WNK4 (17q21.2) PHA2B, Hypertensio essentialis -geenitaustaa

https://www.ncbi.nlm.nih.gov/gene/65266
With No Lysine-kinase.

Miten tällainen proteiini voi ubikityloitua ja mennä proteosomaaliseen systeemiin, jos siinä ei ole lysiinejä(K) ? Tässä on apuna KELCH3-CUL3 - E3 ubikitiiniligaasitie. WNK4  sitoutuu KELCH3:een, joka on defosforyloituna Ser433-P-kohdastansa.  Sitä defosforylaatiosta taas pitää Calcineuriini huolen, sillä se on KELCH3-defosforylaasi.
Mutta siten: Oli kehitelty  Calcineuriini-inhibiittori (TACROLIMUS)  kun  tarvitaan immunosuppressiota  T-soluaktivaatiota vastaan.  Siitä taas on havaittu sivuvaikutusta: hyperkalemista  hypertensiota, jonka mekanismia on alettu selvittää.  Tuollainen sivuvaikutus muistuttaa  geneettistä tautia  familiaalista hyperkalemista  hypertensiota  tyyppiä  PHA2D ja siinä on vikaa KELCH3- proteiinissa.
Nimittäin  defosforyloitunut WNK4-KELCH3-CUL3  kompleksinaubikityloituu ja  johtaa WNK4:n  proteosomaaliseen silppuroitumiseen.  WNK4  pystyy aktivoituna kohottamaan NCC  ilmentymää, natrium-kloridi-kuljetuskanavaa munuaistubuluksessa   ja aiheutuu hypertensiota  jonka piirteenä on  hyperkalemisuus. Tosin suolarajoitus ja tiatsididiureetti  hoitavat tilanteen.

Entä jos  mutaatio on WNK4:n puolella?  Merkitään   tautia  nimellä PHA2B, pseudohyperaldosteronismi   tyyppi II B.

Official Full Name

WNK lysine deficient protein kinase 4

Also known as PHA2B; PRKWNK4

Summary: This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]

Expression Biased expression in kidney (RPKM 12.8), prostate (RPKM 5.7) and 6 other tissues See more

1. The regulation of Na+Cl- cotransporter by with-no-lysine kinase 4. Argaiz ER, et al. Curr Opin Nephrol Hypertens, 2016 Sep. PMID 27322883 Several studies involving in-vivo and in-vitro models have provided paradoxical data regarding WNK4 regulation of the NCC. Although some studies show that WNK4 can activate the NCC, other equally compelling studies show that WNK4 inhibits the NCC. Recent studies have shown that WNK4 is regulated by the intracellular chloride concentration ([Cl]i), which could account for these paradoxical results. In conditions of high [Cl]i, WNK4 could act as an inhibitor via heterodimer formation with other WNKs. In contrast, when [Cl]i is low, WNK4 can activate Ste20-related, proline-alanine-rich kinase (SPAK)/oxidative stress responsive kinase 1 (OSR1) and thus the NCC. Modulation of WNK4 by [Cl]i has been shown to account for the potassium-sensing properties of the distal convoluted tubule. Other regulators of WNK4 include hormones and ubiquitination.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. Defective regulation of WNKs by ubiquitination explains most cases of familial hyperkalemic hypertension.
   
2. Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia. Ghodsian N, et al. J Diabetes Res, 2016. PMID 27314050, Free PMC Article
3. Comprehensive assessment of the association of WNK4 polymorphisms with hypertension: evidence from a meta-analysis. Guo XG, et al. Sci Rep, 2014 Sep 30. PMID 25266424, Free PMC Article
4. Regulation of large-conductance Ca2+-activated K+ channels by WNK4 kinase. Wang Z, et al. Am J Physiol Cell Physiol, 2013 Oct 15. PMID 23885063, Free PMC Article
5. Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites. Na T, et al. Am J Physiol Renal Physiol, 2013 Jan 1. PMID 23054253, Free PMC Article

See all (79) citations in PubMed

1. NM_032387.5 → NP_115763.2  serine/threonine-protein kinase WNK4 isoform 1
   See identical proteins and their annotated locations for NP_115763.2
   
   Status: REVIEWED

   Source sequence(s)

   AC100793, BC136664, BM683764, CA388932

   Consensus CDS

   CCDS11439.1

   UniProtKB/Swiss-Prot

   Q96J92

   Related

   ENSP00000246914.4, ENST00000246914.10

   Conserved Domains (3) summary

   smart00220
   Location:179 → 432

   S_TKc; Serine/Threonine protein kinases, catalytic domain

   cd14033
   Location:172 → 432

   STKc_WNK4; Catalytic domain of the Serine/Threonine protein kinase, With No Lysine (WNK) 4

   pfam12202
   Location:453 → 489

   OSR1_C; Oxidative-stress-responsive kinase 1 C terminal