VRK2 (vaccinia related kinase 2)

Note	The subcellular localization of protein codified from this gene is dependent on two alternatively spliced variants (Blanco et al., 2006). Other alternative splicing messages have been detected but no proteins have been identified expressed from these alternative messages in humans.
	VRK2 gene structure based in data available in Ensembl release 66. Two alternatively spliced variants coding two isoforms, VRK2A and VRK2B. Non-coding regions of exons are indicated in orange and coding regions in yellow. Exon lenght is indicated in scale (and number of base pairs are indicated below). Exon number is indicated within the exon. Introns are not in scale and intron lenght is indicated below each intron.
Description	According to Entrez-Gene, VRK2 gene maps to NC_000002.11 in the region between 58273777 and 58387055 on the plus strand and spans across 113.180 kilobases.
Transcription	Initiation codon located in exon 2. Normal message is 1888 nucleotides and has 13 exons (isoform VRK2A). An alternatively spliced variant have been detected with a message of 2036 nucleotides and 14 exons (isoform VRK2B).
Pseudogene	None. There are two closely related genes: VRK1 and VRK3 (Nichols and Traktman, 2004).

Note	Enzyme number (IUBMB): EC 2.7.11.1.
	Isoforms of human VRK2 protein. They share identical sequence until aminoacid 394.
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).

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