Affinage

STK39

STE20/SPS1-related proline-alanine-rich protein kinase · UniProt Q9UEW8

Length
545 aa
Mass
59.5 kDa
Annotated
2026-06-10
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STK39/SPAK is a STE20-family serine/threonine kinase that functions as the central effector linking WNK kinase signaling to ion cotransporter regulation, thereby controlling intracellular chloride homeostasis, renal salt reabsorption, and blood pressure (PMID:16263722, PMID:20091762). SPAK is activated when WNK kinases (WNK1, WNK3, WNK4) phosphorylate its T-loop threonine (Thr233/Thr243), a modification required for catalytic activation and further amplified ~100-fold by the co-activator MO25 (PMID:16083423, PMID:21423148). SPAK recognizes both its upstream activators and downstream substrates through its conserved C-terminal CCT domain, which docks onto RFX(V/I) motifs; the Leu502 residue of this domain is critical for high-affinity binding, and disrupting docking abolishes substrate phosphorylation in vitro and in vivo (PMID:16669787, PMID:25994507). Through this docking-dependent mechanism SPAK directly phosphorylates the N-terminal regulatory regions of the Na+-driven cotransporters NKCC1, NKCC2, and NCC to stimulate Cl- influx, while phosphorylating a conserved C-terminal site on the K+-driven KCCs to inhibit them, executing coordinated reciprocal control of net intracellular chloride (PMID:16263722, PMID:21321328, PMID:24393035). In vivo this axis is essential for distal nephron NCC/NKCC2 function: loss of SPAK or its WNK-mediated activation produces Gitelman-syndrome-like salt wasting and hypotension, whereas constitutive SPAK activation drives thiazide-treatable hypertension and hyperkalemia (PMID:20813865, PMID:20091762, PMID:28442491). The pathway integrates hormonal and physiological inputs including angiotensin II, aldosterone, and insulin/PI3K signaling, and SPAK activity is opposed by phosphatase recruitment (PP1 scaffolded via cotransporter tails) and by upstream regulators such as ASK3 (PMID:19240212, PMID:22949526, PMID:20223824, PMID:23250415). Beyond ion transport, SPAK contributes to stress and immune signaling—activating p38 and synergizing with PKCθ to drive AP-1 (PMID:10980603, PMID:14988727)—regulates epithelial secretion by phosphorylating CFTR and NBCe1-B (PMID:21317537, PMID:23431199), and in cancer promotes EMT and metastasis by directly phosphorylating SNAI1 at Thr203 to stabilize it (PMID:34335956).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 Medium

    Established SPAK as a catalytically active serine/threonine kinase and first linked it to stress MAPK signaling, defining its enzymatic identity before any transport role was known.

    Evidence In vitro kinase assay, immunofluorescence, and cotransfection reporter assay

    PMID:10980603

    Open questions at the time
    • No physiological substrate identified
    • Caspase-cleaved nuclear form's function unresolved
  2. 2002 High

    Identified the cation-chloride cotransporters as physical SPAK partners and defined the (R/K)FX(V/I)-docking motif, establishing the molecular basis for substrate recognition.

    Evidence Yeast two-hybrid, GST pulldown, co-IP from brain, and choroid plexus immunohistochemistry

    PMID:12386165

    Open questions at the time
    • Binding alone did not establish a catalytic/regulatory consequence
    • Upstream activator of SPAK still unknown
  3. 2003 Medium

    Showed SPAK can act as an activity-dependent scaffold linking p38 to NKCC1 rather than a direct transport regulator, raising the question of how SPAK actually controls cotransporter function.

    Evidence 86Rb+ uptake in Xenopus oocytes and reciprocal co-IP

    PMID:14563843

    Open questions at the time
    • Did not resolve whether SPAK phosphorylates the cotransporter
    • Scaffolding vs catalytic roles not separated
  4. 2004 High

    Placed SPAK in T-cell receptor signaling as a PKCθ substrate driving AP-1, expanding its role beyond transport into immune stress signaling.

    Evidence Co-IP, in vitro kinase assay, S311 mutagenesis, RNAi, and reporter assays

    PMID:14988727

    Open questions at the time
    • Direct AP-1-relevant substrate of SPAK not identified
    • Relationship to transport functions unclear
  5. 2005 High

    Identified WNK kinases as the upstream activators that phosphorylate the SPAK T-loop, and showed SPAK directly phosphorylates NKCC1/NKCC2/NCC, defining the core WNK–SPAK–cotransporter cascade.

    Evidence Co-IP, in vitro kinase assays, phosphopeptide mapping, T-loop mutagenesis, and oocyte expression

    PMID:16083423 PMID:16263722

    Open questions at the time
    • Docking requirement for efficient phosphorylation not yet mechanistically defined
    • Physiological stimulus integration unknown
  6. 2006 High

    Defined the CCT-domain/RFXV docking mechanism and the activation-loop threonines as jointly required for substrate phosphorylation and cotransporter activation, unifying recognition and catalysis.

    Evidence In vitro kinase assays, peptide affinity purification, and activation-loop/CCT mutagenesis with oocyte transport assays

    PMID:16382158 PMID:16669787

    Open questions at the time
    • Structural basis of docking not yet visualized
    • Quantitative contribution of docking to in vivo regulation unaddressed
  7. 2008 High

    Extended the cascade to NCC and NKCC2 with defined phospho-sites and docking motifs, and identified additional upstream activating kinases (PKCδ) and a Cl--sensing WNK3 input, mapping how the pathway integrates osmotic/ionic stress.

    Evidence In vitro kinase assays, RNAi, GST pulldown, and oocyte functional assays with motif mutagenesis

    PMID:18270262 PMID:18550547 PMID:18550832

    Open questions at the time
    • Mechanism of chloride sensing not fully resolved
    • Cross-talk between PKC and WNK activation inputs unclear
  8. 2009 Medium

    Connected SPAK genetic variation to blood pressure and demonstrated hormonal (angiotensin II) input, linking the molecular cascade to human cardiovascular physiology.

    Evidence Allele-specific reporter assay, immunohistochemistry, and AngII oocyte/mpkDCT epistasis with dominant-negative SPAK

    PMID:19114657 PMID:19240212

    Open questions at the time
    • Causal variant mechanism on expression incompletely defined
    • AngII-to-SPAK signaling intermediates unmapped
  9. 2010 High

    Established SPAK as physiologically essential for renal NCC/NKCC2 regulation and blood pressure via knockout and WNK-resistant knock-in mice, and defined opposing PP1 dephosphorylation and SORLA-dependent trafficking that tune the pathway.

    Evidence Knockout and knock-in mouse phenotyping with phospho-specific Westerns, in vitro PP1 dephosphorylation, and SORLA co-IP/knockout

    PMID:20091762 PMID:20223824 PMID:20385770 PMID:20463172 PMID:20813865

    Open questions at the time
    • Phosphatase identity for in vivo dephosphorylation not fully resolved
    • Nephron-segment-specific divergence not yet explained
  10. 2011 High

    Identified MO25 as the ~100-fold co-activator, resolved nephron-segment-specific regulation via a kinase-dead kidney SPAK isoform, and extended SPAK to epithelial secretion (CFTR/NBCe1-B) and angiogenesis.

    Evidence In vitro activation assays, siRNA rescue, segment-specific knockout analysis, secretion/epistasis assays, and HUVEC functional assays

    PMID:21317537 PMID:21321328 PMID:21423148 PMID:21907141 PMID:25362046

    Open questions at the time
    • Regulation balancing full-length vs kinase-dead isoforms unclear
    • Mechanism of SPAK in proliferation distinct from transport undefined
  11. 2012 High

    Proved genetically (SPAK/OSR1 double-knockin ES cells) that SPAK/OSR1 are obligatory intermediaries for WNK1-dependent NKCC1 phosphorylation and revealed feedback suppression of WNK activity, plus aldosterone/insulin hormonal control of the axis.

    Evidence Double-knockin ES cells, knockout mouse localization, knock-in epistasis with PI3K inhibitors, and aldosterone time-course Westerns

    PMID:22032326 PMID:22238094 PMID:22949526 PMID:22977235 PMID:23044422

    Open questions at the time
    • Molecular basis of SPAK/OSR1-to-WNK feedback unresolved
    • Integration of multiple hormonal inputs at the kinase level unclear
  12. 2013 Medium

    Defined SPAK phospho-sites and regulatory module on NBCe1-B and demonstrated SPAK's role in intestinal epithelial barrier and inflammation, broadening its functional reach beyond cation-chloride transport.

    Evidence Co-IP/mutagenesis with transporter assays, aldosterone siRNA studies, and knockout mouse barrier and colitis phenotyping

    PMID:23431199 PMID:23499375 PMID:23739593

    Open questions at the time
    • Mechanism linking SPAK to tight junction protein expression unknown
    • Direct vs indirect effects on barrier function not separated
  13. 2014 High

    Demonstrated reciprocal KCC inhibition by SPAK/OSR1 (completing the coordinated Cl- influx/efflux model) and validated CCT-domain Leu502 docking as essential in vivo, while identifying ASK3 as a negative regulator.

    Evidence In vitro kinase assays with MO25, double-knockin ES cells, KCC3A Site-2 mutagenesis, L502A knock-in mice, and ASK3 knockout phenotyping

    PMID:23250415 PMID:24393035 PMID:25994507

    Open questions at the time
    • Determinants of NKCC-activating vs KCC-inhibiting substrate selection unclear
    • ASK3-WNK regulatory mechanism not fully defined
  14. 2015 High

    Provided crystal structures of the SPAK kinase domain revealing a regulatory domain-swapped dimer architecture, giving a structural basis for activation and substrate phosphorylation.

    Evidence X-ray crystallography of wild-type and T243D SPAK with monomeric-mutant functional assays

    PMID:26208601

    Open questions at the time
    • Full activated state with substrate not captured
    • Functional role of dimerization in vivo not established
  15. 2017 High

    Showed via DCT-specific constitutively active SPAK mice that hyperactive SPAK alone causes thiazide-treatable hypertension with downstream ASDN remodeling, directly proving SPAK as a driver of salt-sensitive hypertension.

    Evidence Conditional CA-SPAK knock-in mice, blood pressure telemetry, thiazide rescue, and phospho-specific IHC/Western

    PMID:28442491

    Open questions at the time
    • Mechanism of ENaC/ROMK downregulation downstream of NCC hyperactivity not fully defined
  16. 2018 Medium

    Advanced SPAK as a druggable target by identifying ATP-independent inhibitors binding the CCT or kinase domain, establishing distinct allosteric inhibition strategies.

    Evidence In silico screening, biochemical binding, and in vitro/cell-based kinase inhibition assays (rafoxanide, verteporfin)

    PMID:28371477 PMID:29999233

    Open questions at the time
    • In vivo selectivity and efficacy not established in these reports
    • Binding-site structural detail limited
  17. 2020 High

    Demonstrated therapeutic potential of selective SPAK inhibition in CNS disease by reducing NKCC1 phosphorylation and CSF hypersecretion and improving stroke/edema outcomes, linking SPAK control of brain ion transport to neurological pathology.

    Evidence ZT-1a treatment in rodent hydrocephalus and stroke models with CCC phosphorylation and brain water readouts

    PMID:31911626

    Open questions at the time
    • Cell-type-specific contributions in brain not dissected
    • Long-term consequences of SPAK inhibition undefined
  18. 2021 High

    Revealed novel SPAK functions in cancer—a PLK1-dependent pro-tumor role and direct SNAI1 Thr203 phosphorylation stabilizing SNAI1 to drive EMT/metastasis—and refined the rapid K+-triggered 'off-switch' regulation of NCC phosphorylation.

    Evidence Mass spec, co-IP, in vitro kinase/SNAI1 mutagenesis with xenograft rescue, and in vitro/ex vivo/in vivo K+ phosphatase studies

    PMID:33500714 PMID:33719576 PMID:34335956

    Open questions at the time
    • Phosphatase mediating rapid K+-induced dephosphorylation unidentified
    • Mechanistic basis of SPAK-PLK1 cooperation in ERK activation unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SPAK selects between activating NKCCs and inhibiting KCCs at the catalytic level, the identity of the phosphatase(s) executing rapid in vivo dephosphorylation, and the reconciliation of its transport-kinase role with its emerging oncogenic SNAI1/PLK1 functions remain open.
  • No unified model of substrate-specific opposing outputs
  • In vivo dephosphorylating phosphatase undefined
  • Transport vs cancer functions not mechanistically connected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3
Partners
MO25NCCNKCC1NKCC2OSR1WNK1WNK3WNK4

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 SPAK is a serine/threonine kinase that autophosphorylates and phosphorylates exogenous substrates in vitro. Full-length SPAK localizes to the cytoplasm in transfected cells, while a caspase-cleaved form localizes predominantly to the nucleus. SPAK specifically activates the p38 MAPK pathway in cotransfection assays. In vitro kinase assay, immunofluorescence localization, cotransfection reporter assay Oncogene Medium 10980603
2002 SPAK physically interacts with the cation-chloride cotransporters NKCC1, NKCC2, and KCC3 (but not KCC1 or KCC4) via an (R/K)FX(V/I)-containing motif on the cotransporters and the C-terminal 100 amino acids of SPAK. In vivo co-immunoprecipitation of SPAK from mouse brain with anti-NKCC1 antibody was confirmed. SPAK co-localizes with NKCC1 on the apical membrane of choroid plexus epithelium; in NKCC1-null mice, SPAK redistributes to the cytoplasm. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunohistochemistry The Journal of biological chemistry High 12386165
2003 SPAK binding to NKCC1 is not required for basal cotransporter activity (NKCC1 mutant lacking SPAK binding showed identical K+ transport to wild-type). However, SPAK co-immunoprecipitates with p38 MAPK and NKCC1 in an activity-dependent manner; cellular stress reduces the amount of p38 co-immunoprecipitated with SPAK/NKCC1, while the SPAK-NKCC1 interaction remains unchanged, suggesting a scaffolding role for SPAK. 86Rb+ uptake functional assay in Xenopus oocytes, co-immunoprecipitation, Western blot The Journal of biological chemistry Medium 14563843
2004 SPAK is a substrate and binding partner of PKCθ. PKCθ phosphorylates SPAK at Ser311 in the kinase domain. TCR/CD28 costimulation enhances SPAK-PKCθ association and SPAK kinase activity. SPAK synergizes with constitutively active PKCθ to activate AP-1 (but not NF-κB); dominant-negative SPAK or SPAK RNAi inhibits PKCθ- and TCR/CD28-induced AP-1 activation. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (S311 mutation), RNAi knockdown, reporter assay The EMBO journal High 14988727
2005 WNK1 co-immunoprecipitates with SPAK from rat testis. WNK1 and WNK4 both phosphorylate SPAK at Thr233 (T-loop) and Ser373 (C-terminal non-catalytic region). Phosphorylation of Thr233 (equivalent to Thr185 in OSR1) by WNK1 is required for SPAK activation; T-loop mutation to Ala abolishes activation, while Glu mutation (phosphomimetic) constitutively activates the kinase. Co-immunoprecipitation, in vitro kinase assay, phosphopeptide mapping, site-directed mutagenesis The Biochemical journal High 16083423
2005 WNK1 phosphorylates SPAK and OSR1, activating them. SPAK and OSR1 directly phosphorylate the N-terminal regulatory regions of cation-chloride cotransporters NKCC1, NKCC2, and NCC. Hypotonic stress activates SPAK/OSR1 and induces NCC phosphorylation in cells. In vitro kinase assay, cell-based phosphorylation assay, Xenopus oocyte expression The Journal of biological chemistry High 16263722
2006 SPAK phosphorylates NKCC1 at Thr203/Thr207/Thr212 (human). The conserved C-terminal CCT domain of SPAK interacts with an RFXV motif present in both its substrate NKCC1 and its activators WNK1/WNK4; this docking interaction is required for efficient phosphorylation of NKCC1 but not of a peptide substrate lacking the RFXV motif. Mutation of specific CCT domain residues abolishes RFXV binding and prevents NKCC1 phosphorylation. In vitro kinase assay, peptide affinity purification, site-directed mutagenesis, osmotic stress cell assay The Biochemical journal High 16669787
2006 Mutation of SPAK activation loop residues Thr243 or Thr247 to Ala prevents WNK4-mediated activation and robustly inhibits NKCC1 cotransporter activity in Xenopus oocytes. SPAK activity is inhibited by staurosporine and K252a. OSR1 exhibits similar kinase properties and functional activation of NKCC1 when coexpressed with WNK4. Site-directed mutagenesis, 86Rb+ uptake functional assay in Xenopus oocytes, in vitro kinase assay with Mn2+/Mg2+ Molecular and cellular biology High 16382158
2007 Physical docking of SPAK to NKCC1 via a single RFXV-containing binding motif (mutation of the Phe residue abrogates both binding and function) is necessary for NKCC1 activation under basal and hyperosmotic conditions. SPAK docking to NKCC1 is required for efficient phosphorylation of NKCC1 at Thr206 and Thr211. Yeast two-hybrid, in vitro 32P-phosphorylation, 86Rb+ uptake assay in Xenopus oocytes, site-directed mutagenesis Cellular physiology and biochemistry High 17595523
2007 SPAK interacts with apoptosis-associated tyrosine kinase (AATYK1) via RFXV-like binding motifs on AATYK1; disruption of these motifs abrogates AATYK1-mediated inhibition of NKCC1. AATYK1 also scaffolds protein phosphatase 1 (PP1) via a PP1-docking motif; this interaction is required for NKCC1 inhibition, suggesting AATYK1 indirectly inhibits SPAK/WNK4 activation of NKCC1 by bringing PP1 into proximity. Xenopus oocyte functional assay, yeast two-hybrid, site-directed mutagenesis American journal of physiology. Cell physiology Medium 17267545
2008 SPAK and OSR1 kinases activated by WNK1 phosphorylate human NCC at Thr46, Thr55, and Thr60. Efficient NCC phosphorylation requires docking via an RFXI motif on NCC. Mutation of Thr60 to Ala markedly inhibits phosphorylation of Thr46 and Thr55 and NCC activation. Hypotonic low-chloride conditions in HEK293 or mpkDCT cells induce SPAK/OSR1-dependent phosphorylation of NCC. In vitro kinase assay, site-directed mutagenesis, cell-based phosphorylation assay (HEK293 and mpkDCT cells) Journal of cell science High 18270262
2008 STK39/SPAK is expressed in the distal nephron in vivo and interacts with WNK kinases and cation-chloride cotransporters in cell-based functional studies. An intronic element with allele-specific transcription activity was identified as a functional candidate for BP association, suggesting variants increase STK39 expression to alter renal Na+ excretion. In vivo expression analysis (immunohistochemistry), cell-based functional assay (co-interaction studies), reporter assay for allele-specific transcription Proceedings of the National Academy of Sciences of the United States of America Medium 19114657
2008 PKCδ directly binds SPAK, phosphorylates and activates it upstream of NKCC1 in human airway epithelial cells during hyperosmotic stress. SPAK siRNA knockdown prevents NKCC1 phosphorylation and functional activation. GST pulldown confirms direct SPAK-NKCC1 interaction; a NKCC1 N-terminal peptide competitively inhibits SPAK-NKCC1 binding. RNAi knockdown, 86Rb+ flux assay, GST pulldown, recombinant protein kinase assay, competitive peptide inhibition The Journal of biological chemistry High 18550547
2008 WNK3 activates NKCC2 through SPAK in a chloride-sensing mechanism; intracellular Cl- depletion activates NKCC2 by promoting phosphorylation at Thr96, Thr101, and Thr111. WNK3 is positioned upstream of SPAK; elimination of WNK3's SPAK-binding motif prevents NKCC2 activation. SPAK is required for chloride-sensitive NKCC2 activation. Xenopus oocyte expression, site-directed mutagenesis, epistasis analysis with dominant-negative constructs Proceedings of the National Academy of Sciences of the United States of America High 18550832
2009 AngII signaling increases NCC activity through a WNK4-SPAK-dependent pathway; dominant-negative SPAK or elimination of the SPAK binding motif on NCC prevents AngII-mediated NCC activation. AngII increases phosphorylation of SPAK and NCC at residues required for their activation in mpkDCT cells. Xenopus oocyte functional assay, dominant-negative SPAK constructs, mpkDCT cell phosphorylation assay Proceedings of the National Academy of Sciences of the United States of America High 19240212
2009 SPAK silencing by shRNA in B cells protects against caspase-dependent apoptosis induced by DNA double-strand breaks but not from osmotic/oxidative stress-induced apoptosis. Caspase 3 cleavage is impaired upon SPAK repression in DNA-damaged B cells, implicating SPAK in a JNK-dependent apoptosis pathway. shRNA knockdown, caspase 3 cleavage assay, apoptosis assays, pharmacological JNK inhibition The American journal of pathology Medium 19717643
2009 SPAK knockout mice exhibit higher nociceptive thresholds, locomotor deficits (rotarod and open-field), and increased anxiety-like behavior, indicating SPAK plays an important role in CNS function consistent with regulating ion transport mechanisms involved in inhibitory neurotransmission. SPAK knockout mouse behavioral analysis (hot plate, tail flick, rotarod, open-field, light/dark box) Behavioural brain research Medium 20006650
2010 SPAK-null mice display Gitelman syndrome phenotype (hypotension, hypokalemia, hypomagnesemia, hypocalciuria) with markedly decreased total and phosphorylated NCC in kidney, but increased p-OSR1 and p-NKCC2. In aortic tissue, NKCC1 expression increased but p-NKCC1 decreased. SPAK-null mice had impaired contractile responses to phenylephrine and bumetanide, indicating SPAK regulates both renal NCC and vascular NKCC1. Targeted gene disruption (exons 9-10), blood pressure measurement, plasma electrolytes, diuretic challenges, phospho-specific Western blot, vascular contractility assay Journal of the American Society of Nephrology : JASN High 20813865
2010 SPAK knock-in mice in which SPAK cannot be activated by WNKs display significantly reduced blood pressure (salt-dependent) and markedly reduced phosphorylation of NCC and NKCC2 at SPAK-targeted residues, as well as reduced NCC and NKCC2 protein expression without mRNA changes. Knock-in mouse model (WNK-resistant SPAK), blood pressure telemetry, phospho-specific Western blot, qPCR EMBO molecular medicine High 20091762
2010 PP1 directly dephosphorylates both NKCC1 and SPAK in vitro. PP1 dephosphorylation of SPAK is markedly enhanced when SPAK is scaffolded to the NKCC1 N-terminal tail; mutation of the PP1 binding motif in NKCC1 reduces PP1 inhibitory effect. The N-terminal tail of NKCC1 thus serves as a regulatory scaffold for both SPAK and PP1. In vitro dephosphorylation assay, Xenopus oocyte functional assay, site-directed mutagenesis of PP1 docking motif The Journal of biological chemistry High 20223824
2010 SPAK substrate recognition requires two threonine residues in NKCC1 separated by four amino acids; addition or removal of a single residue abrogates SPAK-mediated NKCC1 activation. Constitutively active SPAK is created by T243E/S383D double mutation or by S383A mutation alone (which removes autoinhibition). WNK4 can phosphorylate SPAK at S321 in a deletion mutant. Site-directed mutagenesis, Xenopus oocyte 86Rb+ uptake assay American journal of physiology. Cell physiology Medium 20463172
2010 SORLA (an intracellular sorting receptor) interacts with SPAK and controls its intracellular trafficking; SORLA deficiency leads to SPAK missorting, inability to phosphorylate NKCC2, and impaired renal sodium reabsorption under osmotic stress. Co-immunoprecipitation, SORLA knockout mouse model, phospho-specific Western blot, immunofluorescence Molecular and cellular biology Medium 20385770
2011 A kidney-specific SPAK isoform lacking the kinase domain inhibits phosphorylation of NCC and NKCC2 by full-length SPAK in vitro. Kidney-specific SPAK is highly expressed in the thick ascending limb (TAL), while full-length SPAK predominates in the distal convoluted tubule (DCT). SPAK knockout has divergent nephron-segment-specific effects: increased p-NKCC2 in TAL but decreased p-NCC in DCT. In vitro kinase assay, SPAK knockout mouse analysis, nephron segment-specific expression analysis, phospho-specific Western blot Cell metabolism High 21907141
2011 MO25α/β bind to SPAK and OSR1 and induce ~100-fold activation of their kinase activity, dramatically enhancing their ability to phosphorylate NKCC1, NKCC2, and NCC. siRNA knockdown of MO25 in mammalian cells inhibits endogenous NKCC1 phosphorylation at SPAK/OSR1-targeted residues, rescued by MO25α re-expression. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, MS identification of new phosphorylation sites The EMBO journal High 21423148
2011 WNK kinases act as scaffolds to recruit SPAK to the complex with CFTR and NBCe1-B in pancreatic ductal epithelia; SPAK phosphorylates CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposes WNK/SPAK by recruiting PP1 to dephosphorylate CFTR and NBCe1-B, restoring surface expression. Silencing SPAK and IRBIT together rescues ductal secretion lost from IRBIT silencing alone. siRNA knockdown (SPAK, WNK, IRBIT), epithelial secretion assay, surface expression analysis, epistasis rescue experiment The Journal of clinical investigation High 21317537
2011 SPAK directly phosphorylates NKCC2 isoforms at Thr95, Thr100, and Thr105 (and possibly Ser91) through docking at an RFQV motif on NKCC2. Hypotonic low-chloride conditions activate WNK1-SPAK/OSR1 pathway to phosphorylate NKCC2. In contrast to NCC, NKCC2 is constitutively at the membrane and not translocated by SPAK/OSR1 phosphorylation. In vitro kinase assay, cell-based phosphorylation assay, mutagenesis of RFQV motif Journal of cell science High 21321328
2012 NKCC1 is not phosphorylated or activated in SPAK/OSR1 double-knockin embryonic stem cells where both kinases cannot be activated by WNK1, establishing that SPAK and OSR1 are the essential intermediaries for WNK1-dependent NKCC1 phosphorylation. These knockin cells also exhibit markedly elevated WNK1 and WNK3 activity, revealing a feedback whereby SPAK/OSR1 suppresses WNK activity. Double-knockin ES cells, NKCC1 phosphorylation assay, WNK kinase activity measurement The Biochemical journal High 22032326
2012 SPAK and OSR1 co-localize with MO25α at the apical membrane of TAL and DCT. In SPAK-null mice DCT (but not TAL), OSR1 becomes largely inactive, displaced from MO25α and NCC at the apical membrane, and redistributes to dense punctate cytoplasmic structures with WNK1, resulting in decreased NCC phosphorylation and reduced DCT mass. SPAK knockout mouse analysis, co-localization immunofluorescence, phospho-specific Western blot, nephron morphometry The Journal of biological chemistry High 22977235
2012 SPAK and OSR1 kinases phosphorylate and activate NKCC1 in the developing hypothalamus. Estradiol increases SPAK and OSR1 protein levels via transcription-dependent mechanisms. Antisense knockdown of SPAK (and to a lesser degree OSR1) precludes estradiol-mediated NKCC1 phosphorylation enhancement and diminishes GABA-induced Ca2+ influx. Antisense oligonucleotide knockdown, Western blot, Ca2+ imaging in embryonic hypothalamic cultures The Journal of neuroscience Medium 22238094
2012 SPAK phosphorylation at S383 by WNK and p-NKCC2/p-NCC show diurnal rhythms in mouse kidney dependent on aldosterone; spironolactone treatment attenuates phosphorylation and diminishes this diurnal pattern, and exogenous aldosterone restores it. Time-course Western blot with phospho-specific antibodies, mineralocorticoid receptor antagonist treatment Biochemical and biophysical research communications Medium 23044422
2012 The PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC cascade in hyperinsulinemic db/db mice. In SpakT243A/+ and Osr1T185A/+ knock-in db/db mice (preventing WNK-mediated activation), increased NCC phosphorylation and elevated blood pressure are completely corrected, establishing that WNK phosphorylation of SPAK/OSR1 T-loop is required for insulin/PI3K-mediated NCC activation. Knock-in mouse epistasis (T243A/T185A preventing WNK activation), PI3K/Akt inhibitor treatment, phospho-specific Western blot Hypertension High 22949526
2013 SPAK interacts with and phosphorylates NBCe1-B at Ser65; phosphorylation of Thr49 is required for regulation by both IRBIT and SPAK. SPAK-dependent phosphorylation of NBCe1-B and NBCn1-A is mediated through a conserved positively-charged regulatory module within residues 37-65 of NBCe1-B. Co-immunoprecipitation, mutagenesis, functional transporter assay, phospho-site identification Proceedings of the National Academy of Sciences of the United States of America Medium 23431199
2013 Aldosterone acutely stimulates SPAK phosphorylation (requiring mineralocorticoid receptor and SGK1); gene silencing of SPAK eliminates aldosterone-induced NCC activity and phosphorylation. Aldosterone effects on NCC activity are SPAK-dependent. siRNA knockdown of SPAK, NCC activity assay, phospho-specific Western blot, adrenalectomized rodent model with aldosterone infusion American journal of physiology. Renal physiology Medium 23739593
2013 SPAK-deficient mice exhibit significantly increased intestinal transepithelial resistance, decreased paracellular permeability, and altered tight junction protein expression (decreased claudin-2; increased occludin, E-cadherin, β-catenin, claudin-5). SPAK-null mice are more tolerant to DSS- and TNBS-induced colitis with increased IL-10 and decreased proinflammatory cytokines. SPAK knockout mouse analysis, transepithelial resistance measurement, permeability assay, tight junction protein expression, colitis models The American journal of pathology Medium 23499375
2014 SPAK and OSR1 (with MO25 regulatory subunit) directly phosphorylate all KCC isoforms at a conserved C-terminal Thr residue (Site-2, Thr1048 in KCC3A), inhibiting KCC activity. In ES cells lacking SPAK/OSR1 activity, KCC Site-2 phosphorylation is abolished and KCC3A activity is elevated. A Site-2 Ala KCC3A mutant (preventing SPAK/OSR1 phosphorylation) exhibits increased activity. Thus SPAK/OSR1 coordinate reciprocal actions: stimulating NKCCs (Cl- influx) and inhibiting KCCs (Cl- efflux). In vitro kinase assay with MO25, SPAK/OSR1 double-knockin ES cells, 86Rb+ uptake assay, site-directed mutagenesis, pathway inhibitor STOCK1S-50699 The Biochemical journal High 24393035
2014 The SPAK CCT domain Leu502 residue is critical for high-affinity recognition of RFXI/V motifs in WNK1, NCC, and NKCC2; Leu502Ala knock-in mice show abolished co-immunoprecipitation of SPAK with WNK1/NCC/NKCC2, markedly reduced SPAK activity, and reduced phosphorylation and expression of NCC and NKCC2, causing Gitelman syndrome-like phenotype. Knock-in mouse model (L502A), co-immunoprecipitation, phospho-specific Western blot, blood pressure measurement, electrolyte analysis Human molecular genetics High 25994507
2014 SPAK is important for endothelial cell proliferation (distinct from OSR1, which is required for chemotaxis/invasion) in WNK1-dependent angiogenic signaling. In HUVECs, SPAK mediates WNK1-dependent cord formation through effects on cell proliferation. HUVEC siRNA knockdown, cord formation assay, proliferation assay, chemotaxis/invasion assay Proceedings of the National Academy of Sciences of the United States of America Medium 25362046
2015 Crystal structures of SPAK kinase domain (residues 63-403, at 3.1 Å) and SPAK 63-390 T243D (at 2.5 Å) reveal domain-swapped dimer architecture. The T243D activating mutation induces significant conformational changes but retains some inactive features. A monomeric SPAK mutant retains kinase activity and can be activated by WNK1 but has reduced phosphorylation of NKCC2, indicating domain swapping has regulatory roles. X-ray crystallography, site-directed mutagenesis to create monomeric mutant, in vitro kinase assay Biochemistry High 26208601
2016 ASK3 (apoptosis signal-regulating kinase 3) interacts with WNK1 and suppresses the WNK1-SPAK/OSR1 signaling pathway. ASK3 knockdown by siRNA enhances WNK1-SPAK/OSR1 activation; ASK3 knockout mice exhibit hypertensive phenotype with hyperactivation of SPAK/OSR1 in renal tubules. Co-immunoprecipitation, siRNA knockdown, ASK3 knockout mouse model, phospho-specific Western blot, blood pressure measurement Nature communications High 23250415
2017 Constitutively active SPAK (kinase-activating mutation in Stk39 expressed DCT-specifically via Cre) causes NCC hyperphosphorylation, thiazide-treatable hypertension, and hyperkalemia. Additionally, CA-SPAK mice exhibit ASDN remodeling: reduced connecting tubule mass, attenuation of ENaC and ROMK expression and apical localization. Blocking NCC with thiazide gradually restores ASDN structure and K+ excretion. Conditional knock-in mouse (lox-P flanked CA-SPAK, DCT Cre), blood pressure telemetry, thiazide challenge, phospho-specific IHC and Western blot, urinary electrolytes Journal of the American Society of Nephrology : JASN High 28442491
2017 Rafoxanide binds an allosteric pocket on the SPAK C-terminal (CCT) domain and inhibits SPAK and OSR1 activity in an ATP-independent manner. In silico screening, biochemical binding assay, in vitro kinase inhibition assay ChemMedChem Medium 28371477
2018 Verteporfin binds the kinase domain of SPAK and OSR1 and inhibits their catalytic activity in an ATP-independent manner. In cells, verteporfin suppresses SPAK/OSR1-dependent phosphorylation of NKCC1. Binding assay, in vitro kinase assay, cell-based NKCC1 phosphorylation assay Chembiochem Medium 29999233
2019 WNK bodies in the distal convoluted tubule contain phosphorylated SPAK/OSR1 under K+-deprived conditions. In WNK4-deficient mice, WNK bodies still form but contain unphosphorylated SPAK/OSR1, indicating WNK4 is the primary active kinase catalyzing SPAK/OSR1 phosphorylation within WNK bodies. Immunofluorescence microscopy in dietary K+ manipulation mouse models, WNK4-deficient and Kir4.1-deficient mice American journal of physiology. Renal physiology Medium 31736353
2020 ZT-1a, a selective SPAK inhibitor, decreases SPAK-dependent phosphorylation of NKCC1 and increases KCC-mediated Cl- efflux in brain. Intracerebroventricular ZT-1a reduces CSF hypersecretion in post-hemorrhagic hydrocephalus model; systemic ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, and improves stroke outcomes. Selective SPAK inhibitor (ZT-1a) treatment in rodent models of hydrocephalus and stroke, CCC phosphorylation assay, brain water content, neurological scoring Nature communications High 31911626
2021 STK39/SPAK interacts with PLK1 by mass spectrometry; STK39 promotes HCC progression and activates ERK signaling in a PLK1-dependent manner. STK39 knockdown causes G2/M cell cycle arrest and apoptosis in HCC cells; overexpression promotes proliferation, migration, and invasion. Mass spectrometry, co-immunoprecipitation, RNA-seq pathway analysis, gain/loss-of-function assays in HCC cells Theranostics Medium 33500714
2021 STK39 directly phosphorylates SNAI1 at Thr203, which is critical for SNAI1 nuclear retention and stability. STK39 inhibition or knockdown destabilizes SNAI1, impairs EMT, and decreases tumor cell migration, invasion, and metastasis in vitro and in vivo; effects are rescued by ectopic SNAI1 expression. Co-immunoprecipitation, in vitro kinase assay with phospho-site mutagenesis (T203), subcellular fractionation, loss-of-function assays, xenograft rescue experiment Theranostics High 34335956
2021 High extracellular K+ rapidly dephosphorylates SPAK in vitro (HEK293 cells) and ex vivo (kidney slices), causing dissolution of SPAK puncta in DCT1 in vivo. The WNK4-SPAK 'on' switch must be turned off for rapid NCC dephosphorylation by high K+; longer-term WNK-SPAK stimulation attenuates sensitivity to rapid K+-induced NCC dephosphorylation. Neither PP1 nor PP3 alone or together is essential for rapid NCC dephosphorylation. In vitro kinase/phosphatase assay in HEK293 cells, ex vivo kidney slice, in vivo dietary K+ challenge with immunofluorescence and Western blot, phosphatase inhibitor experiments American journal of physiology. Renal physiology Medium 33719576

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. The Biochemical journal 435 16083423
2005 WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. The Journal of biological chemistry 392 16263722
2008 Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1. Journal of cell science 320 18270262
2002 Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). The Journal of biological chemistry 318 12386165
2006 Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. The Biochemical journal 262 16669787
2008 The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway. Journal of cell science 250 18843116
2010 SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction. Journal of the American Society of Nephrology : JASN 239 20813865
2008 From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proceedings of the National Academy of Sciences of the United States of America 237 19114657
2010 Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO molecular medicine 227 20091762
2014 The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Science signaling 214 25028718
2009 Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America 201 19240212
2008 Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases. Proceedings of the National Academy of Sciences of the United States of America 195 18550832
2011 A SPAK isoform switch modulates renal salt transport and blood pressure. Cell metabolism 182 21907141
2014 The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. The Biochemical journal 177 24393035
2003 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. The Journal of biological chemistry 175 14563843
2008 Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. Kidney international 170 18800028
2008 SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. The Biochemical journal 163 18092945
2011 Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. Journal of cell science 162 21321328
2006 Characterization of SPAK and OSR1, regulatory kinases of the Na-K-2Cl cotransporter. Molecular and cellular biology 136 16382158
2011 MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. The EMBO journal 122 21423148
2000 SPAK, a STE20/SPS1-related kinase that activates the p38 pathway. Oncogene 122 10980603
2017 Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules. Journal of the American Society of Nephrology : JASN 120 28442491
2012 SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner. The Journal of biological chemistry 119 22977235
2012 Molecular physiology of SPAK and OSR1: two Ste20-related protein kinases regulating ion transport. Physiological reviews 115 23073627
2012 SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation. The Biochemical journal 114 22032326
2020 Modulation of brain cation-Cl- cotransport via the SPAK kinase inhibitor ZT-1a. Nature communications 88 31911626
2013 SPAK differentially mediates vasopressin effects on sodium cotransporters. Journal of the American Society of Nephrology : JASN 88 23393317
2012 Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice. Hypertension (Dallas, Tex. : 1979) 87 22949526
2011 IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway. The Journal of clinical investigation 87 21317537
2005 Hypotonic shock mediation by p38 MAPK, JNK, PKC, FAK, OSR1 and SPAK in osmosensing chloride secreting cells of killifish opercular epithelium. The Journal of experimental biology 86 15767308
2014 WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. Hypertension (Dallas, Tex. : 1979) 82 25113964
2012 Aldosterone does not require angiotensin II to activate NCC through a WNK4-SPAK-dependent pathway. Pflugers Archiv : European journal of physiology 76 22549242
2004 SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway. The EMBO journal 75 14988727
2013 Convergence of IRBIT, phosphatidylinositol (4,5) bisphosphate, and WNK/SPAK kinases in regulation of the Na+-HCO3- cotransporters family. Proceedings of the National Academy of Sciences of the United States of America 68 23431199
2014 Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK. Proceedings of the National Academy of Sciences of the United States of America 61 25362046
2012 ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney. Nature communications 61 23250415
2014 Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters. Journal of the American Society of Nephrology : JASN 60 25377078
2011 Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. Journal of cell science 58 21486947
2015 SPAK-mediated NCC regulation in response to low-K+ diet. American journal of physiology. Renal physiology 56 25651563
2007 A single binding motif is required for SPAK activation of the Na-K-2Cl cotransporter. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 56 17595523
2006 Genome-wide analysis of SPAK/OSR1 binding motifs. Physiological genomics 55 17032814
2019 WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia. American journal of physiology. Renal physiology 54 31736353
2016 SPAK and OSR1 play essential roles in potassium homeostasis through actions on the distal convoluted tubule. The Journal of physiology 53 27068441
2010 On the substrate recognition and negative regulation of SPAK, a kinase modulating Na+-K+-2Cl- cotransport activity. American journal of physiology. Cell physiology 51 20463172
2007 Apoptosis-associated tyrosine kinase scaffolding of protein phosphatase 1 and SPAK reveals a novel pathway for Na-K-2C1 cotransporter regulation. American journal of physiology. Cell physiology 51 17267545
2006 SPAK and OSR1, key kinases involved in the regulation of chloride transport. Acta physiologica (Oxford, England) 51 16734747
2013 Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II. Hypertension (Dallas, Tex. : 1979) 50 24019400
2011 Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters. Current opinion in nephrology and hypertension 49 21610494
2010 Multiple pathways for protein phosphatase 1 (PP1) regulation of Na-K-2Cl cotransporter (NKCC1) function: the N-terminal tail of the Na-K-2Cl cotransporter serves as a regulatory scaffold for Ste20-related proline/alanine-rich kinase (SPAK) AND PP1. The Journal of biological chemistry 49 20223824
2013 Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway. American journal of physiology. Renal physiology 46 23739593
2010 SORLA/SORL1 functionally interacts with SPAK to control renal activation of Na(+)-K(+)-Cl(-) cotransporter 2. Molecular and cellular biology 46 20385770
2020 Physiological Processes Modulated by the Chloride-Sensitive WNK-SPAK/OSR1 Kinase Signaling Pathway and the Cation-Coupled Chloride Cotransporters. Frontiers in physiology 43 33192599
2019 The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases. Aging and disease 43 31165006
2008 An analysis of candidate autism loci on chromosome 2q24-q33: evidence for association to the STK39 gene. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 43 18348195
2014 Hypotonicity stimulates potassium flux through the WNK-SPAK/OSR1 kinase cascade and the Ncc69 sodium-potassium-2-chloride cotransporter in the Drosophila renal tubule. The Journal of biological chemistry 40 25086033
2006 The TNF receptor, RELT, binds SPAK and uses it to mediate p38 and JNK activation. Biochemical and biophysical research communications 40 16530727
2017 Rafoxanide and Closantel Inhibit SPAK and OSR1 Kinases by Binding to a Highly Conserved Allosteric Site on Their C-terminal Domains. ChemMedChem 39 28371477
2018 The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. Journal of the American Society of Nephrology : JASN 38 29848507
2001 Androgens induce expression of SPAK, a STE20/SPS1-related kinase, in LNCaP human prostate cancer cells. Molecular and cellular endocrinology 37 11514053
2014 A novel Ste20-related proline/alanine-rich kinase (SPAK)-independent pathway involving calcium-binding protein 39 (Cab39) and serine threonine kinase with no lysine member 4 (WNK4) in the activation of Na-K-Cl cotransporters. The Journal of biological chemistry 35 24811174
2021 STK39 is a novel kinase contributing to the progression of hepatocellular carcinoma by the PLK1/ERK signaling pathway. Theranostics 34 33500714
2016 Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 34 26861815
2012 Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant SPAK. Kidney & blood pressure research 34 23235437
2011 SPAK and WNK kinases: a new target for blood pressure treatment? Current opinion in nephrology and hypertension 34 21088576
2012 WNK-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone. Biochemical and biophysical research communications 33 23044422
2015 Critical role of the SPAK protein kinase CCT domain in controlling blood pressure. Human molecular genetics 32 25994507
2012 The WNK/SPAK and IRBIT/PP1 pathways in epithelial fluid and electrolyte transport. Physiology (Bethesda, Md.) 31 23026752
2013 Loss of WNK3 is compensated for by the WNK1/SPAK axis in the kidney of the mouse. American journal of physiology. Renal physiology 30 23427142
2013 Knockout of Ste20-like proline/alanine-rich kinase (SPAK) attenuates intestinal inflammation in mice. The American journal of pathology 30 23499375
2012 WNK3-SPAK interaction is required for the modulation of NCC and other members of the SLC12 family. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 30 22415098
2008 PKCdelta acts upstream of SPAK in the activation of NKCC1 by hyperosmotic stress in human airway epithelial cells. The Journal of biological chemistry 29 18550547
2020 Activated WNK3 induced by intracerebral hemorrhage deteriorates brain injury maybe via WNK3/SPAK/NKCC1 pathway. Experimental neurology 28 32589890
2014 Negative regulation of the creatine transporter SLC6A8 by SPAK and OSR1. Kidney & blood pressure research 28 25531585
2012 Kinases SPAK and OSR1 are upregulated by estradiol and activate NKCC1 in the developing hypothalamus. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 22238094
2014 Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK. American journal of physiology. Renal physiology 27 24808538
2024 Modulation of Cerebrospinal Fluid Dysregulation via a SPAK and OSR1 Targeted Framework Nucleic Acid in Hydrocephalus. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 26 38353402
2020 WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension. Acta pharmacologica Sinica 26 32724175
2009 Ste20-related proline/alanine-rich kinase (SPAK) regulated transcriptionally by hyperosmolarity is involved in intestinal barrier function. PloS one 26 19343169
2022 Role of SPAK-NKCC1 signaling cascade in the choroid plexus blood-CSF barrier damage after stroke. Journal of neuroinflammation 25 35413993
2021 Knockdown of long non-coding RNA CDKN2B-AS1 suppresses the progression of breast cancer by miR-122-5p/STK39 axis. Bioengineered 25 34374638
2019 The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway. Journal of human hypertension 25 30723251
2017 STK39, overexpressed in osteosarcoma, regulates osteosarcoma cell invasion and proliferation. Oncology letters 25 28943960
2019 Suppression of WNK1-SPAK/OSR1 Attenuates Bone Cancer Pain by Regulating NKCC1 and KCC2. The journal of pain 24 31085334
2014 Regulation of ClC-2 activity by SPAK and OSR1. Kidney & blood pressure research 24 25323061
2013 STK39 polymorphism is associated with essential hypertension: a systematic review and meta-analysis. PloS one 24 23527223
2018 WNK-SPAK/OSR1 signaling: lessons learned from an insect renal epithelium. American journal of physiology. Renal physiology 23 29923766
2014 SPAK and OSR1 dependent down-regulation of murine renal outer medullary K channel ROMK1. Kidney & blood pressure research 23 25322850
2014 SPAK dependent regulation of peptide transporters PEPT1 and PEPT2. Kidney & blood pressure research 23 25376088
2022 NF-κB Signaling-Mediated Activation of WNK-SPAK-NKCC1 Cascade in Worsened Stroke Outcomes of Ang II-Hypertensive Mice. Stroke 22 35272484
2019 WNK4-SPAK modulates lipopolysaccharide-induced macrophage activation. Biochemical pharmacology 22 31786261
2021 Roles of WNK4 and SPAK in K+-mediated dephosphorylation of the NaCl cotransporter. American journal of physiology. Renal physiology 21 33719576
2014 STE20/SPS1-related proline/alanine-rich kinase (SPAK) is critical for sodium reabsorption in isolated, perfused thick ascending limb. American journal of physiology. Renal physiology 21 25477470
2009 Epigenetic silencing of Stk39 in B-cell lymphoma inhibits apoptosis from genotoxic stress. The American journal of pathology 20 19717643
2022 MiR-223-3p-loaded exosomes from bronchoalveolar lavage fluid promote alveolar macrophage autophagy and reduce acute lung injury by inhibiting the expression of STK39. Human cell 19 35932362
2021 STK39 promotes breast cancer invasion and metastasis by increasing SNAI1 activity upon phosphorylation. Theranostics 19 34335956
2016 SPAK plays a pathogenic role in IgA nephropathy through the activation of NF-κB/MAPKs signaling pathway. Free radical biology & medicine 19 27519267
2015 Domain-Swapping Switch Point in Ste20 Protein Kinase SPAK. Biochemistry 19 26208601
2020 Staurosporine and NEM mainly impair WNK-SPAK/OSR1 mediated phosphorylation of KCC2 and NKCC1. PloS one 18 32413057
2018 The Photosensitising Clinical Agent Verteporfin Is an Inhibitor of SPAK and OSR1 Kinases. Chembiochem : a European journal of chemical biology 18 29999233
2009 Behavioral analysis of Ste20 kinase SPAK knockout mice. Behavioural brain research 18 20006650

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