6ncg

Structural highlights

Function

[VRK2_HUMAN] Serine/threonine kinase that regulates several signal transduction pathways. Isoform 1 modulates the stress response to hypoxia and cytokines, such as interleukin-1 beta (IL1B) and this is dependent on its interaction with MAPK8IP1, which assembles mitogen-activated protein kinase (MAPK) complexes. Inhibition of signal transmission mediated by the assembly of MAPK8IP1-MAPK complexes reduces JNK phosphorylation and JUN-dependent transcription. Phosphorylates 'Thr-18' of p53/TP53, histone H3, and may also phosphorylate MAPK8IP1. Phosphorylates BANF1 and disrupts its ability to bind DNA and reduces its binding to LEM domain-containing proteins. Downregulates the transactivation of transcription induced by ERBB2, HRAS, BRAF, and MEK1. Blocks the phosphorylation of ERK in response to ERBB2 and HRAS. Can also phosphorylate the following substrates that are commonly used to establish in vitro kinase activity: casein, MBP and histone H2B, but it is not sure that this is physiologically relevant.^{[1] [2] [3] [4] [5] [6] [7]} Isoform 2 phosphorylates 'Thr-18' of p53/TP53, as well as histone H3. Reduces p53/TP53 ubiquitination by MDM2, promotes p53/TP53 acetylation by EP300 and thereby increases p53/TP53 stability and activity.^{[8] [9] [10] [11] [12] [13] [14]}

References

1. ↑ Blanco S, Klimcakova L, Vega FM, Lazo PA. The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. FEBS J. 2006 Jun;273(11):2487-504. PMID:16704422 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05256.x
2. ↑ Nichols RJ, Traktman P. Characterization of three paralogous members of the Mammalian vaccinia related kinase family. J Biol Chem. 2004 Feb 27;279(9):7934-46. Epub 2003 Nov 25. PMID:14645249 doi:http://dx.doi.org/10.1074/jbc.M310813200
3. ↑ Nichols RJ, Wiebe MS, Traktman P. The vaccinia-related kinases phosphorylate the N' terminus of BAF, regulating its interaction with DNA and its retention in the nucleus. Mol Biol Cell. 2006 May;17(5):2451-64. Epub 2006 Feb 22. PMID:16495336 doi:http://dx.doi.org/10.1091/mbc.E05-12-1179
4. ↑ Blanco S, Santos C, Lazo PA. Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. Mol Cell Biol. 2007 Oct;27(20):7273-83. Epub 2007 Aug 20. PMID:17709393 doi:http://dx.doi.org/10.1128/MCB.00025-07
5. ↑ Sanz-Garcia M, Lopez-Sanchez I, Lazo PA. Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. Mol Cell Proteomics. 2008 Nov;7(11):2199-214. doi: 10.1074/mcp.M700586-MCP200., Epub 2008 Jul 9. PMID:18617507 doi:10.1074/mcp.M700586-MCP200
6. ↑ Blanco S, Sanz-Garcia M, Santos CR, Lazo PA. Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein. PLoS One. 2008 Feb 20;3(2):e1660. doi: 10.1371/journal.pone.0001660. PMID:18286207 doi:http://dx.doi.org/10.1371/journal.pone.0001660
7. ↑ Fernandez IF, Blanco S, Lozano J, Lazo PA. VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer. Mol Cell Biol. 2010 Oct;30(19):4687-97. doi: 10.1128/MCB.01581-09. Epub 2010 Aug , 2. PMID:20679487 doi:http://dx.doi.org/10.1128/MCB.01581-09
8. ↑ Blanco S, Klimcakova L, Vega FM, Lazo PA. The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. FEBS J. 2006 Jun;273(11):2487-504. PMID:16704422 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05256.x
9. ↑ Nichols RJ, Traktman P. Characterization of three paralogous members of the Mammalian vaccinia related kinase family. J Biol Chem. 2004 Feb 27;279(9):7934-46. Epub 2003 Nov 25. PMID:14645249 doi:http://dx.doi.org/10.1074/jbc.M310813200
10. ↑ Nichols RJ, Wiebe MS, Traktman P. The vaccinia-related kinases phosphorylate the N' terminus of BAF, regulating its interaction with DNA and its retention in the nucleus. Mol Biol Cell. 2006 May;17(5):2451-64. Epub 2006 Feb 22. PMID:16495336 doi:http://dx.doi.org/10.1091/mbc.E05-12-1179
11. ↑ Blanco S, Santos C, Lazo PA. Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. Mol Cell Biol. 2007 Oct;27(20):7273-83. Epub 2007 Aug 20. PMID:17709393 doi:http://dx.doi.org/10.1128/MCB.00025-07
12. ↑ Sanz-Garcia M, Lopez-Sanchez I, Lazo PA. Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. Mol Cell Proteomics. 2008 Nov;7(11):2199-214. doi: 10.1074/mcp.M700586-MCP200., Epub 2008 Jul 9. PMID:18617507 doi:10.1074/mcp.M700586-MCP200
13. ↑ Blanco S, Sanz-Garcia M, Santos CR, Lazo PA. Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein. PLoS One. 2008 Feb 20;3(2):e1660. doi: 10.1371/journal.pone.0001660. PMID:18286207 doi:http://dx.doi.org/10.1371/journal.pone.0001660
14. ↑ Fernandez IF, Blanco S, Lozano J, Lazo PA. VRK2 inhibits mitogen-activated protein kinase signaling and inversely correlates with ErbB2 in human breast cancer. Mol Cell Biol. 2010 Oct;30(19):4687-97. doi: 10.1128/MCB.01581-09. Epub 2010 Aug , 2. PMID:20679487 doi:http://dx.doi.org/10.1128/MCB.01581-09