342
Views
11
CrossRef citations to date
0
Altmetric
Review

Pharmacological targeting of SPAK kinase in disorders of impaired epithelial transport

ORCID Icon, , &
Pages 795-804 | Received 10 Apr 2017, Accepted 04 Jul 2017, Published online: 12 Jul 2017

References

  • Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9:28–39.
  • Cohen P, Alessi DR. Kinase drug discovery–what’s next in the field? ACS Chem Biol. 2013;8:96–104.
  • Richardson C, Alessi DR. The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway. J Cell Sci. 2008;121:3293–3304.
  • Delpire E, Gagnon KB. SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. Biochem J. 2008;409:321–331.
  • Moriguchi T, Urushiyama S, Hisamoto N, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem. 2005;280:42685–42693.
  • Vitari AC, Deak M, Morrice NA, et al. The WNK1 and WNK4 protein kinases that are mutated in Gordon’s hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. Biochem J. 2005;391:17–24.
  • Filippi BM, De Los Heros P, Mehellou Y, et al. MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. Embo J. 2011;30:1730–1741.
  • Piechotta K, Lu J, Delpire E. Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem. 2002;277:50812–50819.
  • Gagnon KB, England R, Delpire E. Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4. Am J Physiol Cell Physiol. 2006;290:C134–C42.
  • Anselmo AN, Earnest S, Chen W, et al. WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells. Proc Natl Acad Sci U S A. 2006;103:10883–10888.
  • Richardson C, Rafiqi FH, Karlsson HK, et al. Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci. 2008;121:675–684.
  • de Los Heros P, Alessi DR, Gourlay R, et al. The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. Biochem J. 2014;458:559–573.
  • Richardson C, Sakamoto K, De Los Heros P, et al. Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. J Cell Sci. 2011;124:789–800.
  • Gagnon KB, Delpire E. Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts. Am J Physiol Cell Physiol. 2013;304:C693–C714.
  • Arroyo JP, Kahle KT, Gamba G. The SLC12 family of electroneutral cation-coupled chloride cotransporters. Mol Aspects Med. 2013;34:288–298.
  • Kahle KT, Rinehart J, Lifton RP. Phosphoregulation of the Na-K-2Cl and K-Cl cotransporters by the WNK kinases. Biochim Biophys Acta. 2010;1802:1150–1158.
  • Kahle KT, Ring AM, Lifton RP. Molecular physiology of the WNK kinases. Annu Rev Physiol. 2008;70:329–355.
  • Alessi DR, Zhang J, Khanna A, et al. The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Sci Signal. 2014;7:re3.
  • Wilson FH, Disse-Nicodeme S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001;293:1107–1112.
  • Boyden LM, Choi M, Choate KA, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 2012;482:98–102.
  • Ohta A, Schumacher FR, Mehellou Y, et al. 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. Biochem J. 2013;451:111–122.
  • Schumacher FR, Sorrell FJ, Alessi DR, et al. Structural and biochemical characterization of the KLHL3-WNK kinase interaction important in blood pressure regulation. Biochem J. 2014;460:237–246.
  • Wakabayashi M, Mori T, Isobe K, et al. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep. 2013;3:858–868.
  • Louis-Dit-Picard H, Barc J, Trujillano D, et al. KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet. 2012;44(456–460):S1–S3.
  • Grimm PR, Coleman R, Delpire E, et al. Constitutivelyactive SPAK causes hyperkalemia by activating NCC and remodeling distal tubules. J Am Soc Nephrol. 2017. pii: ASN.2016090948. DOI:10.1681/ASN.2016090948
  • Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996;12:24–30.
  • Lin SH, Shiang JC, Huang CC, et al. Phenotype and genotype analysis in Chinese patients with Gitelman’s syndrome. J Clin Endocrinol Metab. 2005;90:2500–2507.
  • Shao L, Ren H, Wang W, et al. Novel SLC12A3 mutations in Chinese patients with Gitelman’s syndrome. Nephron Physiol. 2008;108:p29–p36.
  • Yang SS, Lo YF, Wu CC, et al. SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. J Am Soc Nephrol. 2010;21:1868–1877.
  • McCormick JA, Mutig K, Nelson JH, et al. A SPAK isoform switch modulates renal salt transport and blood pressure. Cell Metab. 2011;14:352–364.
  • Grimm PR, Taneja TK, Liu J, et al. SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner. J Biol Chem. 2012;287:37673–37690.
  • Rafiqi FH, Zuber AM, Glover M, et al. Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med. 2010;2:63–75.
  • Chiga M, Rafiqi FH, Alessi DR, et al. Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. J Cell Sci. 2011;124:1391–1395.
  • Wang Y, O’Connell JR, McArdle PF, et al. Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009;106:226–231.
  • Gordon RD, Hodsman GP. The syndrome of hypertension and hyperkalaemia without renal failure: long term correction by thiazide diuretic. Scott Med J. 1986;31:43–44.
  • Gordon RD, Klemm SA, Tunny TJ, et al. Gordon’s syndrome: A sodium-volume-dependent form of hypertension with a genetic basis. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis, and management. New York: Raven Press; 1995. p. 2111–2123.
  • Ushiro H, Tsutsumi T, Suzuki K, et al. Molecular cloning and characterization of a novel Ste20-related protein kinase enriched in neurons and transporting epithelia. Arch Biochem Biophys. 1998;355:233–240.
  • Johnston AM, Naselli G, Gonez LJ, et al. SPAK, a STE20/SPS1-related kinase that activates the p38 pathway. Oncogene. 2000;19:4290–4297.
  • Yan Y, Nguyen H, Dalmasso G, et al. Cloning and characterization of a new intestinal inflammation-associated colonic epithelial Ste20-related protein kinase isoform. Biochim Biophys Acta. 2007;1769:106–116.
  • Tamari M, Daigo Y, Nakamura Y. Isolation and characterization of a novel serine threonine kinase gene on chromosome 3p22-21.3. J Hum Genet. 1999;44:116–120.
  • Delpire E. The mammalian family of sterile 20p-like protein kinases. Pflugers Arch. 2009;458:953–967.
  • Manning G, Db W, Martinez R, et al. The protein kinase complement of the human genome. Science. 2002;298:1912–1934.
  • Chen W, Yazicioglu M, Cobb MH. Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily. J Biol Chem. 2004;279:11129–11136.
  • Piechotta K, Garbarini N, England R, et al. Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl- cotransporter in the nervous system: evidence for a scaffolding role of the kinase. J Biol Chem. 2003;278:52848–52856.
  • Tsutsumi T, Kosaka T, Ushiro H, et al. PASK (proline-alanine-rich Ste20-related kinase) binds to tubulin and microtubules and is involved in microtubule stabilization. Arch Biochem Biophys. 2008;477:267–278.
  • Koumangoye R, Delpire E. The Ste20 kinases SPAK and OSR1 travel between cells through exosomes. Am J Physiol Cell Physiol. 2016;311:C43–C53.
  • Geng Y, Hoke A, Delpire E. The Ste20 kinases Ste20-related proline-alanine-rich kinase and oxidative-stress response 1 regulate NKCC1 function in sensory neurons. J Biol Chem. 2009;284:14020–14028.
  • Saritas T, Borschewski A, McCormick JA, et al. SPAK differentially mediates vasopressin effects on sodium cotransporters. J Am Soc Nephrol. 2013;24:407–418.
  • Cheng CJ, Yoon J, Baum M, et al. STE20/SPS1-related proline/alanine-rich kinase (SPAK) is critical for sodium reabsorption in isolated, perfused thick ascending limb. Am J Physiol Renal Physiol. 2015;308:F437–F443.
  • Zhang J, Siew K, Macartney T, et al. Critical role of the SPAK protein kinase CCT domain in controlling blood pressure. Hum Mol Genet. 2015;24:4545–4558.
  • Grimm PR, Coleman R, Delpire E, et al. Enhanced NCC function due to constitutively active SPAK causes hyperkalemia by inducing distal tubule remodeling. J Am Soc Nephrol. Forthcoming 2017.
  • Susa K, Kita S, Iwamoto T, et al. Effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Clin Exp Nephrol. 2012;16:530–538.
  • Chu PY, Cheng CJ, Wu YC, et al. SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation. PLoS One. 2013;8:e72969.
  • Lee SJ, Cobb MH, Goldsmith EJ. Crystal structure of domain-swapped STE20 OSR1 kinase domain. Protein Sci. 2009;18:304–313.
  • Villa F, Deak M, Alessi DR, et al. Structure of the OSR1 kinase, a hypertension drug target. Proteins. 2008;73:1082–1087.
  • Ponce-Coria J, Gagnon KB, Delpire E. Calcium-binding protein 39 facilitates molecular interaction between Ste20p proline alanine-rich kinase and oxidative stress response 1 monomers. Am J Physiol Cell Physiol. 2012;303:C1198–C1205.
  • Vitari AC, Thastrup J, Rafiqi FH, et al. Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Biochem J. 2006;397:223–231.
  • Zhang J, Gao G, Begum G, et al. Functional kinomics establishes a critical node of volume-sensitive cation-Cl- cotransporter regulation in the mammalian brain. Sci Rep. 2016;6:35986.
  • Kahle KT, Delpire E. Kinase-KCC2 coupling: cl- rheostasis, disease susceptibility, therapeutic target. J Neurophysiol. 2016;115:8–18.
  • Thastrup JO, Rafiqi FH, Vitari AC, et al. SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation. Biochem J. 2012;441:325–337.
  • Ponce-Coria J, San-Cristobal P, Kahle KT, et al. Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases. Proc Natl Acad Sci U S A. 2008;105:8458–8463.
  • Susa K, Sohara E, Isobe K, et al. WNK-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone. Biochem Biophys Res Commun. 2012;427:743–747.
  • Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the united states a policy statement from the American Heart Association. Circulation. 2011;123:933–944.
  • Vidal-Petiot E, Elvira-Matelot E, Mutig K, et al. WNK1-related familial hyperkalemic hypertension results from an increased expression of L-WNK1 specifically in the distal nephron. Proc Natl Acad Sci U S A. 2013;110:14366–14371.
  • Bergaya S, Faure S, Baudrie V, et al. WNK1 regulates vasoconstriction and blood pressure response to alpha 1-adrenergic stimulation in mice. Hypertension. 2011;58:439–445.
  • Castaneda-Bueno M, Cervantes-Perez LG, Vazquez N, et al. Activation of the renal Na+: cl-cotransporter by angiotensin II is a WNK4-dependent process. Proc Natl Acad Sci U S A. 2012;109:7929–7934.
  • Takahashi D, Mori T, Nomura N, et al. WNK4 is the major WNK positively regulating NCC in the mouse kidney. Biosci Rep. 2014;34:195–205.
  • Glover M, Ware JS, Henry A, et al. Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon’s syndrome). Clin Sci (Lond). 2014;126:721–726.
  • Anderica-Romero AC, Escobar L, Padilla-Flores T, et al. Insights in cullin 3/WNK4 and its relationship to blood pressure regulation and electrolyte homeostasis. Cell Signal. 2014;26:1166–1172.
  • Mori Y, Wakabayashi M, Mori T, et al. Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms. Biochem Biophys Res Commun. 2013;439:30–34.
  • Tsuji S, Yamashita M, Unishi G, et al. A young child with pseudohypoaldosteronism type II by a mutation of Cullin 3. BMC Nephrol. 2013;14:166.
  • Shibata S, Zhang J, Puthumana J, et al. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci U S A. 2013;110:7838–7843.
  • Simon DB, Karet FE, Hamdan JM, et al. Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2CI cotransporter NKCC2. Nat Genet. 1996;13:183–188.
  • Simon DB, Nelson-Williams C, Johnson Bia M, et al. Gitelman’s variant of Barter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996;12:24–30.
  • Ji W, Foo JN, O’Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40:592–599.
  • Adeyemo A, Gerry N, Chen G, et al. A genome-wide association study of hypertension and blood pressure in African Americans. PLoS Genet. 2009;5:e1000564.
  • Yang H, Ye L, Wang Q, et al. A meta-analytical assessment of STK39 three well-defined polymorphisms in susceptibility to hypertension. Sci Rep. 2016;6:25290.
  • Yu L, Cai H, Yue Q, et al. WNK4 inhibition of ENaC is independent of Nedd4-2-mediated ENaC ubiquitination. Am J Physiol Renal Physiol. 2013;305:F31–F41.
  • Hadchouel J, Soukaseum C, Busst C, et al. Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension. Proc Natl Acad Sci U S A. 2010;107:18109–18114.
  • Ahmed M, Salker MS, Elvira B, et al. SPAK sensitive regulation of the epithelial Na channel ENaC. Kidney Blood Press Res. 2015;40:335–343.
  • Markadieu N, Rios K, Spiller BW, et al. Short forms of Ste20-related proline/alanine-rich kinase (SPAK) in the kidney are created by aspartyl aminopeptidase (Dnpep)-mediated proteolytic cleavage. J Biol Chem. 2014;289:29273–29284.
  • Greenberg A. Diuretic complications. Am J Med Sci. 2000;319:10–24.
  • Choate KA, Kahle KT, Wilson FH, et al. WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl- -transporting epithelia. Proc Natl Acad Sci U S A. 2003;100:663–668.
  • Kahle KT, Gimenez I, Hassan H, et al. WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia. Proc Natl Acad Sci U S A. 2004;101:2064–2069.
  • Mendes AI, Matos P, Moniz S, et al. Antagonistic regulation of cystic fibrosis transmembrane conductance regulator cell surface expression by protein kinases WNK4 and spleen tyrosine kinase. Mol Cell Biol. 2011;31:4076–4086.
  • Hong JH, Park S, Shcheynikov N, et al. Mechanism and synergism in epithelial fluid and electrolyte secretion. Pflugers Arch. 2014;466:1487–1499.
  • Hong JH, Yang D, Shcheynikov N, et al. Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3- cotransporters family. Proc Natl Acad Sci U S A. 2013;110:4105–4110.
  • Yang D, Li Q, So I, et al. IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway. J Clin Invest. 2011;121:956–965.
  • Yang CL, Liu X, Paliege A, et al. WNK1 and WNK4 modulate CFTR activity. Biochem Biophys Res Commun. 2007;353:535–540.
  • Yang D, Shcheynikov N, Zeng W, et al. IRBIT coordinates epithelial fluid and HCO3- secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct. J Clin Invest. 2009;119:193–202.
  • Park HW, Nam JH, Kim JY, et al. Dynamic regulation of CFTR bicarbonate permeability by [Cl-](i) and its role in pancreatic bicarbonate secretion. Gastroenterology. 2010;139:620–631.
  • LaRusch J, Jung J, General IJ, et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014;10:e1004376.
  • Yan Y, Laroui H, Ingersoll SA, et al. Overexpression of Ste20-related proline/alanine-rich kinase exacerbates experimental colitis in mice. J Immunol. 2011;187:1496–1505.
  • Zhang Y, Viennois E, Xiao B, et al. Knockout of Ste20-like proline/alanine-rich kinase (SPAK) attenuates intestinal inflammation in mice. Am J Pathol. 2013;182:1617–1628.
  • Yan Y, Dalmasso G, Nguyen HT, et al. Nuclear factor-kappaB is a critical mediator of Ste20-like proline-/alanine-rich kinase regulation in intestinal inflammation. Am J Pathol. 2008;173:1013–1028.
  • Lin TJ, Yang SS, Hua KF, et al. SPAK plays a pathogenic role in IgA nephropathy through the activation of NF-kappaB/MAPKs signaling pathway. Free Radic Biol Med. 2016;99:214–224.
  • Zagorska A, Pozo-Guisado E, Boudeau J, et al. Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress. J Cell Biol. 2007;176:89–100.
  • Kikuchi E, Mori T, Zeniya M, et al. Discovery of novel SPAK inhibitors that block WNK kinase signaling to cation chloride transporters. J Am Soc Nephrol. 2015;26:1525–1536.
  • Alamri MA, Kadri H, Alderwick LJ, et al. Rafoxanide and Closantel inhibit SPAK and OSR1 kinases by binding to a highly conserved allosteric site on their C-terminal domains. ChemMedChem. 2017;12:639–645.
  • Mori T, Kikuchi E, Watanabe Y, et al. Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy. Biochem J. 2013;455:339–345.
  • Yamada K, Park HM, Rigel DF, et al. Small-molecule WNK inhibition regulates cardiovascular and renal function. Nat Chem Biol. 2016;12:896–898.
  • Kadri H, Alamri MA, Navratilova IH, et al. Towards the development of small-molecule MO25 binders as potential indirect SPAK/OSR1 kinase inhibitors. Chembiochem. 2016;18:460–465.
  • Villa F, Goebel J, Rafiqi FH, et al. Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO Rep. 2007;8:839–845.
  • Ishigami-Yuasa M, Watanabe Y, Mori T, et al. Development of WNK signaling inhibitors as a new class of antihypertensive drugs. Bioorg Med Chem. 2017;25:3845–3852.
  • Mehellou Y, Alessi DR, Macartney TJ, et al. Structural insights into the activation of MST3 by MO25. Biochem Biophys Res Commun. 2013;431:604–609.
  • Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005;85:423–493.
  • Adragna NC, Di Fulvio M, Lauf PK. Regulation of K-Cl cotransport: from function to genes. J Membr Biol. 2004;201:109–137.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.