Gene Symbol: SPAK
Description: serine/threonine kinase 39
Alias: DCHT, PASK, SPAK, STE20/SPS1-related proline-alanine-rich protein kinase, STE20/SPS1 homolog, Ste20-like protein kinase, proline-alanine-rich STE20-related kinase, serine threonine kinase 39 (STE20/SPS1 homolog, yeast), serine/threonine-protein kinase 39, small intestine SPAK-like kinase, ste-20-related kinase
Species: human
Products:     SPAK

Top Publications

  1. Dowd B, Forbush B. PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na-K-Cl cotransporter (NKCC1). J Biol Chem. 2003;278:27347-53 pubmed
    ..Piechotta, K., Lu, J., and Delpire, E. (2002) J. Biol. Chem. 277, 50812-50819) reported the binding of PASK (also referred as SPAK (STE20/SPS1-related proline-alanine-rich kinase)) and OSR1 (oxidative stress response kinase)..
  2. Richardson C, Rafiqi F, Karlsson H, Moleleki N, Vandewalle A, Campbell D, et al. Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci. 2008;121:675-84 pubmed publisher
    ..Here, we demonstrate that the SPAK and OSR1 kinases that are activated by WNK1 phosphorylate human NCC at three conserved residues (Thr46, Thr55 and ..
  3. Filippi B, de los Heros P, Mehellou Y, Navratilova I, Gourlay R, Deak M, et al. MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. EMBO J. 2011;30:1730-41 pubmed publisher
    ..These new MO25 targets are SPAK/OSR1 kinases, regulators of ion homeostasis and blood pressure, and MST3/MST4/YSK1, involved in controlling ..
  4. Wang Y, O Connell J, McArdle P, Wade J, Dorff S, Shah S, et al. From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci U S A. 2009;106:226-31 pubmed publisher
    ..Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na(+) excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway. ..
  5. Huang Y, Heist R, Chirieac L, Lin X, Skaug V, Zienolddiny S, et al. Genome-wide analysis of survival in early-stage non-small-cell lung cancer. J Clin Oncol. 2009;27:2660-7 pubmed publisher
    ..80 x 10(-12) and 2.48 x 10(-7) for MGH and Norwegian cohorts, respectively). Five SNPs were identified that may be prognostic of overall survival in early-stage NSCLC. ..
  6. Cunnington M, Kay C, Avery P, Mayosi B, Koref M, Keavney B. STK39 polymorphisms and blood pressure: an association study in British Caucasians and assessment of cis-acting influences on gene expression. BMC Med Genet. 2009;10:135 pubmed publisher
    ..STK39 expression is modified by polymorphisms acting in cis and the typed SNPs are associated with allelic expression of this gene, but there is no evidence for an association with BP in a British Caucasian cohort. ..
  7. Chen L, Zhao W, Tian W, Guo J, Jiang F, Jin L, et al. STK39 is an independent risk factor for male hypertension in Han Chinese. Int J Cardiol. 2012;154:122-7 pubmed publisher
    ..Our results suggest that STK39 is an independent risk factor for hypertension in men and that its intragenic SNPs can interact and function in the control of blood pressure. ..
  8. Yan Y, Nguyen H, Dalmasso G, Sitaraman S, Merlin D. Cloning and characterization of a new intestinal inflammation-associated colonic epithelial Ste20-related protein kinase isoform. Biochim Biophys Acta. 2007;1769:106-16 pubmed
    ..Here, we show that a novel isoform of SPS1-related proline alanine-rich kinase (SPAK/STE20) is involved in this inflammatory signaling cascade...
  9. Ramoz N, Cai G, Reichert J, Silverman J, Buxbaum J. An analysis of candidate autism loci on chromosome 2q24-q33: evidence for association to the STK39 gene. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1152-8 pubmed publisher
    ..012 and rs971257, P = 0.030) or haplotypes (P = 0.003) of the STK39 gene. STK39 encodes a serine/threonine kinase (SPAK/PASK/STE20-SPS1 homolog) abundantly expressed in the brain with roles in cell differentiation, cell transformation ..

More Information

Publications101 found, 100 shown here

  1. Yan Y, Dalmasso G, Nguyen H, Obertone T, Charrier Hisamuddin L, Sitaraman S, et al. Nuclear factor-kappaB is a critical mediator of Ste20-like proline-/alanine-rich kinase regulation in intestinal inflammation. Am J Pathol. 2008;173:1013-28 pubmed publisher
    ..Here we show that the expression of colonic Ste20-like proline-/alanine-rich kinase (SPAK) that lacks a PAPA box and an F-alpha helix loop is increased in patients with IBD...
  2. Gagnon K, 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:C134-42 pubmed
    In the present study, we have demonstrated functional interaction between Ste20-related proline-alanine-rich kinase (SPAK), WNK4 [with no lysine (K)], and the widely expressed Na+-K+-2Cl- cotransporter type 1 (NKCC1)...
  3. Johnston A, Naselli G, Gonez L, Martin R, Harrison L, Deaizpurua H. SPAK, a STE20/SPS1-related kinase that activates the p38 pathway. Oncogene. 2000;19:4290-7 pubmed
    We have cloned a member of the STE20/SPS1 protein kinase family from a transformed rat pancreatic beta cell line. SPAK (STE20/SPS1-related, proline alanine-rich kinase) belongs to the SPS1 subfamily of STE20 kinases and is highly ..
  4. Moriguchi T, Urushiyama S, Hisamoto N, Iemura S, Uchida S, Natsume T, et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem. 2005;280:42685-93 pubmed
    ..shown that WNK1 phosphorylates and regulates the STE20-related kinases, Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1)...
  5. 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;277:50812-9 pubmed
    ..we report the interaction of the stress-related serine-threonine kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) with the cotransporters KCC3, NKCC1, and NKCC2 but not KCC1 and KCC4...
  6. Piechotta K, Garbarini N, England R, Delpire E. 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;278:52848-56 pubmed
    ..basal and activated conditions in the presence and absence of binding of Ste20-related proline-alanine-rich kinase (SPAK)...
  7. Vitari A, Thastrup J, Rafiqi F, Deak M, Morrice N, Karlsson H, et al. Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Biochem J. 2006;397:223-31 pubmed
    The SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase-1) kinases interact and phosphorylate NKCC1 (Na+-K+-2Cl- co-transporter-1), leading to its activation...
  8. Fava C, Danese E, Montagnana M, Sjögren M, Almgren P, Engstrom G, et al. Serine/threonine kinase 39 is a candidate gene for primary hypertension especially in women: results from two cohort studies in Swedes. J Hypertens. 2011;29:484-91 pubmed publisher
    ..The greater effect of the STK39 rs35929607A>G polymorphism in women with respect to men deserves further investigation. ..
  9. Yan Y, Laroui H, Ingersoll S, Ayyadurai S, Charania M, Yang S, et al. Overexpression of Ste20-related proline/alanine-rich kinase exacerbates experimental colitis in mice. J Immunol. 2011;187:1496-505 pubmed publisher
    ..Colonic Ste20-like proline/alanine-rich kinase (SPAK) plays a role in intestinal inflammation, but its underlying mechanisms need to be defined...
  10. Xu J, Ji L, Zhang L, Dong C, Fei L, Hua S, et al. Lack of association between STK39 and hypertension in the Chinese population. J Hum Hypertens. 2013;27:294-7 pubmed publisher
    ..Instead, non-genetic risk factors such as BMI have an important role in Chinese hypertensive subjects, and the 'missing inheritability' requires further investigation. ..
  11. Määttä K, Nikkari S, Lähteelä K, Palmroos P, Kunnas T. A functional variant in the serine-threonine kinase coding gene is associated with hypertension: a case-control study in a Finnish population, the Tampere adult population cardiovascular risk study. J Hypertens. 2013;31:516-20; discussion 520 pubmed publisher
    ..6-fold (P?=?0.001, 95% CI 1.2-2.2). In conclusion, there was a significant association between STK39 genetic variant rs6749447 and hypertension in a Finnish cohort. ..
  12. Xi B, Chen M, Chandak G, Shen Y, Yan L, He J, et al. STK39 polymorphism is associated with essential hypertension: a systematic review and meta-analysis. PLoS ONE. 2013;8:e59584 pubmed publisher
    ..Future studies should include gene-gene and gene-environment interactions to investigate the identified association. ..
  13. Richardson C, Sakamoto K, de los Heros P, Deak M, Campbell D, Prescott A, et al. Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. J Cell Sci. 2011;124:789-800 pubmed publisher
    ..We demonstrate that hypotonic low-chloride conditions that activate the WNK1-SPAK and OSR1 pathway promote phosphorylation of NKCC2 isoforms (A, B and F) at five residues (Ser91, Thr95, Thr100, ..
  14. Wang J, Guo R, Liu S, Chen Q, Zuo S, Yang M, et al. Molecular mechanisms of FK506-induced hypertension in solid organ transplantation patients. Chin Med J (Engl). 2014;127:3645-50 pubmed
    ..kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension...
  15. Xiao Y, Liu Y, Li J, Ma X, Wang Y, Liu Y, et al. Hyperbaric oxygen preconditioning inhibits skin flap apoptosis in a rat ischemia-reperfusion model. J Surg Res. 2015;199:732-9 pubmed publisher
    ..Protein expression of phosphorylated apoptosis signal-regulating kinase 1 (pASK-1), phosphorylated c-Jun N-terminal kinase (pJNK), B-cell lymphoma-2 (Bcl-2), and Bcl2-associated X protein (Bax) ..
  16. Ishizawa K, Xu N, Loffing J, Lifton R, Fujita T, Uchida S, et al. Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3. Biochem Biophys Res Commun. 2016;480:745-751 pubmed publisher
    ..changes are accompanied by the accumulation of the target substrate WNK4, and activation of the downstream kinases SPAK (STE20/SPS1-related proline-alanine-rich protein kinase) and OSR1 (oxidative stress-responsive 1), resulting in NCC ..
  17. Abdel Khalek W, Rafael C, Loisel Ferreira I, Kouranti I, Clauser E, Hadchouel J, et al. Severe Arterial Hypertension from Cullin 3 Mutations Is Caused by Both Renal and Vascular Effects. J Am Soc Nephrol. 2019;: pubmed publisher
    ..mice displayed increased expression of the sodium chloride cotransporter and phosphorylation by the WNK-SPAK kinases...
  18. Ishizawa K, Wang Q, Li J, Yamazaki O, Tamura Y, Fujigaki Y, et al. Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling. Proc Natl Acad Sci U S A. 2019;116:3155-3160 pubmed publisher, tacrolimus increases levels of KLHL3S433-P, resulting in increased levels of WNK4, phosphorylated SPAK, and NCC...
  19. Boscardin E, Perrier R, Sergi C, Maillard M, Loffing J, Loffing Cueni D, et al. Severe hyperkalemia is rescued by low-potassium diet in renal βENaC-deficient mice. Pflugers Arch. 2017;469:1387-1399 pubmed publisher
    ..This is followed by a marked downregulation of STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) and Na+/Cl- co-transporter (NCC) protein expression and activity...
  20. Choi H, Shin J, Leem D, Kim S, Cho W, Lee K. 6-(3,4-Dihydro-1H-isoquinoline-2-yl)-N-(6-methoxypyridine-2-yl) nicotinamide-26 (DIMN-26) decreases cell proliferation by induction of apoptosis and downregulation of androgen receptor signaling in human prostate cancer cells. Chem Biol Interact. 2016;260:196-207 pubmed publisher
    ..B2M), selenoprotein P (SEPP1), and ste20-related proline-alanine-rich kinase (SPAK) in LNCap-LN3 prostate cancer cells...
  21. Tomilin V, Zaika O, Subramanya A, Pochynyuk O. Dietary K+ and Cl- independently regulate basolateral conductance in principal and intercalated cells of the collecting duct. Pflugers Arch. 2018;470:339-353 pubmed publisher
    ..However, co-expression of WNK1 or its major downstream effector Ste20-related proline-alanine-rich kinase (SPAK) had no effect on ClC-Kb over-expressed in Chinese hamster ovary (CHO) cells...
  22. West C, McDonough A, Masilamani S, Verlander J, Baylis C. Renal NCC is unchanged in the midpregnant rat and decreased in the late pregnant rat despite avid renal Na+ retention. Am J Physiol Renal Physiol. 2015;309:F63-70 pubmed publisher
    ..We also measured mRNA expression of NCC and members of the SPAK/NCC regulatory kinase network, serum and glucocorticoid-regulated kinase (SGK)1, total with no lysine kinase (WNK)1,..
  23. Wolley M, Wu A, Xu S, Gordon R, Fenton R, Stowasser M. In Primary Aldosteronism, Mineralocorticoids Influence Exosomal Sodium-Chloride Cotransporter Abundance. J Am Soc Nephrol. 2017;28:56-63 pubmed publisher
    ..pNCC) as well as WNK lysine deficient protein kinase 4 (WNK4) and STE20/SPS1-related, proline alanine-rich kinase (SPAK) in human urinary exosomes...
  24. Rashmi P, Colussi G, Ng M, Wu X, Kidwai A, Pearce D. Glucocorticoid-induced leucine zipper protein regulates sodium and potassium balance in the distal nephron. Kidney Int. 2017;91:1159-1177 pubmed publisher
    ..Finally, in HEK293T cells, exogenous GILZ inhibits NCC activity at least in part by inhibiting SPAK phosphorylation...
  25. Liu Y, Liu Y, Ma X, Xiao Y, Wang Y, Zhang M, et al. Hydrogen-rich saline attenuates skin ischemia/reperfusion induced apoptosis via regulating Bax/Bcl-2 ratio and ASK-1/JNK pathway. J Plast Reconstr Aesthet Surg. 2015;68:e147-56 pubmed publisher
    ..b>pASK-1, pJNK, Bcl-2 and Bax were examined by immunodetection. In addition Bcl-2, Bax and caspase-3 were detected by qPCR...
  26. Sarathy A, Wuebbles R, Fontelonga T, Tarchione A, Mathews Griner L, Heredia D, et al. SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy. Mol Ther. 2017;25:1395-1407 pubmed publisher
    ..through SU9516 inhibitory actions on the p65-NF-κB pro-inflammatory and Ste20-related proline alanine rich kinase (SPAK)/OSR1 signaling pathways...
  27. Xiao Y, Meng X, Zhang H, Guo X, Gu R. [The function and regulation of basolateral Kir4.1 and Kir4.1/Kir5.1 in renal tubules]. Sheng Li Xue Bao. 2018;70:600-606 pubmed
    ..The involved mechanisms include PKC, PI3K, Src family protein tyrosine kinases and WNK-SPAK signal transduction pathways...
  28. Hadchouel J, Ellison D, Gamba G. Regulation of Renal Electrolyte Transport by WNK and SPAK-OSR1 Kinases. Annu Rev Physiol. 2016;78:367-89 pubmed publisher
    ..the modulation of NCC occurs via the phosphorylation by WNKs of other serine-threonine kinases known as SPAK-OSR1. In contrast, the process of regulating the channels is independent of SPAK-OSR1...
  29. Moreno E, Plata C, Rodríguez Gama A, Argaiz E, Vazquez N, Leyva Ríos K, et al. The European Eel NCC? Gene Encodes a Thiazide-resistant Na-Cl Cotransporter. J Biol Chem. 2016;291:22472-22481 pubmed not activated by low-chloride hypotonic stress, although the unique Ste20-related proline alanine-rich kinase (SPAK) binding site in the amino-terminal domain is conserved...
  30. Terker A, Yang C, McCormick J, Meermeier N, Rogers S, Grossmann S, et al. Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension. Hypertension. 2014;64:178-84 pubmed publisher
    ..The results have implications about device- and drug-based treatment of hypertension. ..
  31. Xi B, Shen Y, Zhao X, Chandak G, Cheng H, Hou D, et al. Association of common variants in/near six genes (ATP2B1, CSK, MTHFR, CYP17A1, STK39 and FGF5) with blood pressure/hypertension risk in Chinese children. J Hum Hypertens. 2014;28:32-6 pubmed publisher
  32. Bandrés Ciga S, Price T, Barrero F, Escamilla Sevilla F, Pelegrina J, Arepalli S, et al. Genome-wide assessment of Parkinson's disease in a Southern Spanish population. Neurobiol Aging. 2016;45:213.e3-213.e9 pubmed publisher
    ..A structural variant was found in 1 case in the PARK2 gene locus. This current work represents a comprehensive assessment at a genome-wide level characterizing a novel population in PD genetics. ..
  33. Fezai M, Elvira B, Borras J, Ben Attia M, Hoseinzadeh Z, Lang F. Negative regulation of the creatine transporter SLC6A8 by SPAK and OSR1. Kidney Blood Press Res. 2014;39:546-54 pubmed publisher
    Transport regulation involves several kinases including SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are under control of WNK (with-no-K[Lys]) kinases...
  34. Lan C, Peng C, Tang S, Lin H, Yang S, Wu C, et al. Inhibition of Na-K-Cl cotransporter isoform 1 reduces lung injury induced by ischemia-reperfusion. J Thorac Cardiovasc Surg. 2017;153:206-215 pubmed publisher
    ..Wild-type, SPAK knockout (SPAK-/-), and WNK4 knockin (WNK4D561A/+) mice were divided into control, ischemia-..
  35. Shekarabi M, Zhang J, Khanna A, Ellison D, Delpire E, Kahle K. WNK Kinase Signaling in Ion Homeostasis and Human Disease. Cell Metab. 2017;25:285-299 pubmed publisher
    WNK kinases, along with their upstream regulators (CUL3/KLHL3) and downstream targets (the SPAK/OSR1 kinases and the cation-Cl- cotransporters [CCCs]), comprise a signaling cascade essential for ion homeostasis in the kidney ..
  36. Taylor C, Juang Y, Earnest S, Sengupta S, Goldsmith E, Cobb M. Domain-Swapping Switch Point in Ste20 Protein Kinase SPAK. Biochemistry. 2015;54:5063-71 pubmed publisher
    The related protein kinases SPAK and OSR1 regulate ion homeostasis in part by phosphorylating cation cotransporter family members...
  37. Terker A, Zhang C, Erspamer K, Gamba G, Yang C, Ellison D. Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. Kidney Int. 2016;89:127-34 pubmed publisher
    ..chloride, an inhibitor of the with-no-lysine kinase (WNK)-Ste20p-related proline- and alanine-rich kinase (SPAK) pathway...
  38. Wang L, Cheng L, Lu Z, Sun X, Li J, Peng R. Association of three candidate genetic variants in RAB7L1/NUCKS1, MCCC1 and STK39 with sporadic Parkinson's disease in Han Chinese. J Neural Transm (Vienna). 2016;123:425-30 pubmed publisher
    ..Our study provides strong support for the susceptibility role of rs823118 and rs12637471 in sporadic PD in a Han Chinese population. ..
  39. Torre Villalvazo I, Cervantes Pérez L, Noriega L, Jimenez J, Uribe N, Chavez Canales M, et al. Inactivation of SPAK kinase reduces body weight gain in mice fed a High-fat diet by improving energy expenditure and insulin sensitivity. Am J Physiol Endocrinol Metab. 2017;:ajpendo.00108.2017 pubmed publisher
    The STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) controls the activity of the electroneutral cation-chloride cotransporters (SLC12 family) and thus physiological processes such as modulation of cell volume, intracellular ..
  40. Huang F, Tang J, He L, Ding X, Huang S, Zhang Y, et al. Heterologous expression and antitumor activity analysis of syringolin from Pseudomonas syringae pv. syringae B728a. Microb Cell Fact. 2018;17:31 pubmed publisher
    ..A 22 kb genomic fragment containing the sylA-sylE gene cluster was cloned into the pASK vector, and the obtained recombinant plasmid was transferred into Streptomyces coelicolor and Streptomyces lividans ..
  41. Qi Q, Li D, Luo H, Guan K, Ye K. Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability. Proc Natl Acad Sci U S A. 2015;112:7255-60 pubmed publisher
    ..Hence, our findings support that netrin-1 exerts oncogenic activity through YAP signaling, providing a mechanism coupling extracellular signals to the nuclear YAP oncogene. ..
  42. Zanou N, Mondin L, Fuster C, Seghers F, Dufour I, de Clippele M, et al. Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres. J Physiol. 2015;593:3849-63 pubmed publisher
    ..Hyperosmotic shock also induces phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK)...
  43. Su X, Wang W. The expression, regulation, and function of Kir4.1 (Kcnj10) in the mammalian kidney. Am J Physiol Renal Physiol. 2016;311:F12-5 pubmed publisher
    ..reduced basolateral chloride (Cl(-)) conductance, suppressed the expression of ste20 proline-alanine-rich kinase (SPAK), and decreased Na-Cl cotransporter (NCC) expression and activity. This suggests that Kir4...
  44. Mercado A, de los Heros P, Melo Z, Chavez Canales M, Murillo de Ozores A, Moreno E, et al. With no lysine L-WNK1 isoforms are negative regulators of the K+-Cl- cotransporters. Am J Physiol Cell Physiol. 2016;311:C54-66 pubmed publisher
    ..Elimination of the STE20 proline-alanine rich kinase (SPAK)/oxidative stress-responsive kinase (OSR1) binding site or the HQ motif required for the WNK-WNK interaction ..
  45. Al Qusairi L, Basquin D, Roy A, Rajaram R, Maillard M, Subramanya A, et al. Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion. J Am Soc Nephrol. 2017;28:2431-2442 pubmed publisher
    ..Moreover, K+ restriction increased WNK1 and WNK4 expression and enhanced SPAK-mediated NCC phosphorylation in Nedd4LPax8/LC1 mice, with no change in total NCC...
  46. Chen Y, Cao B, Ou R, Wei Q, Chen X, Zhao B, et al. Determining the Effect of the HNMT, STK39, and NMD3 Polymorphisms on the Incidence of Parkinson's Disease, Amyotrophic Lateral Sclerosis, and Multiple System Atrophy in Chinese Populations. J Mol Neurosci. 2018;64:574-580 pubmed publisher
  47. Chávez Canales M, Zhang C, Soukaseum C, Moreno E, Pacheco Alvarez D, Vidal Petiot E, et al. WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. Hypertension. 2014;64:1047-53 pubmed publisher
    ..In conclusion, WNK kinases form a network in which WNK4 associates with WNK1 and WNK3 to regulate NCC. ..
  48. Zhang C, Meermeier N, Terker A, Blankenstein K, Singer J, Hadchouel J, et al. Degradation by Cullin 3 and effect on WNK kinases suggest a role of KLHL2 in the pathogenesis of Familial Hyperkalemic Hypertension. Biochem Biophys Res Commun. 2016;469:44-48 pubmed publisher
    ..chloride cotransporter (NCC), which is phosphorylated and activated by the WNK-stimulated Ste20-type kinases, SPAK and OSR1...
  49. Penton D, Czogalla J, Wengi A, Himmerkus N, Loffing Cueni D, Carrel M, et al. Extracellular K+ rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl- -dependent and independent mechanisms. J Physiol. 2016;594:6319-6331 pubmed publisher
    ..The Cl- -dependent pathway involves the SPAK/OSR1 kinases, whereas the Cl- independent pathway may include additional signalling cascades...
  50. Bai M, Liu Y, Yin D, Zhang M, Wang Y, Ma X, et al. Inhibition of c-Jun N-terminal kinase signaling suppresses skin flap apoptosis in a rat ischemia and/or reperfusion model. J Surg Res. 2016;206:337-346 pubmed publisher
    ..Early apoptosis was observed using TdT-mediated dUTP-X nick end-labeling staining. pASK-1, pJNK, Bcl-2, and Bax were examined by immunodetection...
  51. Grimm P, Coleman R, Delpire E, Welling P. Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules. J Am Soc Nephrol. 2017;28:2597-2606 pubmed publisher
    ..gene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK)...
  52. Nguyen M, Han J, Ralph D, Veiras L, McDonough A. Short-term nonpressor angiotensin II infusion stimulates sodium transporters in proximal tubule and distal nephron. Physiol Rep. 2015;3: pubmed publisher
    ..Additionally, phosphorylation of cortical NKCC2, NCC, and STE20/SPS1-related proline-alanine-rich kinase (SPAK) were increased; medullary NKCC2 and SPAK were not altered...
  53. Fang Y, Yang S, Cheng C, Tseng M, Hsu H, Lin S. Chronic Metabolic Acidosis Activates Renal Tubular Sodium Chloride Cotransporter through Angiotension II-dependent WNK4-SPAK Phosphorylation Pathway. Sci Rep. 2016;6:18360 pubmed publisher
    ..We examined the role of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and with-no-lysine kinase 4 (WNK4) on expression of NCC in mouse models of CMA...
  54. Zhao H, Qi Y, Wang Y, Wang Y, Lu C, Xiao Y, et al. Interactive contribution of serine/threonine kinase 39 gene multiple polymorphisms to hypertension among northeastern Han Chinese. Sci Rep. 2014;4:5116 pubmed publisher
    ..Taken together, our findings suggest the potential interactive role of STK39 gene multiple polymorphisms in the development of hypertension among northeastern Han Chinese. ..
  55. Yang H, Ye L, Wang Q, Cai D, Chen Q, Pan H, et al. A meta-analytical assessment of STK39 three well-defined polymorphisms in susceptibility to hypertension. Sci Rep. 2016;6:25290 pubmed publisher
    ..In conclusion, our meta-analytical findings suggest that STK39 might not be a hypertension-susceptibility gene. ..
  56. Balatoni C, Dawson D, Suh J, Sherman M, Sanders G, Hong J, et al. Epigenetic silencing of Stk39 in B-cell lymphoma inhibits apoptosis from genotoxic stress. Am J Pathol. 2009;175:1653-61 pubmed publisher
    ..The Stk39 encoded protein, sterile 20-like-related proline-alanine-rich kinase (SPAK), regulates cell stress responses, and microarray studies identified reduced SPAK expression in metastatic prostate ..
  57. Li N, Tan E, Chang X, Mao X, Zhang J, Zhao D, et al. Genetic association study between STK39 and CCDC62/HIP1R and Parkinson's disease. PLoS ONE. 2013;8:e79211 pubmed publisher
    ..Additional replication studies in other populations and functional studies are warranted to better validate the role of the two new loci in PD risk. ..
  58. Zhang J, Siew K, MacArtney T, O Shaughnessy K, Alessi D. Critical role of the SPAK protein kinase CCT domain in controlling blood pressure. Hum Mol Genet. 2015;24:4545-58 pubmed publisher
    The STE20/SPS1-related proline/alanine-rich kinase (SPAK) controls blood pressure (BP) by phosphorylating and stimulating the Na-Cl (NCC) and Na-K-2Cl (NKCC2) co-transporters, which regulate salt reabsorption in the kidney...
  59. Sid B, Miranda L, Vertommen D, Viollet B, Rider M. Stimulation of human and mouse erythrocyte Na(+)-K(+)-2Cl(-) cotransport by osmotic shrinkage does not involve AMP-activated protein kinase, but is associated with STE20/SPS1-related proline/alanine-rich kinase activation. J Physiol. 2010;588:2315-28 pubmed publisher
    ..human and mouse RBCs led to activation loop phosphorylation of the STE20/SPS1-related proline/alanine-rich kinase (SPAK) at Thr233, which was accompanied by phosphorylation of NKCC1 at Thr203/207/212, one of which (Thr207) is ..
  60. Li Z, Zhu W, Xiong L, Yu X, Chen X, Lin Q. Role of high expression levels of STK39 in the growth, migration and invasion of non-small cell type lung cancer cells. Oncotarget. 2016;7:61366-61377 pubmed publisher
    ..On the contrary, overexpression of STK39 in NSCLC cells had inverse effects on cell behaviors. Taken together, STK39 acts as a tumor oncogene in NSCLC and can be a potential biomarker of carcinogenesis. ..
  61. Kumar S, Nakazawa M. Discrete solitons in optical fiber systems with large pre-dispersion. Opt Express. 2017;25:19923-19945 pubmed publisher
    ..In addition, we develop the concept of discrete chirp transform (DChT) and its inverse, and show that the weights of the pulses can be extracted from the field envelope using the ..
  62. Wang Y, Tang B, Yu R, Li K, Liu Z, Xu Q, et al. Association analysis of STK39, MCCC1/LAMP3 and sporadic PD in the Chinese Han population. Neurosci Lett. 2014;566:206-9 pubmed publisher
    ..No statistically significant difference in genotype frequency between cases and controls was observed for the other three SNPs. ..
  63. Koumangoye R, Delpire E. The Ste20 kinases SPAK and OSR1 travel between cells through exosomes. Am J Physiol Cell Physiol. 2016;311:C43-53 pubmed publisher
    Proteomics studies have identified Ste20-related proline/alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) in exosomes isolated from body fluids such as blood, saliva, and urine...
  64. Susa K, Sohara E, Takahashi D, Okado T, Rai T, Uchida S. WNK4 is indispensable for the pathogenesis of pseudohypoaldosteronism type II caused by mutant KLHL3. Biochem Biophys Res Commun. 2017;491:727-732 pubmed publisher
    WNK-OSR1/SPAK-NCC signaling cascade is important for regulating salt balance and blood pressure...
  65. Bazot Q, Paschos K, Allday M. Epstein-Barr Virus (EBV) Latent Protein EBNA3A Directly Targets and Silences the STK39 Gene in B Cells Infected by EBV. J Virol. 2018;92: pubmed publisher
    ..i>STK39 is silenced shortly after primary B cell infection by EBV, and no STK39-encoded protein (SPAK) is detected 3 weeks postinfection...
  66. Duarte J, Lobmeyer M, Wang Z, Chapman A, Gums J, Langaee T, et al. Lack of association between polymorphisms in STK39, a putative thiazide response gene, and blood pressure response to hydrochlorothiazide. Pharmacogenet Genomics. 2010;20:516-9 pubmed publisher
    ..These data suggest that common variants in STK39 likely do not have a clinically relevant role in blood pressure response to HCTZ in hypertensives. ..
  67. Chiu M, Liu H, Wu Y, Shen M, Chou C. SPAK mediates KCC3-enhanced cervical cancer tumorigenesis. FEBS J. 2014;281:2353-65 pubmed publisher
    Ste20-related proline/alanine-rich kinase (SPAK) plays a role in regulating many biological activities, and interacts with K-Cl co-transporter 3 (KCC3); however, the importance of SPAK for KCC3 function has not been demonstrated...
  68. Abousaab A, Warsi J, Elvira B, Alesutan I, Hoseinzadeh Z, Lang F. Down-Regulation of Excitatory Amino Acid Transporters EAAT1 and EAAT2 by the Kinases SPAK and OSR1. J Membr Biol. 2015;248:1107-19 pubmed publisher
    b>SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) are cell volume-sensitive kinases regulated by WNK (with-no-K[Lys]) kinases. SPAK/OSR1 regulate several channels and carriers...
  69. Fezai M, Ahmed M, Hosseinzadeh Z, Elvira B, Lang F. SPAK and OSR1 Sensitive Kir2.1 K+ Channels. Neurosignals. 2015;23:20-33 pubmed publisher
    ..1 channels are sensitive to the transporter and channels regulating kinases SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are in turn ..
  70. Sengupta S, Lorente Rodríguez A, Earnest S, Stippec S, Guo X, Trudgian D, et al. Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals. Proc Natl Acad Sci U S A. 2013;110:18826-31 pubmed publisher
    ..Thus, we identify a previously unrecognized connection of the PI3K pathway through mTORC2 to a Ste20 protein kinase and ion homeostasis. ..
  71. Dbouk H, Weil L, Perera G, Dellinger M, Pearson G, Brekken R, et al. Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK. Proc Natl Acad Sci U S A. 2014;111:15999-6004 pubmed publisher
    ..required for cord formation in HUVECs, but the actions of the two major WNK1 effectors, OSR1 and its close relative SPAK (STE20/SPS1-related proline-, alanine-rich kinase), are distinct...
  72. Tang L, Wang Y, Bao M, Zhang Q, Li J. The rs3754777 polymorphism of the STK39 gene is associated with essential hypertension in central south Chinese Han males. Hypertens Res. 2016;39:480-1 pubmed publisher
  73. Ishigami Yuasa M, Watanabe Y, Mori T, Masuno H, Fujii S, Kikuchi E, et al. Development of WNK signaling inhibitors as a new class of antihypertensive drugs. Bioorg Med Chem. 2017;25:3845-3852 pubmed publisher
    ..activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-..
  74. Shih C, Hsu L, Liao M, Yang S, Ho S, Wu C. Effects of SPAK on vascular reactivity and nitric oxide production in endotoxemic mice. Eur J Pharmacol. 2017;814:248-254 pubmed publisher
    ..STE20/SPS1-realted proline/alanine-rich kinase (SPAK) has been reported to activate mitogen-activated protein kinase and contribute to intestinal inflammation...
  75. Liu Y, Dhall S, Castro A, Chan A, Alamat R, Martins Green M. Insulin regulates multiple signaling pathways leading to monocyte/macrophage chemotaxis into the wound tissue. Biol Open. 2018;7: pubmed publisher
    ..We also show that the kinases PI3K-Akt, SPAK/JNK, and p38 MAPK are key molecules in the insulin-induced signaling pathways that lead to chemoattraction of the ..
  76. Qi H, Labrie Y, Grenier J, Fournier A, Fillion C, Labrie C. Androgens induce expression of SPAK, a STE20/SPS1-related kinase, in LNCaP human prostate cancer cells. Mol Cell Endocrinol. 2001;182:181-92 pubmed
    ..1 nM R1881 for 24 h. We report here that SPAK, a recently identified STE20/SPS1-related kinase that modulates p38 MAP kinase activity, exhibited increased ..
  77. Polek T, Talpaz M, Spivak Kroizman T. The TNF receptor, RELT, binds SPAK and uses it to mediate p38 and JNK activation. Biochem Biophys Res Commun. 2006;343:125-34 pubmed
    ..Using a yeast two-hybrid system, we identified a Ste20-related proline-alanine-rich kinase (SPAK) that binds RELT. Disruption of the SPAK binding motif, 349RFRV, in RELT inhibited RELT activation of p38 and JNK...
  78. Polek T, Talpaz M, Spivak Kroizman T. TRAIL-induced cleavage and inactivation of SPAK sensitizes cells to apoptosis. Biochem Biophys Res Commun. 2006;349:1016-24 pubmed
    Ste20-related proline-alanine-rich kinase (SPAK) has been linked to various cellular processes, including proliferation, differentiation, and ion transport regulation...
  79. Umedani L, Chaudhry B, Mehraj V, Ishaq M. Serene threonine kinase 39 gene single nucleotide A-G polymorphism rs35929607 is weakly associated with essential hypertension in population of Tharparkar, Pakistan. J Pak Med Assoc. 2013;63:199-205 pubmed
  80. Borrás J, Salker M, Elvira B, Warsi J, Fezai M, Hoseinzadeh Z, et al. SPAK and OSR1 Sensitivity of Excitatory Amino Acid Transporter EAAT3. Nephron. 2015;130:221-8 pubmed publisher
    Kinases involved in the regulation of epithelial transport include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1). SPAK and OSR1 are both regulated by WNK (with-no-K(Lys)) kinases...
  81. Li B, Yang M, Liu J. Expression of STK39 in peripheral blood of hypertension patients and the relationship between its genetic polymorphism and blood pressure. Genet Mol Res. 2015;14:16461-8 pubmed publisher
    ..05). In conclusion, STK39 mRNA and protein express abnormally in primary hypertension patients with genetic variation, which is related to the blood pressure. ..
  82. Markkanen M, Ludwig A, Khirug S, Pryazhnikov E, Soni S, Khiroug L, et al. Implications of the N-terminal heterogeneity for the neuronal K-Cl cotransporter KCC2 function. Brain Res. 2017;1675:87-101 pubmed publisher
    ..One possible cause for the epitope masking is the binding site of Ste20-related proline-alanine-rich kinase (SPAK) in the KCC2a N-terminus...
  83. Conway L, Cardarelli R, Moore Y, Jones K, McWilliams L, Baker D, et al. N-Ethylmaleimide increases KCC2 cotransporter activity by modulating transporter phosphorylation. J Biol Chem. 2017;292:21253-21263 pubmed publisher
    ..NEM also reduced with no lysine (WNK) kinase phosphorylation of Ste20-related proline/alanine-rich kinase (SPAK), a kinase that directly phosphorylates KCC2 at residue Thr-1007...
  84. Ponce Coria J, Gagnon K, 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:C1198-205 pubmed publisher
    ..In this study, we used nine glutamine residues to link the carboxyl end of one SPAK (related Ste20 kinase) monomer to the amino end of another SPAK monomer to assess the role of kinase monomers ..
  85. Park H, Curry J, McCormick J. Regulation of NKCC2 activity by inhibitory SPAK isoforms: KS-SPAK is a more potent inhibitor than SPAK2. Am J Physiol Renal Physiol. 2013;305:F1687-96 pubmed publisher
    ..cotransporter (NCC) are phosphorylated and activated by the kinases Ste20-related proline alanine-rich kinase (SPAK) and oxidative stress-responsive kinase (OSR1), and their targeted disruption in mice causes phenotypes resembling ..
  86. Markadieu N, Rios K, Spiller B, McDonald W, Welling P, Delpire E. 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;289:29273-84 pubmed publisher
    The Ste20-related kinase SPAK regulates sodium, potassium, and chloride transport in a variety of tissues. Recently, SPAK fragments, which lack the catalytic domain and are inhibitory to Na(+) transporters, have been detected in kidney...
  87. Warsi J, Hosseinzadeh Z, Elvira B, Bissinger R, Shumilina E, Lang F. Regulation of ClC-2 activity by SPAK and OSR1. Kidney Blood Press Res. 2014;39:378-87 pubmed publisher
    b>SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) are powerful regulators of diverse transport processes...
  88. Vorontsova I, Lam L, Delpire E, Lim J, Donaldson P. Identification of the WNK-SPAK/OSR1 signaling pathway in rodent and human lenses. Invest Ophthalmol Vis Sci. 2014;56:310-21 pubmed publisher
    ..kinase (WNK 1, 3, 4), oxidative stress response kinase 1 (OSR1), and Ste20-like proline alanine rich kinase (SPAK) were determined at either the transcript or protein levels in the rat and human lenses by reverse-transcriptase ..
  89. Mandai S, Mori T, Sohara E, Rai T, Uchida S. Generation of Hypertension-Associated STK39 Polymorphism Knockin Cell Lines With the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 System. Hypertension. 2015;66:1199-206 pubmed publisher
    ..Increased interactions between STE20/SPS1-related proline/alanine-rich kinase and the target cation-chloride cotransporters may be responsible for hypertension susceptibility in individuals with this polymorphism. ..
  90. Persu A, Evenepoel L, Jin Y, Mendola A, Ngueta G, Yang W, et al. STK39 and WNK1 Are Potential Hypertension Susceptibility Genes in the BELHYPGEN Cohort. Medicine (Baltimore). 2016;95:e2968 pubmed publisher
    ..Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted. ..
  91. Kasagi Y, Takahashi D, Aida T, Nishida H, Nomura N, Zeniya M, et al. Impaired degradation of medullary WNK4 in the kidneys of KLHL2 knockout mice. Biochem Biophys Res Commun. 2017;487:368-374 pubmed publisher
    ..increases levels of WNKs because of impaired ubiquitination, leading to abnormal over-activation of the WNK-OSR1/SPAK-NCC cascade in the kidney's distal convoluted tubules (DCT)...
  92. Koumangoye R, Delpire E. DNPEP is not the only peptidase that produces SPAK fragments in kidney. Physiol Rep. 2017;5: pubmed publisher
    b>SPAK (STE20/SPS1-related proline/alanine-rich kinase) regulates Na+ and Cl- reabsorption in the distal convoluted tubule, and possibly in the thick ascending limb of Henle...