WNK pathways in cancer signaling networks

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Abstract

Background

The with no lysine [K] (WNK) pathway consists of the structurally unique WNK kinases, their downstream target kinases, oxidative stress responsive (OSR)1 and SPS/Ste20-related proline-alanine-rich kinase (SPAK), and a multitude of OSR1/SPAK substrates including cation chloride cotransporters.

Main body

While the best known functions of the WNK pathway is regulation of ion transport across cell membranes, WNK pathway components have been implicated in numerous human diseases. The goal of our review is to draw attention to how this pathway and its components exert influence on the progression of cancer, specifically by detailing WNK signaling intersections with major cell communication networks and processes.

Conclusion

Here we describe how WNKs and associated proteins interact with and influence PI3K-AKT, TGF-β, and NF-κB signaling, as well as its unanticipated role in the regulation of angiogenesis.

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Most cited references 51

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Mutations in Kelch-like 3 and Cullin 3 cause hypertension and electrolyte abnormalities

Lynn Boyden, Murim Choi, Keith Choate … (2012)

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. A rare Mendelian syndrome, pseudohypoaldosteronism type II (PHAII), featuring hypertension, hyperkalemia, and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption versus K+ and H+ excretion 1 . We used exome sequencing to identify mutations in Kelch-like 3 (KLHL3) or Cullin 3 (CUL3) in 41 PHAII kindreds. KLHL3 mutations are either recessive or dominant, while CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-Kelch proteins such as KLHL3 are components of Cullin/RING E3 ligase complexes (CRLs) that ubiquitinate substrates bound to Kelch propeller domains 2–8 . Dominant KLHL3 mutations are clustered in short segments within the Kelch propeller and BTB domains implicated in substrate 9 and Cullin 5 binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter (NCC) in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3/CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite combined complexities of locus heterogeneity, mixed models of transmission, and frequent de novo mutation, and establish a fundamental role for KLHL3/CUL3 in blood pressure, K+, and pH homeostasis.

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Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus

Jason K. Karimy, Jinwei Zhang, David B. Kurland … (2017)

In a rat model of hydrocephalus triggered by intraventricular hemorrhage, Kristopher Kahle and colleagues show that TLR4–NF-κB-dependent inflammatory signaling in the choroid plexus causes hypersecretion of cerebrospinal fluid that drives hydrocephalus. Targeting TLR4–NF-κB-mediated signaling or the NKCC1–SPAK complex ameliorates hydrocephalus.

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The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.

Dario Alessi, Maria Deak, Alberto C. Vitari … (2005)

Mutations in the human genes encoding WNK1 [with no K (lysine) protein kinase-1] and the related protein kinase WNK4 are the cause of Gordon's hypertension syndrome. Little is known about the molecular mechanism by which WNK isoforms regulate cellular processes. We immunoprecipitated WNK1 from extracts of rat testis and found that it was specifically associated with a protein kinase of the STE20 family termed 'STE20/SPS1-related proline/alanine-rich kinase' (SPAK). We demonstrated that WNK1 and WNK4 both interacted with SPAK as well as a closely related kinase, termed 'oxidative stress response kinase-1' (OSR1). Wildtype (wt) but not catalytically inactive WNK1 and WNK4 phosphorylated SPAK and OSR1 to a much greater extent than with other substrates utilized previously, such as myelin basic protein and claudin-4. Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1). Mutation of Thr185 to alanine prevented the activation of OSR1 by WNK1, whereas mutation of Thr185 to glutamic acid (to mimic phosphorylation) increased the basal activity of OSR1 over 20-fold and prevented further activation by WNK1. Mutation of Ser325 in OSR1 to alanine or glutamic acid did not affect the basal activity of OSR1 or its ability to be activated by WNK1. These findings suggest that WNK isoforms operate as protein kinases that activate SPAK and OSR1 by phosphorylating the T-loops of these enzymes, resulting in their activation. Our analysis also describes the first facile assay that can be employed to quantitatively assess WNK1 and WNK4 activity.

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Author and article information

Contributors

Sachith Gallolu Kankanamalage: Sachith.GalloluKankanamalage@UTSouthwestern.edu

Aroon S. Karra: Aroon.Karra@UTSouthwestern.edu

Melanie H. Cobb: 214 645-6122 , Melanie.Cobb@UTSouthwestern.edu

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun. Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-811X

Publication date (Electronic): 3 November 2018

Publication date PMC-release: 3 November 2018

Publication date Collection: 2018

Volume: 16

Electronic Location Identifier: 72

Affiliations

ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Pharmacology, , The University of Texas Southwestern Medical Center, ; 6001 Forest Park Road, Dallas, TX 75390-9041 USA

Article

Publisher ID: 287

DOI: 10.1186/s12964-018-0287-1

PMC ID: 6215617

PubMed ID: 30390653

SO-VID: c1f38e10-57a2-4eeb-b265-3573dbe3149d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 August 2018

Date accepted : 22 October 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000928, Welch Foundation;

Award ID: I1243

Award Recipient : Melanie H. Cobb

Custom metadata

ScienceOpen disciplines: Cell biology

Keywords: wnks,osr1,spak,stk39,cellular signaling,ion transport,cancer,pi3k-akt,tgf-β,and nf-κb

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: wnks, osr1, spak, stk39, cellular signaling, ion transport, cancer, pi3k-akt, tgf-β, and nf-κb

WNK pathways in cancer signaling networks

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Abstract

Background

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Conclusion

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Most cited references 51

Mutations in Kelch-like 3 and Cullin 3 cause hypertension and electrolyte abnormalities

Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus

The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.

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