Regulation of WNK1 by an Autoinhibitory Domain and Autophosphorylation

Xu, Bing; Min, Xiaoshan; Stippec, Steve; Lee, Byung‐Hoon; Goldsmith, Elizabeth J.; Cobb, Melanie H.

doi:10.1074/jbc.m207917200

Cited by 152 publications

(197 citation statements)

References 26 publications

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“…The initial biochemical characterization of WNK1 revealed its activation by autophosphorylation, which in turn is regulated by the presence of an autoinhibitory domain [5]. The autoinhibitory domain of WNK1 inhibits not only its autophosphorylation, but also that of WNK2 and WNK4 [6], suggesting that autophosphorylation, and thus presumably the 1…”

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WNK lies upstream of kinases involved in regulation of ion transporters

Gamba

2005

Biochemical Journal

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Two members of a recently discovered family of protein kinases {WNK1 and WNK4 [with no K (lysine) kinases-1 and -4]} are the cause of an inherited disease known as pseudohypoaldosteronism type II that features arterial hypertension. The family is known as WNK due to a lack of the invariant catalytic lysine in kinase subdomain II. The mechanisms by which WNKs regulate blood pressure are beginning to be understood at the physiological level from recent studies showing effects of WNK4 on several plasma membrane co-transporters and ion channels. However, little is known about the function of WNKs at the biochemical level. In this issue of the Biochemical Journal, Vitari et al. have shown that WNK1 and WNK4 interact with other kinases, SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress response kinase-1), which are involved in the regulation of ion transporters. WNK1 and WNK4 phosphorylate SPAK and OSR1, which in turn phosphorylate the N-terminal domain of the basolateral Na + -K + -2Cl − co-transporter, NKCCl. The phosphorylation site involved in SPAK or OSR1 activation is identified as a threonine residue within the T-loop.Key words: hypertension, ion transport regulation, kinase interaction, phosphorylation, pseudohypoaldosteronism type II.Arterial hypertension is one of the most common and dangerous diseases of the industrialized world, which occurs in approx. 20-25 % of the adult population. Arterial hypertension is an asymptomatic disease that accelerates the process of atherosclerosis, increasing the risk of myocardial infarction and stroke. Although the origins of hypertension are unknown, it is a prototype of so-called polygenic diseases, in which single 'normal' changes throughout the genome (SNPs, or single nucleotide polymorphisms) predispose individuals for increased susceptibility to environmental factors, e.g. salt consumption, that will induce the increase in arterial pressure. In addition, it is believed that SNPs will help to explain the different responses to anti-hypertensive drugs observed within the population (pharmacogenomics). Thus the more we understand the genes involved in regulating blood pressure, the more we will be able to understand their participation in this complex disease. One approach that has been successfully used involves defining the genes causing monogenic diseases exhibiting high-or low-blood pressure levels; if altered function of a single gene is enough to produce an abnormal change in blood pressure, it is highly likely that the gene could be involved in the polygenetic cause of essential hypertension. More than 15 genes have been identified by this strategy [1], leading the way to understanding their roles in blood pressure regulation and hypertension.The gene family known as WNKs [with no lysine (K) kinases] was discovered by Xu et al. [2] in a cloning effort designed to identify novel members of the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] family. Lacking the invariant catalytic l...

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confidence: 99%

WNK lies upstream of kinases involved in regulation of ion transporters

Gamba

2005

Biochemical Journal

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“…Notre laboratoire a récemment caractérisé cette isoforme [9]: sa transcription débute au niveau de l'exon 4a sous le contrôle d'un promoteur spécifique (rP), donnant ainsi naissance à une protéine dépourvue des sous-domaines I à X du domaine kinase. Cette isoforme, spécifique du rein, ne possèderait donc pas d'activité kinase [5,9]. Elle contient cependant toujours le domaine d'auto-inhibition situé en aval du domaine kinase.…”

Section: Wnk Et Réabsorption Sodée Dans Le Dctunclassified

“…[3,4]. Outre le domaine kinase, les protéines WNK possèdent un domaine auto-inhibiteur de l'activité kinase [5], deux domaines coiled-coil et trois domaines riches en proline [6]. Malgré leur très forte homologie, les domaines kinase de WNK1 et WNK4 ne semblent pas équivalents.…”

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“…Malgré leur très forte homologie, les domaines kinase de WNK1 et WNK4 ne semblent pas équivalents. Le domaine kinase de WNK1 est actif in vitro et capable d'autophosphorylation, ce qui n'est pas le cas de celui de WNK4 [5,7]. Il est possible que l'activation de WNK4 nécessite l'interaction avec un partenaire protéique, comme le suggère l'action du domaine auto-inhibiteur de WNK1 sur WNK4 et l'agrégation de WNK1 in vitro sous forme de tétramère [5,7].…”

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“…Le domaine kinase de WNK1 est actif in vitro et capable d'autophosphorylation, ce qui n'est pas le cas de celui de WNK4 [5,7]. Il est possible que l'activation de WNK4 nécessite l'interaction avec un partenaire protéique, comme le suggère l'action du domaine auto-inhibiteur de WNK1 sur WNK4 et l'agrégation de WNK1 in vitro sous forme de tétramère [5,7]. De même, on ne connaît pas encore toutes les voies activées par les WNK, mais l'équipe de M. Cobb a récemment montré que WNK1 est capable de phosphoryler ERK5 [8].…”

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