Disease relevance of VRK1

• The human VRK1 protein is a new kinase related to a poxvirus kinase, and more distantly to the casein kinase 1 family [1].
• This gene has therefore been named VRK1 (vaccinia virus B1R kinase related kinase) [2].
• The three most common transcriptionally inactive mutations detected in hereditary (Li-Fraumeni syndrome) and sporadic human cancer, p53(R175H), p53(R248W), and p53(R273H), as well as p53(R280K), are unable to induce downregulation of VRK1 protein [3].
• The level of VRK1 protein behaves like a proliferation marker in this series of head and neck squamous cell carcinomas [4].
• VRK1 protein levels increase in response to E2F1 and are reduced by retinoblastoma and p16 [4].

High impact information on VRK1

• Vaccinia-related kinase 3 (VRK3) is a member of the novel VRK family, but its function has not been defined [5].
• p53 downregulates its activating vaccinia-related kinase 1, forming a new autoregulatory loop [3].
• The degradation of VRK1 is sensitive to chloroquine, an inhibitor of the late endosome-lysosome transport, and to serine protease inhibitors of the lysosomal pathway [3].
• The p53 isoforms Delta40p53 and p53beta, lacking the transactivation and oligomerization domains, respectively, do not downregulate VRK1 [3].
• VRK1 kinase does not phosphorylate Mdm2 [6].

Chemical compound and disease context of VRK1

• Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase [2].

Biological context of VRK1

• The human vaccinia-related kinase 1 (VRK1) phosphorylates threonine-18 within the mdm-2 binding site of the p53 tumour suppressor protein [1].
• We propose VRK1 as the first step in a new pathway regulating p53 activity during cell proliferation [6].
• VRK1 activates c-Jun dependent transcription, which is dependent on phosphorylation of Ser63 and Ser73 [7].
• VRK genes play a role during embryonic development of hematopoiesis [8].
• Taken together, these observations indicate that enzymatically active cellular VRK1 kinases can perform the function(s) of B1 required for genome replication, most likely due to overlapping specificity for cellular and/or viral substrates [9].

Anatomical context of VRK1

• VRK1 proteins possess a basic nuclear localization signal and are indeed nuclear; the extreme C termini of the VRK2 proteins are highly hydrophobic, and the proteins are membrane-associated and colocalize with markers of the endoplasmic reticulum [10].
• We have characterized the biochemical properties of human VRK1 from HeLa cells [1].
• VRK2A is expressed in all cell types, whereas VRK2B is expressed in cell lines in which VRK1 is cytoplasmic [11].
• VRK genes are expressed, particularly at mid-gestation, in embryo thymus and spleen, but in adult thymus and spleen their levels are very low [8].
• In normal squamous epithelium, VRK1 is expressed in the proliferation area [4].

Associations of VRK1 with chemical compounds

• VRK1 phosphorylates murine p53 in threonine 18 [1].
• VRK1 uses preferentially magnesium, but is also functional with manganese and zinc [12].

Physical interactions of VRK1

• The p53 stabilized by VRK1 is transcriptionally active [6].

Regulatory relationships of VRK1

• VRK2 is expressed at lower levels than VRK1 and VRK3 in the mouse embryo [8].

Other interactions of VRK1

• We conclude that VRK1 is an upstream regulator of p53 that belongs to a new signalling pathway [1].
• VRK1 increases the activity of both the CDK2 and SURVIVIN gene promoters [4].
• We show that VRK1 is a critical link in the CCND1 gene expression pathway stimulated by Myc overexpression [13].

References