Affinage

OSR1

Protein odd-skipped-related 1 · UniProt Q8TAX0

Length
266 aa
Mass
29.6 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OSR1 is a STE20-family serine/threonine kinase that serves as the central effector of the WNK-OSR1/SPAK cascade controlling cellular Cl- and ion homeostasis (PMID:16832045, PMID:22032326). Its activity is switched on when WNK1/WNK4 phosphorylate the T-loop residue Thr185; this modification is necessary and sufficient for activation, as alanine substitution abolishes and a phosphomimetic raises basal activity (PMID:16083423). Activation depends on a C-terminal conserved (CCT) domain whose surface groove engages an RFXV/RFXI motif present in both WNK activators and downstream substrates, a docking interaction defined biochemically and by crystal structure of the CCT domain bound to a WNK4 peptide (PMID:16669787, PMID:17721439). MO25 isoforms bind OSR1 and potentiate its activity ~100-fold, and C-terminal S-motif (WEWS) phosphorylation by WNK promotes this MO25 association (PMID:21423148, PMID:30060950). Activated OSR1 directly phosphorylates the N-terminal regulatory regions of the Na+-coupled cotransporters NKCC1, NKCC2, and NCC to stimulate Cl- influx, while phosphorylating a conserved C-terminal site on KCC isoforms to inhibit them, coordinately driving net chloride accumulation (PMID:16263722, PMID:18270262, PMID:24393035, PMID:21321328). Genetic knockin and knockout mouse models establish that this cascade is the dominant route of in vivo NCC and NKCC phosphorylation, governing renal salt handling, plasma potassium sensing, and blood pressure, with aldosterone and PI3K/Akt acting as upstream regulators (PMID:21486947, PMID:22949526, PMID:27068441). Beyond ion transport, OSR1 is an essential WNK1 effector in embryonic cardiovascular development and endothelial chemotaxis (PMID:23386621, PMID:25362046), and it phosphorylates additional targets including the Smad2/3 linker to drive TGF-β1-dependent EMT in breast cancer (PMID:33051597). A distinct Osr1 transcription-factor activity maintains nephron progenitors during kidney development by forming TCF-Groucho repressor complexes and interacting with Wt1 to antagonize Wnt signaling (PMID:24598167, PMID:27442016).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2002 High

    Established that OSR1 physically engages cation-chloride cotransporters, framing it as a regulator of ion transport rather than an orphan kinase.

    Evidence Yeast two-hybrid, GST pull-down, and co-IP from mouse brain mapping binding to the OSR1 C-terminus and an (R/K)FX(V/I) motif on NKCC1/NKCC2/KCC3

    PMID:12386165

    Open questions at the time
    • Did not show direct phosphorylation of the cotransporters
    • Functional consequence of binding not yet established
  2. 2004 Medium

    Identified OSR1 as an osmotic-stress-activated kinase and proposed early substrates, defining its stimulus responsiveness.

    Evidence Kinase assays under sorbitol/NaCl stress, yeast two-hybrid, and in vitro phosphorylation of PAK1 Thr84

    PMID:14707132

    Open questions at the time
    • PAK1 as a physiological substrate not independently replicated
    • Upstream activating kinase not yet identified
  3. 2005 High

    Defined the activating phosphorylation event by showing WNK kinases phosphorylate OSR1 T-loop Thr185 to switch on activity, and that OSR1/SPAK phosphorylate the cotransporter regulatory regions.

    Evidence In vitro phosphorylation, phosphopeptide mapping, and T185A/T185E/S325 mutagenesis; cell-based NCC phosphorylation under hypotonic stress

    PMID:16083423 PMID:16263722

    Open questions at the time
    • Did not resolve the docking mechanism enabling WNK-OSR1 recognition
    • Role of the C-terminal serine site left functionally ambiguous
  4. 2006 High

    Connected docking to catalysis by defining the CCT domain that recognizes RFXV motifs on both activators and substrates, and confirmed WNK1 controls OSR1 in cells.

    Evidence In vitro kinase assays with CATCHtide, CCT-domain mutagenesis, co-IP, in vitro activation, and siRNA of WNK1/OSR1 with NKCC functional readout

    PMID:16669787 PMID:16832045

    Open questions at the time
    • Structural basis of CCT-RFXV recognition not yet determined
    • How phosphorylation dissociates docking unresolved
  5. 2007 High

    Provided the structural mechanism of substrate/activator selection, explaining how phosphorylation near the RFXV motif terminates docking.

    Evidence 2.25 Å crystal structure of the OSR1 CCT domain bound to a WNK4 RFXV peptide with mutational and binding validation

    PMID:17721439

    Open questions at the time
    • Structure of the catalytic domain not addressed
    • Does not capture the full-length active complex
  6. 2008 High

    Established hierarchical NCC phosphorylation and placed aldosterone upstream of the cascade, linking salt intake to transporter activity.

    Evidence In vitro and cell-based kinase assays defining NCC Thr46/55/60 and RFXI docking; mouse dietary salt manipulation with spironolactone/aldosterone

    PMID:18270262 PMID:18800028

    Open questions at the time
    • Aldosterone-to-WNK molecular link not defined
    • Mechanism of hierarchical priming at Thr60 not fully resolved
  7. 2009 High

    Revealed the inactive conformation of the kinase domain, informing how activation reorganizes the active site.

    Evidence 2.25 Å crystal structure showing a domain-swapped inactive dimer with swapped P+1 loop and αEF helix

    PMID:19177573

    Open questions at the time
    • Active-state conformation not captured
    • Relevance of the swapped dimer in cells unclear
  8. 2011 High

    Identified MO25 as a potent allosteric activator and demonstrated entire-cascade dependence on the WNK-OSR1/SPAK axis in vivo for blood pressure control.

    Evidence In vitro kinase activation and siRNA-rescue for MO25; NKCC2 substrate-site mapping; triple-knockin Wnk4(D561A);SPAK/OSR1 T-loop mice with physiological readouts

    PMID:21321328 PMID:21423148 PMID:21486947

    Open questions at the time
    • How MO25 reshapes the kinase active site not structurally defined
    • Tissue-specific MO25 isoform usage not resolved
  9. 2012 High

    Provided genetic proof that OSR1/SPAK activity is essential for NKCC1 regulation, revealed feedback on WNK, and uncovered segment-specific OSR1/SPAK interdependence and additional regulators.

    Evidence Double-knockin ES cells (T-loop mutants), SPAK-null mice with localization imaging, Osr1 knockin phosphate-transport mouse, and ASK3/PI3K-Akt regulatory studies

    PMID:22032326 PMID:22949526 PMID:22977235 PMID:23044422 PMID:23095210 PMID:23250415

    Open questions at the time
    • Mechanism of SPAK-dependent OSR1 localization not defined
    • Negative feedback onto WNK mechanistically uncharacterized
  10. 2013 High

    Established OSR1 as an essential WNK1 effector in embryonic cardiovascular development and identified mTORC2 as an additional input.

    Evidence Endothelial conditional Osr1 knockout with constitutively active OSR1 rescue of WNK1-null embryos; in vitro mTORC2 phosphorylation of Ser339 with siRNA and inhibitor validation

    PMID:23386621 PMID:24191005

    Open questions at the time
    • Ion-transport vs developmental contributions of OSR1 in endothelium not separated
    • Functional role of Ser339 phosphorylation in vivo unclear
  11. 2014 Medium

    Defined OSR1 as a reciprocal regulator that inhibits KCC isoforms while activating Kir channels, and linked it to nephron progenitor maintenance, glioma migration, and endothelial chemotaxis.

    Evidence In vitro KCC Site-2 phosphorylation with KO ES cells and flux assays; Kir2.1/2.3 motif mutagenesis; glioma siRNA functional assays; Osr1-TCF-Groucho co-IP with conditional KO reporter; endothelial siRNA/conditional KO

    PMID:24393035 PMID:24555568 PMID:24598167 PMID:25362046 PMID:29581290

    Open questions at the time
    • Transcription-factor and kinase activities not mechanistically reconciled within one locus
    • Single-lab status for several functional claims
  12. 2016 Medium

    Showed SPAK and OSR1 are jointly essential for distal-tubule potassium sensing and explored intercellular transfer of active kinase, expanding the physiological scope of the pathway.

    Evidence SPAK/OSR1 double-knockout mice under K+ restriction with electrolyte readouts; exosome isolation and phospho-NKCC1 tracking; Osr1-Wt1 endogenous co-IP and double-heterozygous mouse genetics

    PMID:27068441 PMID:27122160 PMID:27442016

    Open questions at the time
    • Exosomal OSR1 lacks direct kinase assay on isolated vesicles
    • Molecular mechanism of DCT plasma-K+ sensing upstream of OSR1 unresolved
  13. 2019 Medium

    Linked OSR1 stability to its activation state by showing S-motif phosphorylation toggles binding to a Cullin4 E3 ligase complex.

    Evidence Affinity pull-down with mass spectrometry, phospho-mutant analysis, and proteasomal/neddylation inhibitors

    PMID:31614064

    Open questions at the time
    • In vivo significance of OSR1 ubiquitylation not established
    • Single-lab finding
  14. 2022 Medium

    Extended OSR1 effector functions into neuronal differentiation through a WNK1(HSN2)-OSR1-GSK3β-LHX8 axis relevant to sensory neuropathy.

    Evidence Zebrafish in vitro kinase assays, co-IP, disease-mutant expression, neurite outgrowth and LHX8 reporter assays

    PMID:36151370

    Open questions at the time
    • Direct OSR1 substrate in this neuronal pathway not identified
    • Single-lab, model-organism finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single OSR1 locus reconciles its cytoplasmic kinase role in the WNK cascade with the nuclear zinc-finger transcriptional-repressor activity in development remains unresolved.
  • Relationship between kinase and transcription-factor isoforms not mechanistically defined
  • Structural basis of MO25-dependent allosteric activation not solved
  • Substrate spectrum beyond cotransporters incompletely mapped

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:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-382551 Transport of small molecules 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-8953897 Cellular responses to stimuli 2
Partners
MO25NCCNKCC1NKCC2SMAD2/3SPAKWNK1WNK4
Complex memberships
OSR1-MO25 complexOsr1-TCF-Groucho repressor complexWNK-OSR1/SPAK signaling complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 WNK1 and WNK4 phosphorylate OSR1 at two sites: Thr185 in the T-loop of the catalytic domain and Ser325 in the C-terminal non-catalytic region. Phosphorylation of Thr185 is required for OSR1 activation; mutation to Ala abolishes activation by WNK1, while mutation to Glu (phosphomimetic) increases basal activity >20-fold. Mutation of Ser325 does not affect OSR1 activity. In vitro phosphorylation assay, phosphopeptide mapping, site-directed mutagenesis (T185A, T185E, S325A, S325E), kinase activity assays The Biochemical journal High 16083423
2002 OSR1 physically interacts with cation-chloride cotransporters NKCC1, NKCC2, and KCC3 (but not KCC1 or KCC4) via the last ~100 amino acids of OSR1. The binding motif on the cotransporters begins with an (R/K)FX(V/I) sequence. Interaction was established by yeast two-hybrid and GST pull-down. Yeast two-hybrid, GST pull-down, co-immunoprecipitation from mouse brain The Journal of biological chemistry High 12386165
2006 OSR1 directly phosphorylates NKCC1 at three conserved residues (Thr203/Thr207/Thr212 in human NKCC1). A 92-residue conserved C-terminal (CCT) domain on OSR1 interacts with an RFXV motif present in both its activators (WNK1/WNK4) and substrate (NKCC1); mutation of the CCT domain inhibits NKCC1 phosphorylation. An intact CCT domain is required for efficient WNK1-mediated phosphorylation and activation of OSR1. In vitro kinase assay, peptide substrate development (CATCHtide), mutagenesis of CCT domain, affinity purification The Biochemical journal High 16669787
2007 Crystal structure of the OSR1 CCT domain in complex with a WNK4-derived RFXV peptide was solved at 2.25 Å. The CCT domain forms a novel protein fold with a surface-exposed groove that engages the Arg-Phe-Xaa-Val motif. Phosphorylation of a Ser/Thr residue preceding the RFXV motif causes steric clash, promoting dissociation from the CCT domain. Mutational analysis confirmed that these interactions are required for binding to WNK1 and NKCC1. X-ray crystallography, mutational analysis, binding assays EMBO reports High 17721439
2009 Crystal structure of the OSR1 kinase domain was solved at 2.25 Å, revealing a domain-swapped dimer in an inactive conformation in which the P+1 loop and αEF helix are swapped between dimer-related monomers. X-ray crystallography Protein science High 19177573
2006 WNK1 regulates OSR1 activity in cells: OSR1 exists in a complex with WNK1 in HeLa cells, is activated by recombinant WNK1 in vitro, and is phosphorylated in a WNK1-dependent manner in cells. siRNA depletion of WNK1 reduces OSR1 kinase activity. Depletion of OSR1 reduces NKCC activity, establishing that both WNK1 and OSR1 are required for NKCC function in volume regulation. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, NKCC activity assay Proceedings of the National Academy of Sciences of the United States of America High 16832045
2005 WNK1 phosphorylates OSR1 at a conserved serine residue outside the kinase domain; mutation of this serine causes enhanced OSR1 kinase activity. SPAK and OSR1 directly phosphorylate the N-terminal regulatory regions of NKCC1, NKCC2, and NCC. Phosphorylation of NCC is induced by hypotonic stress. In vitro kinase assay, mutational analysis, cell-based phosphorylation assays The Journal of biological chemistry High 16263722
2008 SPAK and OSR1 (activated by WNK1) phosphorylate human NCC at Thr46, Thr55, and Thr60. Efficient phosphorylation requires a docking interaction between an RFXI motif in NCC and SPAK/OSR1. Mutation of Thr60 to Ala markedly inhibits phosphorylation of Thr46 and Thr55 and abolishes NCC activation by hypotonic low-chloride treatment. In vitro kinase assay, mutagenesis, cell-based phosphorylation assays in HEK293 and mpkDCT cells Journal of cell science High 18270262
2011 MO25α and MO25β bind to OSR1 and induce ~100-fold activation of OSR1, dramatically enhancing its ability to phosphorylate NKCC1, NKCC2, and NCC. siRNA-mediated reduction of MO25 isoforms in mammalian cells inhibited phosphorylation of endogenous NKCC1 at SPAK/OSR1-dependent sites, which was rescued by re-expression of MO25α. In vitro kinase assay, co-immunoprecipitation, siRNA knockdown with rescue, phospho-specific immunoblot The EMBO journal High 21423148
2014 WNK-activated SPAK/OSR1 directly phosphorylates all KCC isoforms at a conserved C-terminal threonine (Site-2, Thr1048 in KCC3A) in vitro, inhibiting KCC activity. In ES cells lacking SPAK/OSR1 activity, KCC Site-2 phosphorylation is abolished and KCC3A activity is elevated. A KCC3A Site-2 alanine mutant shows increased activity, confirming SPAK/OSR1-mediated inhibition. In vitro phosphorylation assay with MO25, SPAK/OSR1 knockout ES cells, 86Rb+ flux assay, WNK pathway inhibitor (STOCK1S-50699), mutagenesis The Biochemical journal High 24393035
2012 OSR1 (with SPAK) directly phosphorylates NKCC2 at Thr95, Thr100, Thr105 (and possibly Ser91) via interaction with an RFQV motif on NKCC2. Unlike NCC, NKCC2 membrane localization is constitutive and not triggered by SPAK/OSR1 phosphorylation. In vitro kinase assay, mutagenesis, cell-based phosphorylation, functional NKCC2 activity measurements Journal of cell science High 21321328
2012 In double-knockin ES cells where SPAK and OSR1 cannot be activated by WNK1 (T-loop mutations), NKCC1 is not phosphorylated or activated, providing genetic proof that SPAK/OSR1 activity is essential for WNK1-mediated NKCC1 regulation. Additionally, SPAK/OSR1 activity significantly suppresses WNK1 and WNK3 activity (negative feedback). Double-knockin ES cells (SPAK and OSR1 T-loop alanine mutations), phospho-specific immunoblot, kinase assay The Biochemical journal High 22032326
2011 NCC phosphorylation in vivo is almost completely abolished in Wnk4(D561A/+) mice crossed with SPAK and OSR1 T-loop knockin mice (T243A and T185A), demonstrating that in vivo NCC phosphorylation is entirely dependent on the WNK-OSR1/SPAK cascade. High blood pressure, hyperkalemia, and metabolic acidosis observed in Wnk4(D561A/+) mice were corrected in triple knockin mice. Triple-knockin mouse model, phospho-specific immunoblot, blood pressure measurement, metabolic analysis Journal of cell science High 21486947
2004 OSR1 is activated selectively by osmotic stresses (sorbitol, NaCl) in mammalian cells. OSR1 phosphorylates threonine 84 in the N-terminal regulatory domain of PAK1; replacement of Thr84 with Glu reduces PAK1 activation by Cdc42, suggesting OSR1 modulates G-protein sensitivity of PAK isoforms. Kinase activity assays, yeast two-hybrid, in vitro phosphorylation, mutagenesis The Journal of biological chemistry Medium 14707132
2005 OSR1 phosphorylates RELT family members (RELT, RELL1, RELL2) in an in vitro kinase assay. OSR1 was identified as an interactor of RELL1 via yeast two-hybrid screen and shown to interact with all three RELT family members by co-immunoprecipitation. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay Biochemical and biophysical research communications Medium 16389068
2013 mTORC2 phosphorylates OSR1 on Ser339 in vitro, and inhibition of PI3K or depletion of Sin1 (an mTORC2 component) decreases OSR1 activation by osmotic stress and reduces NKCC activity. Mutation of Ser339 eliminates mTORC2-mediated phosphorylation of OSR1. In vitro kinase assay, siRNA depletion, pharmacological inhibition, mutagenesis, NKCC activity assay Proceedings of the National Academy of Sciences of the United States of America Medium 24191005
2013 Global and endothelial-specific deletion of Osr1 in mice causes embryonic lethality with angiogenesis and cardiac defects identical to WNK1 knockout. Endothelial-specific expression of a constitutively active OSR1 transgene rescues angiogenesis and cardiac defects in global WNK1-null embryos, establishing OSR1 as an essential downstream effector of WNK1 in embryonic cardiovascular development. Conditional knockout mice (Osr1 flox/Tie2-Cre), constitutively active OSR1 transgenic rescue, embryo phenotyping The Journal of biological chemistry High 23386621
2014 In endothelial cells, WNK1-OSR1 signaling is required for HUVEC chemotaxis and invasion, while SPAK mediates endothelial cell proliferation. Knockdown experiments in HUVECs showed OSR1 (not SPAK) is required for cord formation and chemotaxis. OSR1 KO embryos can be rescued by constitutively active OSR1 in endothelium, separating OSR1 and SPAK functions. siRNA knockdown, cord formation assay, chemotaxis/invasion assay, endothelial-specific conditional knockout Proceedings of the National Academy of Sciences of the United States of America Medium 25362046
2012 In SPAK-null mice, OSR1 becomes largely inactive, displaced from MO25α and NCC at the apical membrane of the distal convoluted tubule, and redistributes to dense punctate structures containing WNK1 in the cytoplasm. OSR1 in the DCT depends on SPAK for its proper localization and activity, demonstrating that SPAK and OSR1 act in a nephron-segment-specific manner with interdependence. SPAK knockout mouse model, immunofluorescence, subcellular fractionation, phospho-specific immunoblot The Journal of biological chemistry Medium 22977235
2012 OSR1 coexpression in Xenopus oocytes significantly upregulates phosphate-induced currents via NaPiIIa (the major renal tubular phosphate transporter). In osr1tg/(+) knockin mice (carrying a WNK-resistant OSR1 allele), urinary phosphate excretion is increased and NaPiIIa abundance in the brush border is reduced, suggesting OSR1 positively regulates renal phosphate transport. Xenopus oocyte co-expression with voltage clamp, knockin mouse model, immunohistochemistry Kidney & blood pressure research Medium 23095210
2014 OSR1 activates inward rectifier K+ channels Kir2.1 and Kir2.3 via a variant binding motif (R-x-F-x-V/I) in these channels. Mutation of this motif in Kir2.3 prevents activation by OSR1. siRNA knockdown of OSR1 and WNK inhibition disrupt NaCl-induced plasma membrane localization of Kir2.3, suggesting OSR1 promotes channel activity by increasing plasma membrane localization. siRNA knockdown, WNK inhibitor treatment, mutagenesis of R-x-F-x-V motif, plasma membrane localization assay Proceedings of the National Academy of Sciences of the United States of America Medium 29581290
2019 The E3 ubiquitin ligase complex Cullin4-DDB1-WDR3/WDR6 binds OSR1 in a manner dependent on phosphorylation of the S-motif (conserved serine in the WEWS motif). S-motif phosphorylation under osmotic stress abolishes this binding, and proteasomal/neddylation inhibitors show that OSR1 ubiquitylation is suppressed when the S-motif is phosphorylated. Affinity pull-down, mass spectrometry, proteasomal and neddylation inhibitors, phospho-mutant analysis Chembiochem Medium 31614064
2018 C-terminal serine phosphorylation of OSR1 in the WEWS motif (S-motif), carried out by WNK kinases in vitro and in cells, enhances binding of MO25 to OSR1. Mutagenesis identified key MO25 residues required for MO25 binding and subsequent activation of OSR1. In vitro kinase assay, mutagenesis, co-immunoprecipitation/binding assays Biochemical and biophysical research communications Medium 30060950
2020 OSR1 (as a kinase) directly phosphorylates the linker region of Smad2 at Thr220 and Smad3 at Thr179 in breast cancer cells. Phosphorylated Smad2/3 translocates to the nucleus to enhance TGF-β1 autocrine signaling and increase transcription of EMT regulators. OSR1 directly interacts with Smad2/3 as shown by co-immunoprecipitation. Co-immunoprecipitation, in vitro kinase assay, mutagenesis, reporter assays, loss-of-function with specific phenotypic readouts (EMT, metastasis in vitro and in vivo) Oncogene Medium 33051597
2012 OSR1 phosphorylation in the kidney displays a circadian rhythm dependent on aldosterone; phosphorylation levels of OSR1 (and downstream SPAK and NCC) are elevated around the start of the active period. Eplerenone (aldosterone receptor blocker) attenuates OSR1 phosphorylation and diminishes the diurnal rhythm. Time-course immunoblotting in mouse kidneys, pharmacological blockade with eplerenone Biochemical and biophysical research communications Medium 23044422
2008 Dietary salt regulates phosphorylation of OSR1 (and SPAK) and NCC through aldosterone. Low-salt diet increases OSR1/SPAK and NCC phosphorylation; high-salt decreases it. These effects are reversed by spironolactone or exogenous aldosterone administration, placing aldosterone upstream of the WNK-OSR1/SPAK-NCC cascade. Mouse dietary manipulation, spironolactone/aldosterone treatment, phospho-specific immunoblot Kidney international Medium 18800028
2012 ASK3 interacts with WNK1 and suppresses the WNK1-SPAK/OSR1 signaling pathway in the kidney. Knockdown of Ask3 by siRNA enhances WNK1-SPAK/OSR1 activation; Ask3 knockout mice exhibit hyperactivation of SPAK/OSR1 in renal tubules and a hypertensive phenotype. Co-immunoprecipitation, siRNA knockdown, knockout mouse model, phospho-specific immunoblot, blood pressure measurement Nature communications Medium 23250415
2012 The PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice. Increased NCC phosphorylation and blood pressure in db/db mice were completely corrected in compound knockin mice carrying the Osr1(T185A) mutation (preventing WNK-mediated OSR1 activation), demonstrating that OSR1 phosphorylation by WNK is required for NCC activation in this model. Knockin mouse model (Osr1T185A), PI3K/Akt inhibitors (NVP-BEZ235, GDC-0941, MK-2206), phospho-specific immunoblot, blood pressure measurement Hypertension High 22949526
2016 SPAK/OSR1 double-knockout mice develop severe hypokalemia under dietary potassium restriction due to inability to phosphorylate NCC, whereas single knockouts maintain plasma K+. This establishes that SPAK and OSR1 together are essential effectors of the pathway by which the distal convoluted tubule senses plasma K+ and activates NCC. Double-knockout mouse model, dietary manipulation, plasma electrolyte measurements, phospho-specific immunoblot for NCC/NKCC2 The Journal of physiology High 27068441
2016 SPAK and OSR1 kinases are packaged into exosomes and transported between cells. Exosomal OSR1 is preferentially localized at the plasma membrane after uptake and maintains NKCC1 in a phosphorylated state, demonstrating that exosome-delivered OSR1 is functionally active. Differential centrifugation exosome isolation, Western blot, immunogold electron microscopy, fluorescent protein tracking, phospho-NKCC1 immunoblot American journal of physiology. Cell physiology Low 27122160
2014 OSR1 acts in the WNK1/OSR1/NKCC1 signaling pathway in glioma cells. siRNA knockdown of OSR1 abolishes NKCC1 regulatory phospho-activation, reduces intracellular K+ and Cl- content and regulatory volume increase, and significantly decreases glioma cell migration after temozolomide treatment. siRNA knockdown, cell volume measurement, ion content assays, chemotaxis assay, live cell imaging Molecular cancer Medium 24555568
2014 In the developing kidney, Osr1 and Six2 act synergistically to prevent premature differentiation of cap mesenchyme nephron progenitors. Osr1, but not Six2, enhances TCF interaction with Groucho family transcriptional co-repressors, and loss of Osr1 results in β-catenin/TCF-mediated ectopic activation of a Wnt4 enhancer reporter. Osr1 protein forms complexes with TCF proteins. Tissue-specific conditional knockout, co-immunoprecipitation of Osr1-TCF-Groucho complexes, in vivo reporter gene assay Development (Cambridge, England) Medium 24598167
2016 Osr1 interacts with Wt1 protein in the developing kidney as shown by CRISPR-tagged endogenous Osr1. Osr1+/-;Wt1+/- double heterozygous mice exhibit metanephric kidney agenesis/hypoplasia and reduced Pax2+/Six2+ nephron progenitor cells with decreased Gdnf expression, demonstrating synergistic genetic interaction. CRISPR-mediated endogenous protein tagging, co-immunoprecipitation, double-heterozygous mouse genetics, immunofluorescence, in situ hybridization PloS one Medium 27442016
2012 In Xenopus, Osr1 and Osr2 repress Bmp4 expression in the lateral plate mesoderm, and this repression is required for Wnt2b/Wnt2b-mediated lung specification. FGF and RA signals are upstream activators of osr1/osr2 expression. Depletion of both Osr1 and Osr2 results in agenesis of lungs, trachea, and esophagus. Morpholino knockdown, in situ hybridization, epistasis analysis Development (Cambridge, England) Medium 22791896
2022 In zebrafish, the HSN2 isoform of WNK1 phosphorylates and activates OSR1, which in turn regulates neurite outgrowth through GSK3β and LHX8 transcription factor induction. HSN2 mutations from HSANII patients suppress OSR1 activation and LHX8 induction, demonstrating a WNK1(HSN2)-OSR1/GSK3β-LHX8 pathway in neuronal differentiation. In vitro kinase assay, co-immunoprecipitation, dominant-negative/mutant expression, neurite outgrowth assay, LHX8 reporter assay Scientific reports Medium 36151370

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
2008 Osr1 expression demarcates a multi-potent population of intermediate mesoderm that undergoes progressive restriction to an Osr1-dependent nephron progenitor compartment within the mammalian kidney. Developmental biology 239 18835385
2014 The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Science signaling 214 25028718
2014 The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. The Biochemical journal 177 24393035
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 WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells. Proceedings of the National Academy of Sciences of the United States of America 158 16832045
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
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
2004 Caenorhabditis elegans OSR-1 regulates behavioral and physiological responses to hyperosmotic environments. Genetics 107 15166144
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
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
2007 Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO reports 82 17721439
2014 WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- cotransporter facilitates glioma migration. Molecular cancer 80 24555568
2004 Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily. The Journal of biological chemistry 72 14707132
2014 Osr1 acts downstream of and interacts synergistically with Six2 to maintain nephron progenitor cells during kidney organogenesis. Development (Cambridge, England) 70 24598167
2018 Odd skipped-related 1 (Osr1) identifies muscle-interstitial fibro-adipogenic progenitors (FAPs) activated by acute injury. Stem cell research 64 30149291
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
2010 Effect of angiotensin II on the WNK-OSR1/SPAK-NCC phosphorylation cascade in cultured mpkDCT cells and in vivo mouse kidney. Biochemical and biophysical research communications 61 20175999
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
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
2012 The longevity effect of cranberry extract in Caenorhabditis elegans is modulated by daf-16 and osr-1. Age (Dordrecht, Netherlands) 51 22864793
2006 SPAK and OSR1, key kinases involved in the regulation of chloride transport. Acta physiologica (Oxford, England) 51 16734747
2011 Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters. Current opinion in nephrology and hypertension 49 21610494
2013 WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade. The Journal of biological chemistry 48 23386621
2012 Suppression of Bmp4 signaling by the zinc-finger repressors Osr1 and Osr2 is required for Wnt/β-catenin-mediated lung specification in Xenopus. Development (Cambridge, England) 46 22791896
2009 Crystal structure of domain-swapped STE20 OSR1 kinase domain. Protein science : a publication of the Protein Society 45 19177573
2012 OSR1-sensitive renal tubular phosphate reabsorption. Kidney & blood pressure research 44 23095210
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
2012 Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Clinical and experimental nephrology 43 22294159
2011 The zinc finger transcription factors Osr1 and Osr2 control synovial joint formation. Developmental biology 42 21262216
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
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
2011 A variant OSR1 allele which disturbs OSR1 mRNA expression in renal progenitor cells is associated with reduction of newborn kidney size and function. Human molecular genetics 38 21821672
2006 Comparative expression pattern of Odd-skipped related genes Osr1 and Osr2 in chick embryonic development. Gene expression patterns : GEP 38 16554187
2015 Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation. Journal of molecular and cellular cardiology 37 25986147
2012 Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination. Biochemical and biophysical research communications 36 22846565
2002 Molecular cloning and characterization of OSR1 on human chromosome 2p24. International journal of molecular medicine 36 12119563
2014 Curcumin-mediated oxidative stress resistance in Caenorhabditis elegans is modulated by age-1, akt-1, pdk-1, osr-1, unc-43, sek-1, skn-1, sir-2.1, and mev-1. Free radical research 35 24313805
2020 OSR1 phosphorylates the Smad2/3 linker region and induces TGF-β1 autocrine to promote EMT and metastasis in breast cancer. Oncogene 33 33051597
2012 WNK-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone. Biochemical and biophysical research communications 33 23044422
2009 Functional equivalence of the zinc finger transcription factors Osr1 and Osr2 in mouse development. Developmental biology 33 19389375
2005 Identification of RELT homologues that associate with RELT and are phosphorylated by OSR1. Biochemical and biophysical research communications 31 16389068
2017 OSR1 is a novel epigenetic silenced tumor suppressor regulating invasion and proliferation in renal cell carcinoma. Oncotarget 29 28404905
2017 Osr1 functions downstream of Hedgehog pathway to regulate foregut development. Developmental biology 28 28501478
2016 Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation. Human molecular genetics 28 26744331
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
2013 Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals. Proceedings of the National Academy of Sciences of the United States of America 27 24191005
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
2018 OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant. Proceedings of the National Academy of Sciences of the United States of America 26 29581290
2011 The Osr1 and Osr2 genes act in the pronephric anlage downstream of retinoic acid signaling and upstream of Wnt2b to maintain pectoral fin development. Development (Cambridge, England) 26 22129829
2021 Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases. Antioxidants (Basel, Switzerland) 25 33477989
2011 The nephrogenic potential of the transcription factors osr1, osr2, hnf1b, lhx1 and pax8 assessed in Xenopus animal caps. BMC developmental biology 25 21281489
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
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 Downregulation of peptide transporters PEPT1 and PEPT2 by oxidative stress responsive kinase OSR1. Kidney & blood pressure research 22 25531100
2014 osr1 is required for podocyte development downstream of wt1a. Journal of the American Society of Nephrology : JASN 21 24722440
2022 WNK1-OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy. International journal of molecular sciences 18 36292952
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
2018 Odd-skipped related transcription factor 1 (OSR1) suppresses tongue squamous cell carcinoma migration and invasion through inhibiting NF-κB pathway. European journal of pharmacology 17 30244004
2023 Dysregulation of the WNK4-SPAK/OSR1 pathway has a minor effect on baseline NKCC2 phosphorylation. American journal of physiology. Renal physiology 16 37881876
2021 High glucose-induced effects on Na+-K+-2Cl- cotransport and Na+/H+ exchange of blood-brain barrier endothelial cells: involvement of SGK1, PKCβII, and SPAK/OSR1. American journal of physiology. Cell physiology 16 33406028
2021 Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke. International journal of molecular sciences 16 33513812
2021 The nephric mesenchyme lineage of intermediate mesoderm is derived from Tbx6-expressing derivatives of neuro-mesodermal progenitors via BMP-dependent Osr1 function. Developmental biology 16 34256037
2016 Osr1 Interacts Synergistically with Wt1 to Regulate Kidney Organogenesis. PloS one 16 27442016
2021 Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice. Pflugers Archiv : European journal of physiology 15 33432425
2020 Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease. Laboratory investigation; a journal of technical methods and pathology 15 33005011
2016 The CUL3/KLHL3-WNK-SPAK/OSR1 pathway as a target for antihypertensive therapy. American journal of physiology. Renal physiology 15 27076645
2011 Generation of Osr1 conditional mutant mice. Genesis (New York, N.Y. : 2000) 15 21462293
2022 osr1 Maintains Renal Progenitors and Regulates Podocyte Development by Promoting wnt2ba via the Antagonism of hand2. Biomedicines 13 36359386
2019 The Cul4-DDB1-WDR3/WDR6 Complex Binds SPAK and OSR1 Kinases in a Phosphorylation-Dependent Manner. Chembiochem : a European journal of chemical biology 11 31614064
2012 OSR1-sensitive regulation of Na+/H+ exchanger activity in dendritic cells. American journal of physiology. Cell physiology 11 22648948
2012 The odd-skipped related genes Osr1 and Osr2 are induced by 1,25-dihydroxyvitamin D3. The Journal of steroid biochemistry and molecular biology 11 23238298
2018 C-terminal phosphorylation of SPAK and OSR1 kinases promotes their binding and activation by the scaffolding protein MO25. Biochemical and biophysical research communications 10 30060950
2015 Up-Regulation of Intestinal Phosphate Transporter NaPi-IIb (SLC34A2) by the Kinases SPAK and OSR1. Kidney & blood pressure research 10 26506223
2014 The OSR1 rs12329305 polymorphism contributes to the development of congenital malformations in cases of stillborn/neonatal death. Medical science monitor : international medical journal of experimental and clinical research 10 25164089
2023 A local subset of mesenchymal cells expressing the transcription factor Osr1 orchestrates lymph node initiation. Immunity 9 37160119
2022 WNK1/HSN2 mediates neurite outgrowth and differentiation via a OSR1/GSK3β-LHX8 pathway. Scientific reports 9 36151370
2022 Osr1 Regulates Macrophage-mediated Liver Inflammation in Nonalcoholic Fatty Liver Disease Progression. Cellular and molecular gastroenterology and hepatology 9 36581078
2021 osr1 couples intermediate mesoderm cell fate with temporal dynamics of vessel progenitor cell differentiation. Development (Cambridge, England) 9 34338289
2016 The Ste20 kinases SPAK and OSR1 travel between cells through exosomes. American journal of physiology. Cell physiology 9 27122160

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