신경발달과 유방암에서의 VRK2 단백질의 역할에 대한 연구

Abstract

Vaccinia-related kinase 2 (VRK2) is an active serine/threonine kinase that is firstly discovered in 1989. Since the discovery, several studies have revealed some roles of VRK2 especially in pathological conditions. However, we still cannot understand its physiological role under healthy condition. Moreover, no report has shown that regulatory mechanism of kinase activity of VRK2. In the present studies, I showed that VRK2 has a neurodevelopmental role in synapse elimination by microglia. Next, I showed that RNA editing of VRK2 can regulate its kinase activity and RNA editing of VRK2 was altered in human breast cancer tissues. First, I showed that neurodevelopmental role of VRK2. During development, some of the excessively formed synapses should be eliminated by ‘synaptic pruning’ by microglia in order to complete a functional brain connectivity. For synaptic pruning to occur, synapse-to-be-lost should be tagged by opsonins. Especially, complement component C3 (C3) serves as opsonins for synapses in nervous system. Here I showed that VRK2, which is expressed in microglia, phosphorylates C3 and enhances its opsonization by releasing the intermolecular thioester bond-containing domain of C3. In VRK2-deficeint mice (VRK2KO), lack of C3 phosphorylation resulted in reduction of opsonization by C3. As a result, synaptic pruning was not efficiently performed as needed, in turn, VRK2KO mice showed impaired hippocampal learning and sociability due to delayed neurodevelopment. Similar to VRK2KO mice, 2p15-p16.1 microdeletion syndrome of human, which includes deletion of VRK2, showed impairment of neurodevelopment. Thus, our findings can be one of the possible explanations of 2p15-p16.1 microdeletion syndrome. Next, I showed that RNA editing of VRK2 can regulate its kinase activity. Genetic information is transcribed from genomic DNA (gDNA) to mRNA, and then translated into three‐dimensional proteins. mRNAs can undergo various posttranscriptional modifications including RNA editing, which can change the mRNA sequence and ultimately can affect protein function. Regulation of RNA editing can be altered in various types of diseases, especially in cancer. In this study, we found that RNA editing occurs at the 499th base (c.499) of human vaccinia‐related kinase 2 (VRK2). Both adenosine (A)-to-guanine (G) and G-to-A RNA editing was observed at this site. This base substitution is nonsynonymous, which changes the amino acid from isoleucine (when the base is A) to valine (when the base is G) , which is in the catalytic domain of VRK2. Kinase assays indicated that isoleucine-containing VRK2 has higher kinase activity than valine-containing VRK2. Intriguingly, G-to-A RNA editing of VRK2 was significantly elevated in human breast cancer tissue compared to that in normal adjacent breast tissue.