OXSR1

Summary

OXSR1 (oxidative stress responsive kinase 1, HGNC:8508) is a protein-coding gene on chromosome 3p22.2, encoding Serine/threonine-protein kinase OSR1 (O95747). Effector serine/threonine-protein kinase component of the WNK-SPAK/OSR1 kinase cascade, which is involved in various processes, such as ion transport, response to hypertonic stress and blood pressure.

The product of this gene belongs to the Ser/Thr protein kinase family of proteins. It regulates downstream kinases in response to environmental stress, and may play a role in regulating the actin cytoskeleton.

Source: NCBI Gene 9943 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 58 total
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005109

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8508
Approved symbol	OXSR1
Name	oxidative stress responsive kinase 1
Location	3p22.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1101
Ensembl gene	ENSG00000172939
Ensembl biotype	protein_coding
OMIM	604046
Entrez	9943

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000311806, ENST00000426620, ENST00000446845, ENST00000467900, ENST00000483695, ENST00000492714, ENST00000855343, ENST00000855344

RefSeq mRNA: 1 — MANE Select: NM_005109 NM_005109

CCDS: CCDS2675

Canonical transcript exons

ENST00000311806 — 18 exons

Exon	Start	End
ENSE00001224474	38252817	38255484
ENSE00001290268	38183003	38183115
ENSE00001295015	38251403	38251471
ENSE00001304209	38236839	38236961
ENSE00001307124	38190731	38190839
ENSE00001316420	38252328	38252392
ENSE00001326005	38230365	38230430
ENSE00003460443	38224571	38224704
ENSE00003489951	38223812	38223913
ENSE00003541364	38216096	38216151
ENSE00003555998	38246075	38246221
ENSE00003559906	38249966	38250018
ENSE00003591187	38242743	38242778
ENSE00003624711	38198722	38198863
ENSE00003636794	38229687	38229735
ENSE00003656392	38221578	38221687
ENSE00003687529	38247668	38247732
ENSE00003843593	38165537	38165946

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.2921 / max 360.6979, expressed in 925 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36096	18.8517	1809
27060	13.2921	925
36097	3.2105	1201

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.62	gold quality
lower esophagus mucosa	UBERON:0035834	93.99	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.29	gold quality
pharyngeal mucosa	UBERON:0000355	92.78	gold quality
body of tongue	UBERON:0011876	92.07	gold quality
saphenous vein	UBERON:0007318	91.47	gold quality
gastrocnemius	UBERON:0001388	91.36	gold quality
embryo	UBERON:0000922	91.32	gold quality
ganglionic eminence	UBERON:0004023	91.29	gold quality
gluteal muscle	UBERON:0002000	91.20	gold quality
muscle of leg	UBERON:0001383	91.19	gold quality
esophagus mucosa	UBERON:0002469	91.18	gold quality
muscle organ	UBERON:0001630	90.82	gold quality
skeletal muscle organ	UBERON:0014892	90.82	gold quality
ventricular zone	UBERON:0003053	90.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.62	gold quality
deltoid	UBERON:0001476	90.58	gold quality
bone marrow	UBERON:0002371	90.45	gold quality
monocyte	CL:0000576	90.44	gold quality
cartilage tissue	UBERON:0002418	90.43	gold quality
mononuclear cell	CL:0000842	90.34	gold quality
secondary oocyte	CL:0000655	90.28	gold quality
skeletal muscle tissue	UBERON:0001134	90.28	gold quality
cortical plate	UBERON:0005343	90.28	gold quality
biceps brachii	UBERON:0001507	90.27	gold quality
leukocyte	CL:0000738	90.24	gold quality
tibialis anterior	UBERON:0001385	90.08	gold quality
esophagus squamous epithelium	UBERON:0006920	90.08	gold quality
oral cavity	UBERON:0000167	90.01	gold quality
epithelium of esophagus	UBERON:0001976	89.76	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

168 targeting OXSR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-545-3P	99.95	70.74	2783

Literature-anchored findings (GeneRIF, showing 36)

• interacts with cation chloride cotransporters (PMID:12386165)
• isolation and characterization of OSR1 (oxidative stress-responsive 1), one of two human Fray homologs. OSR1 is a 58-kDa protein of 527 amino acids that is widely expressed in mammalian tissues and cell lines (PMID:14707132)
• WNK1 and SPAK/OSR1 mediate the hypotonic stress signaling pathway to cation-chloride-coupled cotransporters (PMID:16263722)
• OXSR1 kinase is shown to interact with the three RELT family members RELT, RELL1, and RELL2 by in vitro co-immunoprecipitation; additionally, OXSR1 phosphorylates RELT family members in an in vitro kinase assay. (PMID:16389068)
• Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. (PMID:16669787)
• WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells. (PMID:16832045)
• These results provide the first molecular insight into the mechanism by which the SPAK and OSR1 kinases specifically recognize their upstream activators and downstream substrates. (PMID:17721439)
• Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1. (PMID:18270262)
• Structure of the OSR1 kinase, a hypertension drug target. (PMID:18831043)
• crystal structure of OSR1 kinase domain has been solved at 2.25 A; OSR1 forms a domain-swapped dimer in an inactive conformation, in which P+1 loop and alphaEF helix are swapped between dimer-related monomers (PMID:19177573)
• OXSR1 and WNK3 transcripts were substantially overexpressed in subjects with schizophrenia relative to comparison subjects. (PMID:20819979)
• Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. (PMID:21321328)
• Data show that intracellular association between WNK1 and oxidative stress-responsive 1 (OSR1) is required for stimulation of OSR1 and Na(+), K(+), Cl(-)-Cotransporter NKCC1 and NKCC2 activities by osmotic stress. (PMID:22989884)
• SPAK and OSR1, which are often coexpressed in cells, can form functional heterodimers. (PMID:23034389)
• Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals. (PMID:24191005)
• our data show a novel role for the WNK1/OSR1/NKCC1 pathway in glioma migration (PMID:24555568)
• Regulation of ClC-2 activity by SPAK and OSR1. (PMID:25323061)
• study identifies a separation of functions for the WNK1-activated protein kinases OSR1 and SPAK in mediating proliferation, invasion, and gene expression in endothelial cells (PMID:25362046)
• The CCT domain directly interacts with the kinase domain to block substrate access and inhibit the domain-swapped homodimerization of the kinase domain of OSR1. (PMID:25389294)
• Identification of the WNK-SPAK/OSR1 signaling pathway in rodent and human lenses. (PMID:25515571)
• Downregulation of peptide transporters PEPT1 and PEPT2 by oxidative stress responsive kinase OSR1. (PMID:25531100)
• Negative regulation of the creatine transporter SLC6A8 by SPAK and OSR1. (PMID:25531585)
• SPAK and OSR1 Sensitivity of Excitatory Amino Acid Transporter EAAT3. (PMID:26112741)
• SPAK and OSR1 are powerful negative regulators of the excitatory glutamate transporters EAAT1 and EAAT2. (PMID:26233565)
• Up-Regulation of Intestinal Phosphate Transporter NaPi-IIb (SLC34A2) by the Kinases SPAK and OSR1. (PMID:26506223)
• SPAK and OSR1 Sensitive Cell Membrane Protein Abundance and Activity of KCNQ1/E1 K+ Channels. (PMID:26584301)
• SPAK and OSR1 are both stimulators of Kir2.1 activity. (PMID:26673921)
• Both SPAK and OSR1 kinases entering cells through exosomes are preferentially expressed at the plasma membrane and that the kinases in exosomes are functional and maintain NKCC1 in a phosphorylated state. (PMID:27122160)
• Increased expression of proteins STAT5B, GRB2, and OXSR1 was related to a higher probability of metastasis. Multivariate analysis demonstrated that tumor grade and STAT5B were independent prognostic factors. (PMID:30054970)
• report the optimisation and expression of isotopically labelled OSR1 C-terminal domain (CTD) in E.coli and a structural model based on the sequence specific NMR assignments giving insights into the structure of apo OSR1 CTD (PMID:30894278)
• Association of OSR-1 With Vascular Dysfunction and Hypertension in Polycystic Kidney Disease. (PMID:31020807)
• The Cul4-DDB1-WDR3/WDR6 Complex Binds SPAK and OSR1 Kinases in a Phosphorylation-Dependent Manner. (PMID:31614064)
• High expression of OSR1 as a predictive biomarker for poor prognosis and lymph node metastasis in breast cancer. (PMID:32424721)
• SPAK and OSR1 kinases bind and phosphorylate the beta2-Adrenergic receptor. (PMID:32828531)
• Structures of the Human SPAK and OSR1 Conserved C-Terminal (CCT) Domains. (PMID:34726826)
• Association of genetic variants of oxidative stress responsive kinase 1 (OXSR1) with asthma exacerbations in non-smoking asthmatics. (PMID:34983467)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Oxsr1	ENSMUSG00000036737
rattus_norvegicus	Oxsr1	ENSRNOG00000013136

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP4K1 (ENSG00000104814), MAP3K8 (ENSG00000107968), MAP2K6 (ENSG00000108984), NEK4 (ENSG00000114904), STK25 (ENSG00000115694), NRK (ENSG00000123572), PAK4 (ENSG00000130669), STK26 (ENSG00000134602), TAOK3 (ENSG00000135090), PAK6 (ENSG00000137843), MINK1 (ENSG00000141503), PAK1 (ENSG00000149269), TAOK2 (ENSG00000149930), TNIK (ENSG00000154310), TAOK1 (ENSG00000160551), MAP4K2 (ENSG00000168067), MAP3K19 (ENSG00000176601), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Serine/threonine-protein kinase OSR1 — O95747 (reviewed: O95747)

Alternative names: Oxidative stress-responsive 1 protein

All UniProt accessions (3): O95747, C9JIG9, F8WBK9

UniProt curated annotations — full annotation on UniProt →

Function. Effector serine/threonine-protein kinase component of the WNK-SPAK/OSR1 kinase cascade, which is involved in various processes, such as ion transport, response to hypertonic stress and blood pressure. Specifically recognizes and binds proteins with a RFXV motif. Acts downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4): following activation by WNK kinases, catalyzes phosphorylation of ion cotransporters, such as SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A3/NCC, SLC12A5/KCC2 or SLC12A6/KCC3, regulating their activity. Mediates regulatory volume increase in response to hyperosmotic stress by catalyzing phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1 and SLC12A6/KCC3 downstream of WNK1 and WNK3 kinases. Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx; simultaneously, phosphorylation of K-Cl cotransporters SLC12A5/KCC2 and SLC12A6/KCC3 inhibit their activity, blocking ion efflux. Acts as a regulator of NaCl reabsorption in the distal nephron by mediating phosphorylation and activation of the thiazide-sensitive Na-Cl cotransporter SLC12A3/NCC in distal convoluted tubule cells of kidney downstream of WNK4. Also acts as a regulator of angiogenesis in endothelial cells downstream of WNK1. Acts as an activator of inward rectifier potassium channels KCNJ2/Kir2.1 and KCNJ4/Kir2.3 downstream of WNK1: recognizes and binds the RXFXV/I variant motif on KCNJ2/Kir2.1 and KCNJ4/Kir2.3 and regulates their localization to the cell membrane without mediating their phosphorylation. Phosphorylates RELL1, RELL2 and RELT. Phosphorylates PAK1. Phosphorylates PLSCR1 in the presence of RELT.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitously expressed in all tissue examined.

Post-translational modifications. Phosphorylation at Thr-185 by WNK kinases (WNK1, WNK2, WNK3 or WNK4) is required for activation. Autophosphorylated; promoting its activity.

Activity regulation. Activated following phosphorylation by WNK kinases (WNK1, WNK2, WNK3 or WNK4).

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.

RefSeq proteins (1): NP_005100* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR024678	Kinase_OSR1/WNK_CCT	Domain
IPR050629	STE20/SPS1-PAK	Family

Pfam: PF00069, PF12202

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (79 total): helix 19, mutagenesis site 16, strand 12, modified residue 9, turn 8, sequence variant 3, sequence conflict 3, region of interest 2, binding site 2, initiator methionine 1, chain 1, domain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7OKW	X-RAY DIFFRACTION	1.62
2V3S	X-RAY DIFFRACTION	1.7
2VWI	X-RAY DIFFRACTION	2.15
3DAK	X-RAY DIFFRACTION	2.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95747-F1	77.17	0.44

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 146 (proton acceptor)

Ligand- & substrate-binding residues (2): 23–31; 46

Post-translational modifications (9): 185, 310, 324, 325, 339, 347, 359, 427, 2

Mutagenesis-validated functional residues (16):

Position	Phenotype
46	loss of autophosphorylation and kinase activity.
46	loss of relt, rell1 and rell2 phosphorylation. retention of some autophosphorylation activity may be due to complex form
185	prevents phosphorylation and activation by wnk kinases.
185	mimics phosphorylation; promoting kinase activity independently of wnk kinases.
325	does not affect activation by wnk kinases.
325	mimics phosphorylation; slightly promoting kinase activity independently of wnk kinases.
446	decreased interaction with wnk4.
448	decreased interaction with wnk4.
449	decreased interaction with wnk4.
450	abolished interaction with wnk4.
451	decreased interaction with wnk4.
459	abolished interaction with slc12a2/nkcc1 and wnk4.
467	abolished interaction with wnk4.
468	abolished interaction with wnk4.
471	decreased interaction with wnk4.
473	abolished interaction with slc12a2/nkcc1 and wnk4.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 572 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, ATF_B, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_URETER_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GOBP_REGULATION_OF_T_CELL_CHEMOTAXIS, GOBP_METANEPHROS_DEVELOPMENT, TGCGCANK_UNKNOWN, GOBP_CARTILAGE_DEVELOPMENT

GO Biological Process (19): protein phosphorylation (GO:0006468), cell volume homeostasis (GO:0006884), response to oxidative stress (GO:0006979), signal transduction (GO:0007165), osmosensory signaling pathway (GO:0007231), response to xenobiotic stimulus (GO:0009410), positive regulation of T cell chemotaxis (GO:0010820), intracellular signal transduction (GO:0035556), chemokine (C-C motif) ligand 21 signaling pathway (GO:0038116), chemokine (C-X-C motif) ligand 12 signaling pathway (GO:0038146), protein autophosphorylation (GO:0046777), renal sodium ion absorption (GO:0070294), cellular hyperosmotic response (GO:0071474), cellular hypotonic response (GO:0071476), negative regulation of potassium ion transmembrane transport (GO:1901380), cellular response to chemokine (GO:1990869), homeostatic process (GO:0042592), cellular response to osmotic stress (GO:0071470), potassium ion transmembrane transport (GO:0071805)

GO Molecular Function (15): magnesium ion binding (GO:0000287), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), potassium channel inhibitor activity (GO:0019870), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), ion channel regulator activity (GO:0099106), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular response to osmotic stress	3
intracellular anatomical structure	2
chemokine-mediated signaling pathway	2
protein kinase activity	2
protein binding	2
cellular anatomical structure	2
phosphorylation	1
protein modification process	1
regulation of cell size	1
cellular homeostasis	1
response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signal transduction	1
response to chemical	1
T cell chemotaxis	1
regulation of T cell chemotaxis	1
positive regulation of lymphocyte chemotaxis	1
positive regulation of T cell migration	1
signal transduction	1
protein phosphorylation	1
renal sodium ion transport	1
renal absorption	1
hyperosmotic response	1
hypotonic response	1
negative regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of potassium ion transmembrane transport	1
negative regulation of cation transmembrane transport	1
cellular response to cytokine stimulus	1
response to chemokine	1
biological_process	1
response to osmotic stress	1
cellular response to chemical stress	1
cellular response to abiotic stimulus	1
potassium ion transport	1
monoatomic cation transmembrane transport	1

Protein interactions and networks

STRING

1114 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OXSR1	RELT	Q969Z4	885
OXSR1	RELL2	Q8NC24	856
OXSR1	SLC12A3	P55017	856
OXSR1	RELL1	Q8IUW5	847
OXSR1	SLC12A2	P55011	844
OXSR1	XYLB	O75191	839
OXSR1	SLC22A14	Q9Y267	836
OXSR1	SLC22A13	Q9Y226	828
OXSR1	SLC12A1	Q13621	812
OXSR1	KCNJ1	P48048	762
OXSR1	SLC12A6	Q9UHW9	720
OXSR1	CAB39	Q9Y376	715
OXSR1	PHF12	Q96QT6	693
OXSR1	WNK4	Q96J92	653
OXSR1	SLC12A5	Q9H2X9	626
OXSR1	SLC12A4	Q9UP95	626

IntAct

167 interactions, top by confidence:

A	B	Type	Score
OXSR1	RELL2	psi-mi:“MI:0915”(physical association)	0.830
RELL2	OXSR1	psi-mi:“MI:0915”(physical association)	0.830
OXSR1	WNK1	psi-mi:“MI:0915”(physical association)	0.830
OXSR1	WNK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.830
RELL2	OXSR1	psi-mi:“MI:0914”(association)	0.830
OXSR1	WNK1	psi-mi:“MI:0407”(direct interaction)	0.830
WNK1	OXSR1	psi-mi:“MI:0915”(physical association)	0.830
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
OXSR1	WNK4	psi-mi:“MI:0407”(direct interaction)	0.680
WNK4	OXSR1	psi-mi:“MI:0407”(direct interaction)	0.680

BioGRID (187): RELL2 (Two-hybrid), OXSR1 (Affinity Capture-MS), OXSR1 (Co-fractionation), OXSR1 (Co-fractionation), OXSR1 (Co-fractionation), OXSR1 (Co-fractionation), THUMPD1 (Co-fractionation), OXSR1 (Affinity Capture-MS), OXSR1 (Affinity Capture-MS), OXSR1 (Affinity Capture-MS), OXSR1 (Affinity Capture-MS), OXSR1 (Affinity Capture-MS), OXSR1 (Affinity Capture-MS), OXSR1 (Affinity Capture-MS), OXSR1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8C0TYJ0, A0A8I5ZNK2, A2AWA9, A6QQZ7, A8KBF6, O55047, O88506, O95747, P20936, P23727, P26450, P27986, P31016, P78352, Q08CW1, Q08E27, Q12959, Q15139, Q15700, Q1ECX4, Q28C55, Q5PYH5, Q5PYH6, Q5PYH7, Q5R372, Q5R495, Q5R685, Q5R6Y5, Q5RAN1, Q5RCW6, Q5SRX1, Q5T2T1, Q5U2Y3, Q5ZIL4, Q5ZMW5, Q62101, Q62108, Q62696, Q63622, Q68FK8

Diamond homologs: A0A8I5ZNK2, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, B0LT89, F1LP90, F1NBT0, G5EEN4, G5EFU0, G5EGQ3, H2L099, O00506, O14047, O14305, O23304, O24527, O54748, O61122, O61125, O75011, O75914, O88506, O88643, O95747, O95819, O96013, P08458, P35465, P83510, Q03497, Q08E52, Q0IHQ8, Q12851, Q13043, Q13153

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
OXSR1	up-regulates	SLC12A2	phosphorylation
WNK1	up-regulates	OXSR1	phosphorylation
OXSR1	up-regulates	SLC12A3	phosphorylation
OXSR1	“down-regulates activity”	PAK1	phosphorylation
OXSR1	“up-regulates activity”	SLC12A1	phosphorylation
WNK4	“up-regulates activity”	OXSR1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

58 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3426 predictions. Top by Δscore:

Variant	Effect	Δscore
3:38165937:G:GT	donor_gain	1.0000
3:38182997:TTTTA:T	acceptor_loss	1.0000
3:38182998:TTTA:T	acceptor_loss	1.0000
3:38183001:A:AG	acceptor_gain	1.0000
3:38183001:AG:A	acceptor_gain	1.0000
3:38183001:AGG:A	acceptor_gain	1.0000
3:38183002:G:GG	acceptor_gain	1.0000
3:38183002:GG:G	acceptor_gain	1.0000
3:38183002:GGG:G	acceptor_gain	1.0000
3:38183002:GGGA:G	acceptor_gain	1.0000
3:38183144:A:T	donor_gain	1.0000
3:38189500:G:GT	donor_gain	1.0000
3:38190729:A:AG	acceptor_gain	1.0000
3:38190730:G:GG	acceptor_gain	1.0000
3:38190730:GAAA:G	acceptor_gain	1.0000
3:38190839:GGTG:G	donor_loss	1.0000
3:38190840:G:GA	donor_loss	1.0000
3:38190841:TGA:T	donor_loss	1.0000
3:38190842:GAG:G	donor_loss	1.0000
3:38198713:T:TA	acceptor_gain	1.0000
3:38198718:TCA:T	acceptor_loss	1.0000
3:38198720:A:AG	acceptor_gain	1.0000
3:38198720:AG:A	acceptor_gain	1.0000
3:38198720:AGGT:A	acceptor_loss	1.0000
3:38198721:G:GA	acceptor_gain	1.0000
3:38198721:GG:G	acceptor_gain	1.0000
3:38198721:GGT:G	acceptor_gain	1.0000
3:38198721:GGTT:G	acceptor_gain	1.0000
3:38198721:GGTTC:G	acceptor_gain	1.0000
3:38198861:CAG:C	donor_gain	1.0000

AlphaMissense

3432 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:38165904:T:A	W10R	1.000
3:38165904:T:C	W10R	1.000
3:38165946:G:A	G24R	1.000
3:38165946:G:C	G24R	1.000
3:38165946:G:T	G24W	1.000
3:38183003:G:A	G24E	1.000
3:38183003:G:T	G24V	1.000
3:38183008:G:A	G26R	1.000
3:38183008:G:C	G26R	1.000
3:38183009:G:A	G26E	1.000
3:38183009:G:T	G26V	1.000
3:38183015:C:T	T28I	1.000
3:38183017:G:C	A29P	1.000
3:38183018:C:A	A29D	1.000
3:38183018:C:T	A29V	1.000
3:38183024:T:A	V31D	1.000
3:38183033:C:A	A34D	1.000
3:38183062:G:C	A44P	1.000
3:38183063:C:A	A44E	1.000
3:38183066:T:A	I45N	1.000
3:38183068:A:C	K46Q	1.000
3:38183068:A:G	K46E	1.000
3:38183069:A:C	K46T	1.000
3:38183069:A:T	K46I	1.000
3:38183070:A:C	K46N	1.000
3:38183070:A:T	K46N	1.000
3:38183072:G:C	R47P	1.000
3:38183075:T:A	I48K	1.000
3:38183075:T:C	I48T	1.000
3:38183075:T:G	I48R	1.000

dbSNP variants (sampled 300 via entrez): RS1000033372 (3:38238126 A>G), RS1000047977 (3:38250509 A>C), RS1000071933 (3:38230911 A>G), RS1000104424 (3:38212872 T>A,C), RS1000175175 (3:38222774 A>G), RS1000227393 (3:38223220 T>C), RS1000237610 (3:38222878 G>A), RS1000259975 (3:38191729 A>C,G), RS1000341159 (3:38230165 A>G,T), RS1000376905 (3:38172319 G>A), RS1000392509 (3:38243465 A>T), RS1000435011 (3:38179854 G>A), RS1000485100 (3:38194011 A>G), RS1000500287 (3:38209494 G>A), RS1000521186 (3:38175828 CAGA>C)

Disease associations

OMIM: gene MIM:604046 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003875_38	Gut microbiota (bacterial taxa)	6.000000e-09
GCST005992_30	Mean corpuscular hemoglobin concentration	2.000000e-08
GCST90002387_68	Immature fraction of reticulocytes	3.000000e-09
GCST90002392_188	Mean corpuscular volume	8.000000e-18
GCST90002396_193	Mean reticulocyte volume	3.000000e-23
GCST90002397_651	Mean spheric corpuscular volume	3.000000e-20
GCST90002404_44	Red cell distribution width	1.000000e-12

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0010701	mean reticulocyte volume
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1163104 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 102,363 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL230011	TG100-115	2	1,504
CHEMBL475251	R-406	2	762
CHEMBL1908397	KW-2449	1	622

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — FRAY subfamily

ChEMBL bioactivities

17 potent at pChembl≥5 of 17 total, top 16 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.32	IC50	47.4	nM	STAUROSPORINE
7.32	Kd	48	nM	TAE-684
6.36	Kd	440	nM	STAUROSPORINE
6.28	Kd	530	nM	SUNITINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.89	Kd	1300	nM	NINTEDANIB
5.80	Kd	1600	nM	SU-014813
5.77	Kd	1700	nM	KW-2449
5.60	Kd	2500	nM	TG100-115
5.57	Kd	2700	nM	RUXOLITINIB
5.51	Kd	3100	nM	R-406
5.41	Kd	3900	nM	PLX-4720
5.38	Kd	4200	nM	CHEMBL464552
5.10	Kd	8000	nM	LESTAURTINIB

PubChem BioAssay actives

14 with measured affinity, of 308 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	2198349: Inhibition of human OSR1 using RRHYYYDTHTNTYYLRTFGHNTRR as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.0474	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624977: Binding constant for OSR1 kinase domain	kd	0.0480	uM
Sunitinib	507651: Binding affinity to OSR1	kd	0.5300	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624977: Binding constant for OSR1 kinase domain	kd	1.3000	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624977: Binding constant for OSR1 kinase domain	kd	1.6000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624977: Binding constant for OSR1 kinase domain	kd	1.7000	uM
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	624977: Binding constant for OSR1 kinase domain	kd	2.5000	uM
Ruxolitinib	624977: Binding constant for OSR1 kinase domain	kd	2.7000	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624977: Binding constant for OSR1 kinase domain	kd	3.1000	uM
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide	624977: Binding constant for OSR1 kinase domain	kd	3.9000	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	624977: Binding constant for OSR1 kinase domain	kd	4.2000	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	624977: Binding constant for OSR1 kinase domain	kd	8.0000	uM

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	3
Mustard Gas	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
2,4,6-tribromophenol	increases expression	1
bisphenol A	increases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	affects binding, affects reaction, increases reaction, decreases expression	1
tetrabromobisphenol A	increases expression	1
benzo(e)pyrene	decreases methylation	1
cadmium sulfide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
vanadium pentoxide	decreases expression	1
chloropicrin	increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
nutlin 3	increases secretion, affects cotreatment	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Aerosols	increases expression	1
Arsenic	increases expression, affects cotreatment	1
Cisplatin	increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dinitrochlorobenzene	affects binding	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1

ChEMBL screening assays

107 unique, capped per target: 107 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1166598	Binding	Inhibition of OSR1 at 1 uM	Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1PG	Abcam K-562 OXSR1 KO	Cancer cell line	Female
CVCL_D2L2	Abcam Raji OXSR1 KO	Cancer cell line	Male
CVCL_E1N9	HyCyte U-251MG KO-hOXSR1	Cancer cell line	Male
CVCL_WQ19	Abcam Jurkat OXSR1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.