SGK3

Summary

SGK3 (serum/glucocorticoid regulated kinase family member 3, HGNC:10812) is a protein-coding gene on chromosome 8q13.1, encoding Serine/threonine-protein kinase Sgk3 (Q96BR1). Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, proliferation, survival and migration.

This gene is a member of the Ser/Thr protein kinase family and encodes a phosphoprotein with a PX (phox homology) domain. The protein phosphorylates several target proteins and has a role in neutral amino acid transport and activation of potassium and chloride channels. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 23678 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypophosphatemic rickets (Limited, GenCC)
• GWAS associations: 3
• Druggable target: yes — 13 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001033578

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10812
Approved symbol	SGK3
Name	serum/glucocorticoid regulated kinase family member 3
Location	8q13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000104205
Ensembl biotype	protein_coding
OMIM	607591
Entrez	23678

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 38 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000345714, ENST00000396596, ENST00000494528, ENST00000518388, ENST00000519396, ENST00000520976, ENST00000521152, ENST00000521198, ENST00000521435, ENST00000521960, ENST00000522398, ENST00000522629, ENST00000523260, ENST00000523401, ENST00000894045, ENST00000894046, ENST00000894047, ENST00000894048, ENST00000894049, ENST00000894050, ENST00000894051, ENST00000894052, ENST00000894053, ENST00000894054, ENST00000894055, ENST00000894056, ENST00000894057, ENST00000894058, ENST00000894059, ENST00000894060, ENST00000917829, ENST00000952508, ENST00000952509, ENST00000952510, ENST00000952511, ENST00000952512, ENST00000952513, ENST00000952514, ENST00000952515, ENST00000952516, ENST00000952517, ENST00000952518

RefSeq mRNA: 3 — MANE Select: NM_001033578 NM_001033578, NM_013257, NM_170709

CCDS: CCDS6196

Canonical transcript exons

ENST00000521198 — 17 exons

Exon	Start	End
ENSE00002100302	66712781	66712833
ENSE00002124835	66859411	66862022
ENSE00003898042	66828654	66828703
ENSE00003898068	66798542	66798625
ENSE00003898103	66840211	66840247
ENSE00003898111	66793616	66793832
ENSE00003898211	66831254	66831311
ENSE00003898272	66840003	66840115
ENSE00003898285	66843452	66843547
ENSE00003898315	66804375	66804447
ENSE00003898406	66822372	66822459
ENSE00003898462	66813853	66813928
ENSE00003898544	66835943	66836074
ENSE00003898649	66847193	66847348
ENSE00003898691	66835763	66835846
ENSE00003898809	66850831	66850920
ENSE00003898830	66841024	66841110

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 98.49.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4979 / max 108.5483, expressed in 72 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89217	4.5724	1104
89216	3.7729	1152
184666	0.7512	108
184669	0.4979	72
89220	0.4752	257
184664	0.4477	81
89215	0.3650	165
89219	0.2129	102
89218	0.1355	25
89214	0.0808	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	98.49	gold quality
corpus callosum	UBERON:0002336	96.66	gold quality
inferior vagus X ganglion	UBERON:0005363	96.00	gold quality
kidney epithelium	UBERON:0004819	95.88	gold quality
ileal mucosa	UBERON:0000331	95.34	gold quality
subthalamic nucleus	UBERON:0001906	94.81	gold quality
upper arm skin	UBERON:0004263	93.86	gold quality
substantia nigra pars reticulata	UBERON:0001966	93.52	gold quality
jejunal mucosa	UBERON:0000399	93.42	gold quality
medulla oblongata	UBERON:0001896	93.38	gold quality
skin of hip	UBERON:0001554	92.81	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.61	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.49	gold quality
lateral globus pallidus	UBERON:0002476	92.40	gold quality
superior vestibular nucleus	UBERON:0007227	92.19	gold quality
dorsal plus ventral thalamus	UBERON:0001897	91.89	gold quality
colonic mucosa	UBERON:0000317	91.78	gold quality
monocyte	CL:0000576	91.42	gold quality
substantia nigra pars compacta	UBERON:0001965	91.42	gold quality
pons	UBERON:0000988	91.36	gold quality
spinal cord	UBERON:0002240	91.29	gold quality
upper leg skin	UBERON:0004262	91.09	gold quality
caput epididymis	UBERON:0004358	91.00	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.97	gold quality
leukocyte	CL:0000738	90.80	gold quality
trabecular bone tissue	UBERON:0002483	90.71	gold quality
bronchial epithelial cell	CL:0002328	90.60	gold quality
layer of synovial tissue	UBERON:0007616	90.58	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.45	silver quality
left ventricle myocardium	UBERON:0006566	90.38	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

166 targeting SGK3, 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-126-5P	100.00	72.71	3180
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548P	99.98	72.25	3784
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-4803	99.98	71.99	3117
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821

Literature-anchored findings (GeneRIF, showing 40)

• Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction (PMID:12054501)
• low steady-state expression level of SGK-1 is due to polyubiquitination and subsequent degradation by the 26S proteasome (PMID:12218062)
• Powerful stimulating effect of all three isoforms of SGK on K(+) channels. Those effects may participate in regulation of epithelial transport, cell proliferation, and neuromuscular excitability. (PMID:12397388)
• The stimulating effect of SGK1 on the Xenopus oocyte Na(+)/K(+)-ATPase is mimicked by the isoforms SGK2 and SGK3 (PMID:12590200)
• SGK2 and SGK3 mimic the function of SGK1 and are likely to participate in the regulation of ENaC activity. (PMID:12632189)
• All three members of the SGK family of kinases SGK1-3 and protein kinase B stimulate the slowly activating K(+) channel KCNE1/KCNQ1. The kinases may thus participate in the regulation of KCNE1-dependent transport and excitability. (PMID:12634932)
• peroxisomal targeting signal (PTS)-tagged CISK with deleted PX domain was able to direct 3-phosphoinositide-dependent protein kinase-1 (PDK-1) into peroxisomes (PMID:14604990)
• ClC-Ka/barttin channels are regulated by SGK1 and SGK3, which may thus participate in the regulation of transport in kidney and inner ear. (PMID:15496163)
• Co-expression of SGK1, but not of SGK2 or SGK3, increased Kv 4.3/KChIP2b channel currents. (PMID:15578212)
• In conclusion, the kinases SGK1 and SGK3 increase EAAT5 activity by increasing cell surface abundance of the carrier. (PMID:15737648)
• SGK1 and SGK3 increase SLC6A8 activity by increasing the maximal transport rate of the carrier. Deranged SGK1 and/or SGK3 dependent regulation of SLC6A8 may affect energy storage particularly in skeletal muscle, heart, and neurons (PMID:16036218)
• SGK3 and stargazin regulate GluR1 independently, and thus, their effects on glutamate-induced currents are additive. (PMID:16485113)
• Targeting of SGK3 to endosomes, mediated by its Phox homology domain, is essential for proper SGK3 activation. (PMID:16790420)
• CISK plays an important role in specifically attenuating ubiquitin-dependent degradation of CXCR4, and provide a mechanistic link between the PI 3-kinase pathway and CXCR4 stability. (PMID:16888620)
• SGK3 participates in the regulation of HERG by increasing HERG protein abundance in the plasma membrane and may thus modify the duration of the cardiac action potential. (PMID:17167223)
• These findings support the model that CISK phosphorylates FLII and activates nuclear receptor transcription and suggest a new cell survival signaling pathway mediated by PI 3-kinase and CISK. (PMID:19293151)
• Glucocorticoid inducible kinase isoforms SGK1-3 are novel potent stimulators of Slc6a19 and may thus participate in the regulation of neutral amino acid transport in vivo. (PMID:20511718)
• SGK3 is not required for insulin-induced PFK-2 activation and that this effect is likely mediated by PKBalpha. (PMID:20687898)
• SGK3 is an estrogen receptor (ER) transcriptional target and promotes estrogen-mediated cell survival of ER-positive breast cancer cells. (PMID:21084382)
• found that expression of SGK3, which like AKT is activated by PI3K/PDK1 signaling, has more significance than overexpression of AKT in predicting poor outcome in hepatocellular carcinoma patients (PMID:22262416)
• A positive correlation between SGK3 expression and breast tumor prognosis. (PMID:22576469)
• SGK1,3 enhances the expression level of mature hERG channels by inhibiting Nedd4-2 as well as by promoting Rab11-mediated hERG recycling. (PMID:23589291)
• SGK3 stability and kinase activation are regulated by the Hsp90-Cdc37 chaperone complex. (PMID:24379398)
• SGK3 is a novel regulator of K(ir)2.1. (PMID:24556932)
• SGK3 is an androgen receptor (AR) target and induces cell proliferation through the AR-SGK3-p70S6K-cyclin D1 pathway in prostate cancer cells. (PMID:24739041)
• VPS34-IN1 will provide a useful tool to decipher the kinase-dependent functions of Vps34, with acute changes in SGK3 phosphorylation and subcellular localization being new biomarkers of Vps34 activity (PMID:25395352)
• Breast cancers harboring oncogenic PIK3CA activate SGK3 signaling while suppressing Akt, indicative of oncogenic functions for both INPP4B and SGK3 in these tumors. (PMID:25458846)
• SGK3 is a key mediator of PDK1 activity in melanoma. (PMID:25712345)
• It is unlikely that SGK3 plays a significant role for oncogenic signalling in multiple myeloma. (PMID:25837824)
• Data show that activation of serum- and glucocorticoid-regulated kinase 3 (SGK3) plays an important role in inositol polyphosphate 4-phosphatase type II (INPP4B)-mediated melanoma cell proliferation. (PMID:26573229)
• These findings highlight the importance of the hVps34-SGK3 pathway in counteracting inhibition of PI3K/Akt signalling. (PMID:27481935)
• High SGK3 expression is associated with epithelial-mesenchymal transition in hepatocellular carcinoma. (PMID:27602769)
• SGK3 a kinase transcriptionally regulated by estrogen receptor alpha (ERalpha) in breast cancer, sustains ERalpha signaling and drives the acquired aromatase inhibitors resistance by protecting against endoplasmic reticulum (EnR) stress-induced ERalpha downregulation and cell death through preserving SERCA2b function. (PMID:28174265)
• Hence, we concluded that miR1443p, which is frequently downregulated in hepatocellular carcinoma (HCC) can inhibit proliferation, migration and repress angiogenesis by regulating SGK3 activation with PI3K independent signal pathway, and acts as a prognostic factor for HCC patients. (PMID:28849156)
• Mechanism of activation of SGK3 by IGF1 via the class 1 and class 3 phosphatidylinositol 3-kinases has been described. (PMID:29150437)
• overexpression of INPP4B promotes NPM1-mutated leukemia cell proliferation through SGK3 activation. High levels of INPP4B are at least partially induced by the NPM1 mutant via ERK/Ets-1 signaling. (PMID:29343273)
• In patients with polycystic ovary syndrome, miR-335-5p is involved in granulosa cells proliferation by reducing SGK3 expression. (PMID:30328340)
• Study data from human hepatocellular carcinoma (HCC) liver samples, human HCC cells, and Sgk3 knockout mice model suggest that SGK3 plays a role in transducing helical domain mutant PIK3CA signaling during liver tumor development. (PMID:30975125)
• Mutation of SGK3, a Novel Regulator of Renal Phosphate Transport, Causes Autosomal Dominant Hypophosphatemic Rickets. (PMID:31821448)
• MiR-377-3p inhibits cell metastasis and epithelial-mesenchymal transition in cervical carcinoma through targeting SGK3. (PMID:32432732)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sgk3	ENSDARG00000062460
mus_musculus	Sgk3	ENSMUSG00000025915
rattus_norvegicus	Sgk3	ENSRNOG00000049052
caenorhabditis_elegans		WBGENE00004789

Paralogs (13): MAST4 (ENSG00000069020), MAST2 (ENSG00000086015), MAST3 (ENSG00000099308), SGK2 (ENSG00000101049), DMPK (ENSG00000104936), MAST1 (ENSG00000105613), SGK1 (ENSG00000118515), MASTL (ENSG00000120539), LATS1 (ENSG00000131023), LATS2 (ENSG00000150457), STK32B (ENSG00000152953), STK32C (ENSG00000165752), STK32A (ENSG00000169302)

Protein

Protein identifiers

Serine/threonine-protein kinase Sgk3 — Q96BR1 (reviewed: Q96BR1)

Alternative names: Cytokine-independent survival kinase, Serum/glucocorticoid-regulated kinase 3, Serum/glucocorticoid-regulated kinase-like

All UniProt accessions (6): E5RHR8, E5RHX2, E5RHY6, E5RJV7, Q96BR1, E5RK28

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, proliferation, survival and migration. Up-regulates Na(+) channels: SCNN1A/ENAC and SCN5A, K(+) channels: KCNA3/KV1.3, KCNE1, KCNQ1 and KCNH2/HERG, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channel: BSND, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, amino acid transporters: SLC1A5/ASCT2 and SLC6A19, glutamate transporters: SLC1A3/EAAT1, SLC1A6/EAAT4 and SLC1A7/EAAT5, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase. Plays a role in the regulation of renal tubular phosphate transport and bone density. Phosphorylates NEDD4L and GSK3B. Positively regulates ER transcription activity through phosphorylation of FLII. Negatively regulates the function of ITCH/AIP4 via its phosphorylation and thereby prevents CXCR4 from being efficiently sorted to lysosomes.

Subunit / interactions. Interacts with GSK3B and FLII. Interacts with PDPK1 in a phosphorylation-dependent manner.

Subcellular location. Cytoplasmic vesicle. Early endosome. Recycling endosome.

Tissue specificity. Expressed in most tissues with highest levels in pancreas, kidney liver, heart and brain and lower levels in lung, placenta and skeletal muscle. Expression is higher in ER-positive breast tumors than ER-negative breast tumors.

Post-translational modifications. Activated by phosphorylation on Ser-486 by an unknown kinase (may be mTORC2 but not confirmed), transforming it into a substrate for PDPK1 which then phosphorylates it on Thr-320.

Activity regulation. Two specific sites, one in the kinase domain (Thr-320) and the other in the C-terminal regulatory region (Ser-486), need to be phosphorylated for its full activation.

Induction. Induced by estrogen/ER in breast cancer cells.

Similarity. Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96BR1-1	1	yes
Q96BR1-2	2

RefSeq proteins (3): NP_001028750, NP_037389, NP_733827 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR000961	AGC-kinase_C	Domain
IPR001683	PX_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR017892	Pkinase_C	Domain
IPR036871	PX_dom_sf	Homologous_superfamily
IPR037709	SGK3_dom	Domain
IPR037900	CISK_PX	Domain

Pfam: PF00069, PF00433, PF00787

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 (36 total): helix 6, sequence conflict 5, modified residue 4, domain 3, mutagenesis site 3, strand 3, binding site 2, sequence variant 2, region of interest 2, compositionally biased region 2, chain 1, splice variant 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6EDX	X-RAY DIFFRACTION	2.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BR1-F1	83.74	0.55

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): 286 (proton acceptor)

Ligand- & substrate-binding residues (2): 168–176; 191

Post-translational modifications (4): 126, 129, 320, 486

Mutagenesis-validated functional residues (3):

Position	Phenotype
90	partially localized to the membrane.
191	abolishes activity.
486	increased activation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-382551	Transport of small molecules
R-HSA-983712	Ion channel transport

MSigDB gene sets: 328 (showing top): HNF3ALPHA_Q6, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_GROWTH, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, HNF1_Q6, CTATGCA_MIR153, CAGCTG_AP4_Q5, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_NEGATIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, TCF4_Q5, GGGCATT_MIR365, CATTTCA_MIR203

GO Biological Process (7): regulation of cell growth (GO:0001558), intracellular signal transduction (GO:0035556), regulation of cell population proliferation (GO:0042127), negative regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001240), protein phosphorylation (GO:0006468), regulation of cell migration (GO:0030334), obsolete regulation of DNA-binding transcription factor activity (GO:0051090)

GO Molecular Function (13): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), calcium channel regulator activity (GO:0005246), ATP binding (GO:0005524), potassium channel regulator activity (GO:0015459), sodium channel regulator activity (GO:0017080), chloride channel regulator activity (GO:0017081), phosphatidylinositol binding (GO:0035091), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (6): early endosome (GO:0005769), cytosol (GO:0005829), recycling endosome (GO:0055037), cytoplasm (GO:0005737), endosome (GO:0005768), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ion channel regulator activity	4
intracellular anatomical structure	2
protein kinase activity	2
endosome	2
cytoplasm	2
cellular anatomical structure	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
signal transduction	1
cell population proliferation	1
regulation of cellular process	1
extrinsic apoptotic signaling pathway in absence of ligand	1
negative regulation of signal transduction in absence of ligand	1
negative regulation of extrinsic apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1
phosphorylation	1
protein modification process	1
cell migration	1
regulation of cell motility	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
calcium channel activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
potassium channel activity	1
sodium channel activity	1
chloride channel activity	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
endomembrane system	1
cytoplasmic vesicle	1
intracellular vesicle	1

Protein interactions and networks

STRING

1719 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SGK3	UBE2G1	P62253	770
SGK3	ASIC1	P78348	707
SGK3	INPP4B	O15327	605
SGK3	IGF1	P01343	603
SGK3	SNX3	O60493	585
SGK3	NDRG1	Q92597	568
SGK3	TP53	P04637	521
SGK3	PIK3CA	P42336	515
SGK3	EGFR	P00533	496
SGK3	SYVN1	Q86TM6	493
SGK3	NEDD4L	Q96PU5	484
SGK3	PDPK1	O15530	475
SGK3	TRIB3	Q96RU7	459
SGK3	PLCG1	P19174	440
SGK3	NR3C1	P04150	433

IntAct

29 interactions, top by confidence:

A	B	Type	Score
ITCH	SGK3	psi-mi:“MI:0915”(physical association)	0.640
SGK3	ITCH	psi-mi:“MI:0915”(physical association)	0.640
ITCH	SGK3	psi-mi:“MI:0217”(phosphorylation reaction)	0.640
ITCH	SGK3	psi-mi:“MI:0403”(colocalization)	0.640
	SGK3	psi-mi:“MI:0407”(direct interaction)	0.600
SGK3	CDC37	psi-mi:“MI:0914”(association)	0.530
SMCO1	SGK3	psi-mi:“MI:0915”(physical association)	0.490
SGK3	SMCO1	psi-mi:“MI:0915”(physical association)	0.490
SGK3	PDK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.490
SGK3	PDK1	psi-mi:“MI:0403”(colocalization)	0.490
HSP90AB1	SGK3	psi-mi:“MI:0915”(physical association)	0.400
SGK3	GSK3B	psi-mi:“MI:0915”(physical association)	0.370
ICAM1	RTL8C	psi-mi:“MI:0914”(association)	0.350
CD79B	GOLIM4	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
ROCK2	CLTB	psi-mi:“MI:0914”(association)	0.350
ULK1	HNRNPCL1	psi-mi:“MI:0914”(association)	0.350
SGK3	AIP	psi-mi:“MI:0914”(association)	0.350
SGK2	AIP	psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
AMHR2	ZFPL1	psi-mi:“MI:0914”(association)	0.350
CYP19A1	KLHL7	psi-mi:“MI:0914”(association)	0.350
AMHR2	ILVBL	psi-mi:“MI:0914”(association)	0.350
gatB	SGK3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (80): SGK3 (Affinity Capture-MS), SGK3 (Affinity Capture-MS), SGK3 (Two-hybrid), GSK3B (Two-hybrid), GSK3B (Affinity Capture-Western), CDC37 (Affinity Capture-MS), SGK3 (Affinity Capture-MS), DNLZ (Affinity Capture-MS), HSP90AA4P (Affinity Capture-MS), CTNNBIP1 (Affinity Capture-MS), SGK3 (Affinity Capture-MS), SGK3 (Affinity Capture-MS), SGK3 (Affinity Capture-Western), SGK3 (Affinity Capture-MS), SGK3 (Affinity Capture-MS)

ESM2 similar proteins: A7MB74, A8XJQ6, A8XNJ6, O00141, O55173, O75582, P05986, P10665, P10666, P18652, P18653, P18654, P21901, P51812, Q02111, Q04759, Q05655, Q06226, Q12706, Q15349, Q15418, Q2PJ68, Q4R633, Q5BKK4, Q5F3L1, Q5PU49, Q5Q0U5, Q5R4K3, Q5R7A7, Q63531, Q6GLY8, Q6GPN6, Q6PFQ0, Q6U1I9, Q7JP68, Q7TPS0, Q7ZTW4, Q8C050, Q8R4U9, Q8R4V0

Diamond homologs: A1A4I4, A1Z7T0, A1Z9X0, A7MBL8, A8KBH6, A8WUG4, F1M7Y5, O08874, O19111, O42632, P04409, P05126, P05128, P05129, P05130, P05696, P05771, P05772, P09215, P09216, P09217, P10102, P10829, P10830, P13677, P13678, P16054, P17252, P20444, P23298, P24583, P24723, P28867, P31748, P31749, P31750, P31751, P34722, P34885, P36582

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
PDPK1	up-regulates	SGK3	phosphorylation
SGK3	up-regulates	FLII	phosphorylation
SGK3	“down-regulates activity”	FOXO3	phosphorylation
SGK3	“down-regulates activity”	GSK3A	phosphorylation
SGK3	“down-regulates activity”	GSK3B	phosphorylation
SGK3	“down-regulates activity”	FOXO	phosphorylation
“2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid”	“down-regulates activity”	SGK3	“chemical inhibition”
SGK3	“up-regulates activity”	SCN5A	phosphorylation
SGK3	“up-regulates activity”	PIKFYVE	phosphorylation
SGK3	“down-regulates activity”	NDRG1	phosphorylation
SGK3	“down-regulates quantity by destabilization”	PTOV1	phosphorylation
SGK3	“up-regulates activity”	TSC2	phosphorylation
SGK3	“down-regulates activity”	ARL6IP4	phosphorylation
SGK3	“down-regulates activity”	NEDD4L	phosphorylation
PDPK1	“up-regulates activity”	SGK3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
protein phosphorylation	5	18.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

5874 predictions. Top by Δscore:

Variant	Effect	Δscore
20:43559157:CAG:C	donor_loss	1.0000
20:43559158:AG:A	donor_loss	1.0000
20:43559159:GGTG:G	donor_loss	1.0000
20:43559160:G:T	donor_loss	1.0000
20:43559161:T:G	donor_loss	1.0000
20:43567066:A:AG	acceptor_gain	1.0000
20:43567067:G:GG	acceptor_gain	1.0000
20:43567118:G:GG	donor_gain	1.0000
20:43567659:CCCCA:C	acceptor_gain	1.0000
20:43567660:CCCA:C	acceptor_gain	1.0000
20:43567660:CCCAG:C	acceptor_gain	1.0000
20:43567661:CCAG:C	acceptor_gain	1.0000
20:43567662:CA:C	acceptor_gain	1.0000
20:43567662:CAG:C	acceptor_gain	1.0000
20:43567663:A:AG	acceptor_gain	1.0000
20:43567663:A:C	acceptor_gain	1.0000
20:43567663:AGT:A	acceptor_gain	1.0000
20:43567663:AGTGC:A	acceptor_gain	1.0000
20:43567664:G:A	acceptor_gain	1.0000
20:43567664:G:GT	acceptor_gain	1.0000
20:43567664:G:T	acceptor_gain	1.0000
20:43567664:GT:G	acceptor_gain	1.0000
20:43567664:GTG:G	acceptor_gain	1.0000
20:43567664:GTGC:G	acceptor_gain	1.0000
20:43567664:GTGCC:G	acceptor_gain	1.0000
20:43567718:GGAAG:G	donor_gain	1.0000
20:43567719:GAAG:G	donor_gain	1.0000
20:43567719:GAAGG:G	donor_gain	1.0000
20:43567721:AGGTG:A	donor_loss	1.0000
20:43567723:G:GG	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000003612 (8:66716463 C>T), RS1000011288 (8:66719295 T>C), RS1000053923 (8:66826866 A>T), RS1000058816 (8:66810320 G>C,T), RS1000066809 (8:66837302 G>A), RS1000106389 (8:66820421 G>T), RS1000111819 (8:66723299 C>G), RS1000141585 (8:66776930 A>G), RS1000146337 (8:66733329 A>G), RS1000146918 (8:66786716 G>T), RS1000157971 (8:66860587 C>A,T), RS1000164643 (8:66754734 C>T), RS1000192886 (8:66849922 T>TA), RS1000215298 (8:66715332 A>G), RS1000257924 (8:66807037 G>A)

Disease associations

OMIM: gene MIM:607591 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hypophosphatemic rickets	Limited	Autosomal dominant

Mondo (1): hypophosphatemic rickets (MONDO:0024300)

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010796_1551	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-09
GCST010796_1552	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_1553	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D063730	Rickets, Hypophosphatemic	C05.116.198.816.875; C18.452.104.816.875; C18.452.174.845.875; C18.452.750.400.750; C18.654.521.500.133.770.734.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5169074 (PROTEIN-PROTEIN INTERACTION), CHEMBL6186 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

13 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 111,600 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1721885	SU-014813	2	363
CHEMBL1908397	KW-2449	1	622
CHEMBL3544960	AT-13148	1	779
CHEMBL494089	GSK-690693	1	2,061
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — SGK family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
Sanofi-14h	Inhibition	8.4	pIC50
compound 14n [PMID: 25589934]	Inhibition	5.51	pIC50

ChEMBL bioactivities

31 potent at pChembl≥5 of 32 total, top 31 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.47	Kd	3.4	nM	STAUROSPORINE
8.24	Kd	5.8	nM	LESTAURTINIB
7.30	IC50	50	nM	AT-13148
7.16	IC50	69.6	nM	STAUROSPORINE
7.12	IC50	76.5	nM	STAUROSPORINE
7.03	IC50	93.6	nM	STAUROSPORINE
7.02	Kd	96	nM	KW-2449
6.82	Kd	150	nM	AST-487
6.68	IC50	211	nM	CHEMBL5082336
6.66	Kd	220	nM	SUNITINIB
6.60	Kd	250	nM	SU-014813
6.52	IC50	300	nM	CHEMBL4795354
6.50	IC50	320	nM	GSK-650394
6.49	Kd	322	nM	CHEMBL4465866
6.47	Kd	338	nM	CHEMBL4576489
6.22	IC50	600	nM	CHEMBL5465169
6.02	Kd	960	nM	DOVITINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
6.00	Kd	1000	nM	NINTEDANIB
5.85	Kd	1400	nM	MIDOSTAURIN
5.85	Kd	1400	nM	RUBOXISTAURIN
5.72	Kd	1900	nM	LINIFANIB
5.72	Kd	1900	nM	GSK-690693
5.71	IC50	1950	nM	CHEMBL6144807
5.60	Kd	2500	nM	FEDRATINIB
5.51	IC50	3100	nM	CHEMBL3092468
5.29	IC50	5170	nM	CHEMBL6159908
5.29	Kd	5100	nM	CHEMBL379218
5.14	Kd	7200	nM	PLX-4720

PubChem BioAssay actives

47 with measured affinity, of 1172 total; 21 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	625073: Binding constant for SGK3 kinase domain	kd	0.0034	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	625073: Binding constant for SGK3 kinase domain	kd	0.0058	uM
(1S)-2-amino-1-(4-chlorophenyl)-1-[4-(1H-pyrazol-4-yl)phenyl]ethanol	1953195: Inhibition of SGK3 (unknown origin)	ic50	0.0500	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625073: Binding constant for SGK3 kinase domain	kd	0.0960	uM
(2S,4R)-1-[(2S)-2-tert-butyl-5-[2-[2-[6-[(2S)-2-[2-[6-[4-[(2-fluoro-5-methylphenyl)sulfonylamino]phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl]ethyl]morpholin-4-yl]hexoxy]ethoxy]ethoxy]-4-oxopentanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1849935: PROTAC activity at VHL/SGK3 (unknown origin) assessed as induction of SGK3 degradation incubated for 2 hrs by cell based assay	ec50	0.1000	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	625073: Binding constant for SGK3 kinase domain	kd	0.1500	uM
N-[4-(3-amino-2H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-5-chloro-2-cyanobenzenesulfonamide	1821046: Inhibition of human SGK3 in presence 500 uM presence of ATP	ic50	0.2110	uM
Sunitinib	625073: Binding constant for SGK3 kinase domain	kd	0.2200	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	625073: Binding constant for SGK3 kinase domain	kd	0.2500	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526232: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged SGK3 (unknown origin) (119 to 496 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.3220	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526232: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged SGK3 (unknown origin) (119 to 496 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.3380	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	625073: Binding constant for SGK3 kinase domain	kd	0.9600	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625073: Binding constant for SGK3 kinase domain	kd	1.0000	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	625073: Binding constant for SGK3 kinase domain	kd	1.4000	uM
Midostaurin	625073: Binding constant for SGK3 kinase domain	kd	1.4000	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	625073: Binding constant for SGK3 kinase domain	kd	1.9000	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	625073: Binding constant for SGK3 kinase domain	kd	1.9000	uM
Fedratinib	625073: Binding constant for SGK3 kinase domain	kd	2.5000	uM
N-[4-(3-amino-2H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluorobenzenesulfonamide	1177303: Inhibition of human SGK3 in presence of 500 uM ATP	ic50	3.1000	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	625073: Binding constant for SGK3 kinase domain	kd	5.1000	uM
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide	625073: Binding constant for SGK3 kinase domain	kd	7.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	8
Benzo(a)pyrene	affects methylation, decreases expression	4
Aflatoxin B1	decreases methylation, affects expression, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	decreases expression, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	affects cotreatment, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, affects methylation	2
Estradiol	increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Tretinoin	increases expression	2
FR900359	increases phosphorylation	1
testosterone enanthate	affects expression	1
afimoxifene	decreases response to substance	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
CGP 52608	increases reaction, affects binding	1
2-palmitoylglycerol	increases expression	1
K 7174	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
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	affects cotreatment, decreases phosphorylation	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	decreases expression	1
Glyphosate	decreases expression	1

ChEMBL screening assays

265 unique, capped per target: 264 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5104657	Binding	PROTAC activity at VHL/SGK3 (unknown origin) assessed as induction of SGK3 degradation incubated for 2 hrs by cell based assay	Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges. — Eur J Med Chem
CHEMBL5464245	Functional	SGK3 degradation assay at 100 nM (48 h incubation, no effect on RPS6KB1, SGK1 and SGK2)	Data for DCP probe SGK3-PROTAC1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TK90	HAP1 SGK3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01237288	PHASE3	COMPLETED	Therapeutic Use of Oral Sodium Phosphate (Z-521) in Primary Hypophosphatemic Rickets
NCT03581591	PHASE3	COMPLETED	Open Label Trial Assessing Safety and Efficacy of Burosumab (KRN23), in a Patient With ENS and Hypophosphatemic Rickets
NCT00473187	PHASE1	UNKNOWN	Effects of GH on Body Proportions and Final Height in X-Linked Hypophosphatemic Rickets
NCT03748966	EARLY_PHASE1	COMPLETED	Calcitriol Monotherapy for X-Linked Hypophosphatemia
NCT00844740	Not specified	WITHDRAWN	Calcimimetics in Hypophosphatemic Rickets
NCT01578824	Not specified	COMPLETED	Assessment Of Vitamin D Role In The Pathogenesis Of Asthma In Vitamin D Resistent Patients
NCT03348644	Not specified	COMPLETED	Milk Products in the Treatment of Hypophosphatemic Rickets
NCT03651505	Not specified	ACTIVE_NOT_RECRUITING	X-linked Hypophosphatemia Disease Monitoring Program
NCT04184661	Not specified	COMPLETED	Burosumab and 1-25 (OH) Vitamin D on Human Osteoclasts