Recombinant Human Serine/threonine-protein kinase WNK4 (WNK4), partial

1. 5 WNK4 sites (S47, S64, S1169, S1180, S1196) are phosphorylated downstream of AngII signaling in cultured cells and in vitro by PKC and PKA. Phosphorylation at S64 and S1196 promoted phosphorylation of the WNK4 kinase T-loop at S332 (required for kinase activation) and increased phosphorylation of SPAK. Volume depletion induced phosphorylation of these sites in vivo, predominantly in the distal convoluted tubule. PMID: 28096417
2. Modulation of WNK4 activity by [Cl]i can account for its dual role on the NCC, and this has important physiological implications regarding the regulation of extracellular potassium concentration. PMID: 27322883
3. This study provides substantial new insights into the role of phosphorylation of KLHL3 in regulating the interaction with WNK4 PMID: 27727489
4. The distribution of allele frequency and genotype of WNK4 gene Ala589Ser polymorphism showed significant differences between essential hypertension subjects, with or without type 2 diabetes mellitus, and normotensive subjects. PMID: 27314050
5. Data indicate that WNK lysine deficient protein kinase 4 protein (WNK4) was degraded not only by proteasomes but also by atypical protein kinase C scaffold protein p62 (p62)-kelch-like 3 protein (KLHL3)-mediated selective autophagy. PMID: 26349538
6. this meta-analysis suggested that WNK4 G1155942T and C6749T gene polymorphisms may contribute to the susceptibility and development of hypertension. PMID: 25266424
7. Akt and PKA phosphorylated KLHL3 at S433, and phosphorylation of KLHL3 by PKA inhibited WNK4 degradation. PMID: 26435498
8. WNK4 is a substrate of SFKs and the association of c-Src and PTP-1D with WNK4 at Tyr(1092) and Tyr(1143) plays an important role in modulating the inhibitory effect of WNK4 on ROMK PMID: 25805816
9. WNK4 inhibits SNARE formation of syntaxin 13 with VAMP2. PMID: 23993962
10. Regulation of WNK4 by CUL3 and its relationship to blood pressure regulation and electrolyte homeostasis. [Review] PMID: 24518042
11. WNK4 inhibits Large-conductance, Ca(2 )-activated K( ) channel activity, in part, by increasing channel degradation through an ubiquitin-dependent pathway. PMID: 23885063
12. analysis of how mutations of KLHL3 show less ability to ubiquitinate WNK4 because of KLHL3's low stability and/or decreased binding to CUL3 or WNK4 PMID: 23962426
13. WNK4 inhibits ENaC channel activity independently of Nedd4-2-mediated ENaC ubiquitination. PMID: 23594824
14. KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex PMID: 23665031
15. The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. PMID: 23387299
16. The Exon 8 G1155942T polymorphism in WNK4 gene was associated with hypertension in the Kazakhs ethnic group in Xinjiang, and the T allele might be the risk factor for essential hypertension. PMID: 20513278
17. R1185C mutation disrupts a CaM binding site at the WNK4 COOH-terminal region and alters the phosphorylation of WNK4 by SGK1. PMID: 23054253
18. Data show that K1169E lost its inhibitory effect on NCC surface expression compared to wild-type WNK4 when expressed in HEK293 cells, while it did not change NCC total protein expression. PMID: 21196779
19. Results show that Tyr512 phosphorylation is a novel signal regulating the prevalence of CFTR at the cell surface and that WNK4 and Syk perform an antagonistic role in this process. PMID: 21807898
20. WNK4 WT inhibits Maxi K activity by reducing Maxi K protein at the membrane, but the inhibition is not due to an increase in clathrin-mediated endocytosis of Maxi K, but likely due to enhancing its lysosomal degradation. PMID: 21613417
21. WNK4 polymorphism rs56116165 is a rare allelic variant that may contribute to a genetic predisposition to osteoporosis PMID: 21236712
22. Data show that 17beta-estradiol/ERalpha regulates human WNK4 expression partly through AP-1 binding to the WNK4 promoter. PMID: 20943203
23. WNK4 kinase negatively regulates the anterograde trafficking of MR through kinase-independent mechanism. PMID: 21118716
24. Exon 7 C1155547T polymorphism in WNK4 gene is associated with essential hypertension. PMID: 20931534
25. The data demonstrate the hWNK4 3'-UTR plays an enhancer role by crosstalking with the promoter, and miR-296 suppresses hWNK4 expression through targeting on its 3'-UTR in a cell-specific fashion. PMID: 20561597
26. Data find that expression of the N termini of all four WNKs results in modest to strong activation of SGK1. PMID: 20525693
27. WNK4 promotes sodium chloride co-transporter targeting to the lysosome for degradation via a mechanism involving sortilin. PMID: 19875813
28. WNK4 suppresses plasma membrane expression of the thiazide-sensitive NaCl cotransporter (NCC), diverting it from the trans-Golgi network to the lysosome via an intracellular route. PMID: 19401467
29. The WNK4 gene probably plays an important role in the pathogenesis of essential hypertension. As a missense mutation, the Ala589Ser polymorphism may bring changes to the enzyme's function(s), resulting in increased susceptibility to the disease. PMID: 19340547
30. Single-nucleotide polymorphims of WNK4 in whites and African Americans with hypertension. PMID: 12719438
31. general role for WNK4 in the regulation of electrolyte flux in diverse epithelia PMID: 14769928
32. The WNK4 mutant possesses a gain-of-function activity and that the claudins may be important molecular targets of WNK4 kinase. PMID: 15070779
33. Mutations in the WNK4 gene identified in Japanese hypertensives may contribute to hypertension and progression of hypertensive complications to some extent. PMID: 15110905
34. In familial hyperkalemia and hypertension with WNK4 mutations, all affected subjects will apparently develop hypertension. Hypercalciuria accompanies hyperkalemia, and both precede hypertension. WNK4 may interact with a calcium channel or transporter. PMID: 15292344
35. data suggest that WNK4 wild type significantly inhibits sodium chloride cotransporter (NCC) surface expression, not owing to an increase in clathrin-mediated endocytosis of NCC, but likely from enhanced degradation of NCC through a lysosomal pathway PMID: 16688122
36. an SGK1 site in WNK4 regulates Na+ channel and K+ channel activity PMID: 17360471
37. WNK4 regulates transport proteins in different directions and cellular mechanisms. Familial hyperkalemic hypertension-causing mutants of WNK4 exhibit differences regulating ion transport proteins. PMID: 17634397
38. Data demonstrate that WNK4 is a new glucocorticoid-regulated gene whose expression is inhibited through the interaction of glucocorticoid receptor with negative glucocorticoid response elements in the promoter region. PMID: 18096992
39. WNK4-induced MAP kinase stimulation caused by hypertonicity PMID: 18312414
40. These results confirm the important role of the acidic motif of WNK4 in its protein-protein interaction with the ROMK channel. PMID: 18755144
41. using real-time PCR and Western blot assays, we show that trichostatin A (TSA), a histone deacetylase inhibitor, upregulated hWNK4 mRNA and protein expression in human embryo kidney 293 cells. PMID: 18793746
42. identified P561L WNK4 mutation which has not been described previously is the probable cause of pseudohypoaldosteronism type II PMID: 19016006
43. c-Src inhibits SGK1-mediated phosphorylation hereby restoring the WNK4-mediated inhibition of ROMK channels thus suppressing K secretion. PMID: 19706464

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HGNC: 14544

OMIM: 601844

KEGG: hsa:65266

STRING: 9606.ENSP00000246914

UniGene: Hs.105448