversely with ErbB2 in breast carcinomas (Fernandez et al., 2010). |
Localisation | VRK2A contains a hydrophobic domain in the C-terminal region that anchors this protein to reticulum endoplasmic and mitochondria membranes. VRK2B lacks this region and it is a soluble protein localized in cytosol and nucleus (Blanco et al., 2006). |
Function | Serine-threonine kinase activity (Nichols and Traktman, 2004). VRK2 modulates signals mediated by mitogen-activated protein kinases (MAPK). Both isoforms interacts with JIP1 protein inhibiting the phosphorylation state of JNK and the AP-1 transcriptional responses mediated by IL-1 and hypoxia signals (Blanco et al., 2007; Blanco et al., 2008). Also, VRK2A interacts with the anchorage protein KSR1 and Mek1 inhibiting Raf-Ras-Mek1-Erk1/2 signaling mediated by EGF (Fernandez et al., 2010). VRK2A interacts with BHFR1 protein from Epstein-Barr virus (a homologue of human anti-apoptotic Bcl-2 protein) enhancing viral survival after infection (Li et al., 2006). VRK2A and VRK2B phosphorylate p53 in T18 in vitro, but only VRK2B stabilizes and activates p53 in vivo (Blanco et al., 2006). VRK2 activity is inhibited by the small GTPase RAN protein (Sanz-Garcia et al., 2008). |
Homology | The kinase domain of VRK2 presents several differences to most of protein kinases. DFG and APE motifs, that limited activation loop, are substituted by DYG and SID motifs respectively. VRK2 protein structure, as well as other VRK proteins, presents an additional helix (αC4) in the N-lobule that anchors αC helix to the C-lobule (Scheeff et al., 2009). |
The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. |
Blanco S, Klimcakova L, Vega FM, Lazo PA. |
FEBS J. 2006 Jun;273(11):2487-504. |
PMID 16704422 |
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Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein. |
Blanco S, Sanz-Garcia M, Santos CR, Lazo PA. |
PLoS One. 2008 Feb 20;3(2):e1660. |
PMID 18286207 |
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The facial dysmorphy in the newly recognised microdeletion 2p15-p16.1 refined to a 570 kb region in 2p15. |
Chabchoub E, Vermeesch JR, de Ravel T, de Cock P, Fryns JP. |
J Med Genet. 2008 Mar;45(3):189-92. |
PMID 18310269 |
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Further characterization of microdeletion syndrome involving 2p15-p16.1. |
Felix TM, Petrin AL, Sanseverino MT, Murray JC. |
Am J Med Genet A. 2010 Oct;152A(10):2604-8. |
PMID 20799320 |
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VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer. |
Fernandez IF, Blanco S, Lozano J, Lazo PA. |
Mol Cell Biol. 2010 Oct;30(19):4687-97. Epub 2010 Aug 2. |
PMID 20679487 |
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Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16. |
Kjellman M, Roshani L, Teh BT, Kallioniemi OP, Hoog A, Gray S, Farnebo LO, Holst M, Backdahl M, Larsson C. |
J Clin Endocrinol Metab. 1999 Feb;84(2):730-5. |
PMID 10022445 |
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Human cellular protein VRK2 interacts specifically with Epstein-Barr virus BHRF1, a homologue of Bcl-2, and enhances cell survival. |
Li LY, Liu MY, Shih HM, Tsai CH, Chen JY. |
J Gen Virol. 2006 Oct;87(Pt 10):2869-78. |
PMID 16963744 |
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Late onset of spermatogenesis and gain of fertility in POG-deficient mice indicate that POG is not necessary for the proliferation of spermatogonia. |
Lu B, Bishop CE. |
Biol Reprod. 2003 Jul;69(1):161-8. Epub 2003 Feb 5. |
PMID 12606378 |
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The protein kinase complement of the human genome. |
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. |
Science. 2002 Dec 6;298(5600):1912-34. |
PMID 12471243 |
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Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase. |
Nezu J, Oku A, Jones MH, Shimane M. |
Genomics. 1997 Oct 15;45(2):327-31. |
PMID 9344656 |
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Characterization of three paralogous members of the Mammalian vaccinia related kinase family. |
Nichols RJ, Traktman P. |
J Biol Chem. 2004 Feb 27;279(9):7934-46. Epub 2003 Nov 25. |
PMID 14645249 |
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Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. |
Sanz-Garcia M, Lopez-Sanchez I, Lazo PA. |
Mol Cell Proteomics. 2008 Nov;7(11):2199-214. Epub 2008 Jul 9. |
PMID 18617507 |
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Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site. |
Scheeff ED, Eswaran J, Bunkoczi G, Knapp S, Manning G. |
Structure. 2009 Jan 14;17(1):128-38. |
PMID 19141289 |
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Common variants at VRK2 and TCF4 conferring risk of schizophrenia. |
Steinberg S, de Jong S; Irish Schizophrenia Genomics Consortium, Andreassen OA, Werge T, Borglum AD, Mors O, Mortensen PB, Gustafsson O, Costas J, Pietilainen OP, Demontis D, Papiol S, Huttenlocher J, Mattheisen M, Breuer R, Vassos E, Giegling I, Fraser G, Walker N, Tuulio-Henriksson A, Suvisaari J, Lonnqvist J, Paunio T, Agartz I, Melle I, Djurovic S, Strengman E; GROUP, Jurgens G, Glenthoj B, Terenius L, Hougaard DM, Orntoft T, Wiuf C, Didriksen M, Hollegaard MV, Nordentoft M, van Winkel R, Kenis G, Abramova L, Kaleda V, Arrojo M, Sanjuan J, Arango C, Sperling S, Rossner M, Ribolsi M, Magni V, Siracusano A, Christiansen C, Kiemeney LA, Veldink J, van den Berg L, Ingason A, Muglia P, Murray R, Nothen MM, Sigurdsson E, Petursson H, Thorsteinsdottir U, Kong A, Rubino IA, De Hert M, Rethelyi JM, Bitter I, Jonsson EG, Golimbet V, Carracedo A, Ehrenreich H, Craddock N, Owen MJ, O'Donovan MC; Wellcome Trust Case Control Consortium 2, Ruggeri M, Tosato S, Peltonen L, Ophoff RA, Collier DA, St Clair D, Rietschel M, Cichon S, Stefansson H, Rujescu D, Stefansson K. |
Hum Mol Genet. 2011 Oct 15;20(20):4076-81. Epub 2011 Jul 26. |
PMID 21791550 |
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