Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have cloned and characterized a novel human serine/threonine protein kinase gene from chromosome 12p13.3 encoding 2382 amino acids. Remarkably, the catalytic domain sequence contains a cysteine in place of a lysine residue conserved in subdomain II of most kinases. The same amino acid alteration was recently described for rat WNK1 (with no K=lysine) in which another nearby lysine residue was shown to confer kinase activity to the protein. Rat WNK1 is 85% identical to a splice variant lacking exons 11 and 12 of the described human kinase which we have called human WNK1. The WNK1 catalytic domain has closest homology with human PAK2, MEKK3, and Raf-1. Three additional, partial human protein kinase sequences, WNK2, WNK3 and WNK4, are also reported here with catalytic domains that are 95% homologous to WNK1. These genes differ both in chromosomal location and tissue-specific expression. Moreover, we have identified in the database a total of 18 WNK-related genes, all exclusively from multi-cellular organisms, which share a WNK kinase sequence signature within subdomains I and II of the catalytic domain. We suggest that they constitute a novel subfamily of protein kinases that evolved together with cell adhesion and tissue-formation.
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PMID:WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. 1157 56

The complete genome sequence of Arabidopsis thaliana revealed that this higher plant has a tremendous number of protein kinases. We recently isolated a novel type of protein kinase, named AtWNK1, which shows an in vitro ability to phosphorylate the APRR3 member of the APRR1/TOC1 quintet that has been implicated in a mechanism underlying circadian rhythms in Arabidopsis. We here address two issues, one general and one specific, as to this novel protein kinase. We first asked the general question of how many WNK family members are present in this higher plant, then whether or not other members are also relevant to circadian rhythms. The results of our analyses showed that Arabidopsis has at least 9 members of the WNK1 family of protein kinases (designated here as WNK1 to WNK9), the structural design of which is clearly distinct from those of other known protein kinases, such as receptor-like kinases and mitogen-activated protein kinases. They were examined with special reference to the circadian-related APRR1/TOC1 quintet. It was found that not only the transcription of the WNK1 gene, but also those of three other members (WNK2, WNK4, and WNK6) are under the control of circadian rhythms. These results suggested that certain members of the WNK family of protein kinases might play roles in a mechanism that generates circadian rhythms in Arabidopsis.
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PMID:Compilation and characterization of a novel WNK family of protein kinases in Arabiodpsis thaliana with reference to circadian rhythms. 1250 83

WNKs are large serine/threonine protein kinases structurally distinct from all other members of the protein kinase superfamily. Of the four human WNK family members, WNK1 and WNK4 have been linked to a hereditary form of hypertension, pseudohypoaldosteronism type II. We characterized the biochemical properties and regulation of WNK1 that may contribute to its physiological activities and abnormal function in disease. We showed that WNK1 is activated by hypertonic stress in kidney epithelial cells and in breast and colon cancer cell lines. In addition, hypotonic stress also led to a modest increase in WNK1 activity. Gel filtration suggested that WNK1 exists as a tetramer, and yeast two-hybrid data showed that the N terminus of WNK1 (residues 1-222) interacts with residues 481-660, which includes the WNK1 autoinhibitory domain and a C-terminal coiled-coil domain. Although cell biological studies have suggested a functional interaction between WNK1 and WNK4, we found no evidence of stable interactions between these kinases. However, WNK1 phosphorylated both WNK4 and WNK2. In addition, the WNK1 autoinhibitory domain inhibited the catalytic activity of these WNKs. These findings suggest potential mechanisms for interconnected regulation of WNK family members.
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PMID:Properties of WNK1 and implications for other family members. 1588 53

Human cancer genome and epigenome projects aim to identify new cancer genes and targets for therapy that have been overlooked by conventional approaches. Here we integrated large-scale genomics and epigenomics of 31 human infiltrative gliomas and identified low-frequency deletion and highly recurrent epigenetic silencing of WNK2, encoding a putative serine/threonine kinase. Prior cancer genome sequencing projects also identified point mutations in WNK1-4, suggesting that WNK family genes may have a role in cancers. We observed consistent gene silencing in tumors with dense aberrant methylation across 1.3 kb of the CpG island but more variable expression when the 5'-most region remained unmethylated. This primary tumor data fit well with WNK2 promoter analysis, which showed strong promoter activity in the 5'-most region, equivalent to the simian virus 40 promoter, but no activity in the 3' region. WT WNK2 exhibited autophosphorylation and protein kinase activity that was enhanced in cells exposed to hypertonic conditions, similar to WNK1. WNK2 inhibited up to 78% of colony formation by glioma cells but in an unexpectedly kinase-independent manner. The WNK2 silencing by epigenetic mechanisms was significantly associated (P < 0.01) with a known genetic signature of chemosensitive oligodendroglial tumors, 1p and 19q deletion, in two small but independent tumor sets. Taken together, the epigenetic silencing, occasional deletion and point mutation, and functional assessment suggest that aberrations of WNK2 may contribute to unregulated tumor cell growth. Thus, our integrated genetic and epigenetic approach might be useful to identify genes that are widely relevant to cancer, even when genetic alterations of the locus are infrequent.
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PMID:Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. 1757 25

WNK protein kinases form a kinase subfamily expressed in multi-cellular organisms and the human genome encodes four distinct WNK genes. Human WNK2 has been recently identified as a cell growth regulator that modulates activation of the ERK1/2 protein kinase and is epigenetically silenced in gliomas. Here we provide mechanistic insight into how WNK2 affects ERK activation. We found that WNK2 depletion decreased RhoA activation and promoted GTP-loading of Rac1, leading to stimulation of the Rac1-effector PAK1, which is the kinase responsible for subsequent phosphorylation of MEK1 at serine 298, thereby increasing MEK affinity towards ERK1/2. We propose that WNK2 controls a RhoA-mediated cross-talk mechanism that regulates the efficiency with which MEK1 can activate ERK1/2 upon growth factor stimulation.
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PMID:WNK2 modulates MEK1 activity through the Rho GTPase pathway. 1859 98

The gene encoding protein kinase WNK2 was recently identified to be silenced by promoter hypermethylation in gliomas and meningiomas, suggesting a tumour-suppressor role in these brain tumours. Following experimental depletion in cell lines, WNK2 was further found to control GTP-loading of Rac1, a signalling guanosine triphosphatase involved in cell migration and motility. Here we show that WNK2 promoter methylation also occurs in 17.5% (29 out of 166) of adult gliomas, whereas it is infrequent in its paediatric forms (1.6%; 1 out of 66). Re-expression of WNK2 in glioblastoma cells presenting WNK2 gene silencing reduced cell proliferation in vitro, tumour growth in vivo and also cell migration and invasion, an effect correlated with reduced activation of Rac1. In contrast, when endogenous WNK2 was depleted from glioblastoma cells with unmethylated WNK2 promoter, changes in cell morphology, an increase in invasion and activation of Rac1 were observed. Together, these results validate the WNK2 gene as a recurrent target for epigenetic silencing in glia-derived brain tumours and provide first mechanistic evidence for a tumour-suppressing role of WNK2 that is related to Rac1 signalling and tumour cell invasion and proliferation.
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PMID:Loss of WNK2 expression by promoter gene methylation occurs in adult gliomas and triggers Rac1-mediated tumour cell invasiveness. 2303 50