Affinage

SGK1

Serine/threonine-protein kinase Sgk1 · UniProt O00141

Length
431 aa
Mass
48.9 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SGK1 is a serine/threonine kinase that operates downstream of PI3-kinase to couple growth factor, hormonal, and stress signals to ion transport, transcription factor control, protein turnover, and cell survival (PMID:10357815, PMID:11154281). Its activation requires PDK1, which directly binds the SGK1 catalytic domain and phosphorylates an activating residue; unlike PKB, this activation proceeds without a pleckstrin homology domain or PIP3, as established by yeast complementation in which SGK substitutes for Ypk1/Ykr2 and is activated by the PDK1 counterpart Pkh1 (PMID:10357815, PMID:10074427). Additional inputs converge on SGK1: WNK family kinases activate it through a non-catalytic mechanism dependent on their N-terminal regions (PMID:16081417, PMID:20525693), ERK phosphorylates it at Ser78 (PMID:16553792), and mTORC2 acts upstream of SGK1 in epithelial sodium handling (PMID:26163195). A central output is regulation of the ubiquitin ligase Nedd4-2: SGK1 phosphorylates Nedd4-2 to block its inhibition of ENaC, increasing channel surface expression and Na+ transport (PMID:15328345, PMID:11208606), and the same phosphorylation feeds back to drive Nedd4-2-mediated ubiquitination and proteasomal degradation of SGK1 itself, an effect reinforced by the chaperone-associated E3 ligase CHIP near the endoplasmic reticulum (PMID:15576372, PMID:16895519, PMID:12218062). SGK1 also controls forkhead transcription factors, phosphorylating FOXO3a/FKHRL1 and Foxo1 to drive their nuclear exclusion and thereby promote cell survival, adipocyte differentiation, and T cell fate decisions (PMID:11154281, PMID:19965929, PMID:29346764). Through these substrates SGK1 governs diverse physiology: it tunes K+ and Ca2+ channels and glucose transporters (PMID:15793248, PMID:12397388, PMID:16443776, PMID:22682960), promotes p53 turnover via MDM2 (PMID:19756449), triggers the meiotic G2/M transition by phosphorylating Cdc25 and Myt1 (PMID:31537708), supports T cell-driven hypertension and Th17 differentiation (PMID:28679951, PMID:29346764, PMID:31013255), and is required for vascular development, with SGK1 knockout causing embryonic lethality from angiogenic and myocardial defects (PMID:20568246). The kinase can be directly and selectively inhibited at Asp177 by small molecules, linking its activity to cardiomyocyte hypertrophy via FoxO1 (PMID:34761560).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Established how SGK1 is switched on, placing it firmly downstream of PI3K and defining PDK1 as its direct activator independent of a PIP3-binding module.

    Evidence Kinase and GST-pulldown assays with PDK1, phosphatase inactivation and wortmannin inhibition; yeast complementation with Pkh1 activation

    PMID:10074427 PMID:10357815

    Open questions at the time
    • Did not resolve the relative contribution of distinct upstream activating inputs in mammalian cells
    • Physiological stimuli driving nuclear translocation not exhaustively mapped
  2. 2001 High

    Defined SGK1's substrate selectivity, showing it phosphorylates FKHRL1/FOXO3a and B-Raf at sites distinct from Akt preferences, establishing non-redundant survival and signaling roles.

    Evidence In vitro kinase assays, phosphosite mutagenesis, co-IP for substrate association, nuclear translocation and survival readouts

    PMID:11154281 PMID:11410590

    Open questions at the time
    • Did not establish the in vivo balance between SGK1 and Akt on shared substrates
    • Cellular contexts dictating substrate choice not defined
  3. 2001 High

    Connected SGK1 to epithelial Na+ handling, showing it stimulates ENaC-mediated transport via PI3K-dependent signaling and direct interaction with ENaC subunits.

    Evidence PI3K inhibitor studies in kidney cells and oocytes, GST-ENaC pulldown, electrophysiology

    PMID:11208606

    Open questions at the time
    • Direct vs. indirect regulation of ENaC not yet distinguished from the Nedd4-2 mechanism
    • Stoichiometry of ENaC interaction unclear
  4. 2002 High

    Revealed that SGK1 protein abundance is post-translationally constrained, identifying an N-terminal degron required for polyubiquitination and proteasomal turnover.

    Evidence Ubiquitination assays, proteasome inhibitors, N-terminal truncation mutants, subcellular fractionation

    PMID:12218062

    Open questions at the time
    • The E3 ligase was not identified in this study
    • Signals coupling degradation to activity state unresolved
  5. 2004 High

    Defined the Nedd4-2 axis in both directions: SGK1 phosphorylates Nedd4-2 to relieve ENaC inhibition, and Nedd4-2 reciprocally ubiquitinates SGK1, creating a self-limiting feedback loop.

    Evidence In vitro phosphorylation with site mutants, RNAi, dominant-negatives, co-expression ubiquitination assays, half-life measurement, electrophysiology

    PMID:15328345 PMID:15576372

    Open questions at the time
    • Quantitative kinetics of the feedback loop not modeled
    • Did not resolve crosstalk with the CHIP-dependent degradation pathway
  6. 2005 High

    Identified WNK1 as an upstream activator of SGK1 acting through a non-catalytic, PI3K-dependent mechanism, expanding the input network beyond canonical PDK1 signaling.

    Evidence SGK1 activity assays with WNK1 deletion and kinase-dead mutants, PI3K inhibitors, siRNA

    PMID:16081417

    Open questions at the time
    • Molecular mechanism by which the WNK1 N-terminus activates SGK1 not defined
    • Whether WNK1 acts as a scaffold or allosteric effector unresolved
  7. 2006 Medium

    Identified CHIP as a chaperone-dependent E3 ligase controlling SGK1 turnover near the ER, providing a quality-control route distinct from Nedd4-2.

    Evidence Reciprocal Co-IP, ubiquitination assays, immunofluorescence co-localization

    PMID:16895519

    Open questions at the time
    • Relative contribution of CHIP versus Nedd4-2 to SGK1 stability not quantified
    • Single laboratory without independent confirmation
  8. 2006 High

    Linked SGK1 to neuronal plasticity, showing ERK phosphorylates SGK1 at Ser78 and that SGK1 activity is required for LTP expression and spatial memory.

    Evidence In vitro kinase assay with site mutants, ERK inhibition, phospho-immunoblot, dominant-negative/constitutively active mutants, hippocampal electrophysiology and behavior

    PMID:16553792 PMID:16585788

    Open questions at the time
    • Synaptic substrates of SGK1 mediating LTP not defined
    • Causal chain from Ser78 phosphorylation to PSD-95 upregulation incomplete
  9. 2009 Medium

    Extended SGK1's survival role to the p53 axis and to Foxo1-dependent differentiation, broadening its impact on cell fate.

    Evidence RNAi, dominant-negative and overexpression, ubiquitylation assays, fractionation, mouse model

    PMID:19756449 PMID:19965929

    Open questions at the time
    • Whether SGK1 acts directly on MDM2 or upstream regulators not resolved
    • Direct phosphosites on the p53 pathway not mapped
  10. 2012 Medium

    Showed SGK1 controls Ca2+ entry machinery and cytoskeletal dynamics, regulating Orai1/STIM1 abundance via Nedd4-2/14-3-3 and platelet migration via WASP phosphorylation.

    Evidence Active/inactive SGK1 mutants, Nedd4-2/14-3-3 co-IP, store-operated Ca2+ measurements; SGK1 KO platelet migration and phospho-substrate assays in vitro and in vivo

    PMID:22682960 PMID:22759972

    Open questions at the time
    • Direct vs. indirect effects on WASP not fully separated
    • Generality of the Nedd4-2/14-3-3 mechanism across cell types untested
  11. 2015 Medium

    Placed mTORC2 upstream of SGK1 in renal Na+ regulation through pharmacological epistasis, and implicated SGK1 in prefrontal synaptic function and mood-related behavior.

    Evidence PP242/rapamycin in WT and SGK1 KO mice, perfused tubule Na+ flux; PFC SGK1 inhibition with behavioral, spine morphology, and electrophysiology readouts

    PMID:26163195 PMID:26506154

    Open questions at the time
    • Direct mTORC2 phosphorylation of SGK1 not demonstrated in these studies
    • Molecular targets in PFC synapses not identified
  12. 2018 Medium

    Defined SGK1 as a node in immune cell fate, restraining Treg suppressive function and promoting Th17 differentiation through Foxo1 localization and IL-23R signaling.

    Evidence Treg-specific conditional knockout, Foxo1 localization and Foxp3 CNS1 binding assays, T cell differentiation; T cell SGK1 KO hypertension and NKCC1 analyses

    PMID:28679951 PMID:29346764

    Open questions at the time
    • Direct Foxo1 phosphosites in Tregs not mapped
    • Relationship between salt sensing, NKCC1, and SGK1 activation incompletely defined
  13. 2019 High

    Established a conserved meiotic role, showing SGK directly phosphorylates Cdc25 and Myt1 to trigger Cdk1 activation at the G2/M transition, and identified EPO-R signaling as a negative regulator of SGK1 in T cells.

    Evidence In vitro kinase assays with purified SGK and phosphosite mapping plus oocyte rescue; T cell differentiation with EPO-R conditional KO and p38 inhibition

    PMID:31013255 PMID:31537708

    Open questions at the time
    • Conservation of the Cdc25/Myt1 mechanism in mammalian meiosis not established
    • How EPO-R suppresses both SGK1 transcription and phosphorylation mechanistically unclear
  14. 2021 Medium

    Connected SGK1 to anabolic metabolism, showing it drives glucose uptake into the pentose phosphate pathway and acts downstream of YAP to activate mTORC1/SREBP lipogenesis.

    Evidence SGK1 loss/gain-of-function, glucose uptake and metabolic flux assays, GLUT1 transcription readout; YAP-SGK1 epistasis with mTORC1/SREBP/lipogenesis assays

    PMID:33730592 PMID:35216681

    Open questions at the time
    • Direct substrates linking SGK1 to mTORC1/SREBP not identified
    • Mechanism of GLUT1 transcriptional control by SGK1 undefined
  15. 2021 High

    Demonstrated SGK1 is a druggable target, identifying a direct small-molecule inhibitor whose action depends on Asp177 and which suppresses FoxO1-driven cardiomyocyte hypertrophy.

    Evidence Thermal shift, KINOMEscan, molecular docking, Asp177 site-directed mutagenesis, cardiomyocyte hypertrophy assays

    PMID:34761560

    Open questions at the time
    • Selectivity against related kinases not exhaustively profiled
    • In vivo efficacy and pharmacokinetics not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple upstream inputs (PDK1, mTORC2, WNK1-4, ERK, p38) are integrated to set SGK1 activity in a tissue-specific manner, and which substrates dominate in each physiological context, remains unresolved.
  • No unified quantitative model of competing activating inputs
  • Tissue-specific substrate hierarchy not defined
  • Structural basis of substrate selectivity versus Akt incompletely characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1640170 Cell Cycle 2
Partners
BRAFFOXO1FOXO3NEDD4LPDK1STIM1STUB1WNK1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SGK1 phosphorylates the forkhead transcription factor FKHRL1 (FOXO3a) at Thr-32 and Ser-315, promoting FKHRL1 nuclear exit and inactivation, thereby promoting cell survival. SGK1 shows a marked preference for Ser-315 whereas Akt favors Ser-253. In vitro kinase assay, phosphosite mutagenesis, cell survival assays, nuclear translocation experiments Molecular and cellular biology High 11154281
1999 SGK1 is activated downstream of PI3-kinase via phosphorylation at Thr256 and Ser422; PDK1 directly interacts with the catalytic domain of SGK1 (GST pulldown) and phosphorylates/activates it; treatment with protein phosphatase 2A inactivates SGK1. Growth factor stimulation induces SGK1 hyperphosphorylation and nuclear translocation, both blocked by wortmannin. Peptide kinase assay, GST pulldown, phosphatase treatment, inhibitor studies (LY294002, wortmannin), co-transfection with PDK1, subcellular fractionation The EMBO journal High 10357815
1999 Yeast Ypk1 and Ykr2 are functional counterparts of SGK; rat SGK (but not mouse PKB or rat p70 S6 kinase) rescues otherwise inviable ypk1Δ ykr2Δ yeast cells. Yeast Pkh1 (PDK1 counterpart) activates mammalian SGK by phosphorylating the same residue as PDK1, and this activation does not require phosphatidylinositol 3,4,5-trisphosphate, consistent with the absence of a pleckstrin homology domain in SGK. Genetic complementation in yeast, in vitro kinase assay with purified Pkh1 and SGK, deletion mutant rescue Current biology : CB High 10074427
2004 SGK and PKA both phosphorylate Nedd4-2 at overlapping sites (Ser-327, Ser-221, Thr-246) to inhibit its binding to ENaC, thereby increasing ENaC surface expression and Na+ transport. SGK overexpression blunts ENaC stimulation by cAMP, and cAMP agonists decrease ENaC stimulation by SGK, indicating convergent regulation through Nedd4-2. In vitro phosphorylation assay, RNA interference, dominant-negative constructs, electrophysiology The Journal of biological chemistry High 15328345
2001 SGK1 phosphorylates and negatively regulates B-Raf kinase activity by phosphorylating a single Akt consensus site, Ser364, in B-Raf's amino-terminal regulatory domain. SGK displays stronger inhibitory effect on B-Raf than Akt, and enhanced association between SGK and B-Raf (vs. Akt preference for FKHR) explains the selective substrate specificity. In vitro kinase assay, co-immunoprecipitation, phosphosite mapping The Journal of biological chemistry High 11410590
2002 SGK1 steady-state protein levels are kept low by polyubiquitination and subsequent degradation by the 26S proteasome. Deletion of the N-terminal 60 amino acids prevents polyubiquitination and proteasomal degradation. A fraction of SGK1 localizes to the plasma membrane and the polyubiquitin-modified form is enriched in the membrane-associated fraction. Ubiquitination assays, proteasome inhibitor treatment, truncation mutants, subcellular fractionation The Journal of biological chemistry High 12218062
2004 Nedd4-2 mediates ubiquitin-dependent degradation of SGK1 in a feedback loop: SGK1 phosphorylates Nedd4-2, and this phosphorylation increases Nedd4-2-mediated ubiquitination and proteasomal degradation of SGK. Nedd4-2 overexpression decreases SGK steady-state levels, and Nedd4-2 knockdown by RNAi stabilizes SGK. Co-expression ubiquitination assays, RNA interference, SGK half-life measurement, mutants blocking phosphorylation The Journal of biological chemistry High 15576372
2006 The E3 ubiquitin ligase CHIP forms a complex with SGK-1, mediates its ubiquitin modification and rapid proteasomal degradation, and co-localizes with SGK-1 at or near the endoplasmic reticulum. CHIP-mediated regulation of SGK-1 levels alters its kinase activity. Co-immunoprecipitation, ubiquitination assay, immunofluorescence co-localization The Biochemical journal Medium 16895519
2005 WNK1 activates SGK1 through a PI3K-dependent but non-catalytic mechanism; neither WNK1 kinase activity nor its kinase domain is required—rather the N-terminal 220 residues of WNK1 are necessary and sufficient for SGK1 activation. WNK1 phosphorylation at Thr-58 contributes to SGK1 activation. WNK1 is required for IGF-1-stimulated SGK1 activation. SGK1 activity assay, WNK1 deletion/kinase-dead mutants, PI3K inhibitor studies, siRNA knockdown of WNK1 The Journal of biological chemistry High 16081417
2010 All four WNK family members (WNK1-4) can activate SGK1 through their N-terminal regions, and all four increase amiloride-sensitive sodium current (ENaC) in reconstitution experiments. Nedd4-2 binds to WNK1, and endogenous SGK1 has reduced activity when WNK1 is knocked down by siRNA. SGK1 activity assay, electrophysiology (amiloride-sensitive current), Co-IP of WNK1 and Nedd4-2, siRNA knockdown The Journal of biological chemistry Medium 20525693
2001 SGK1 stimulates ENaC-mediated Na+ transport in a PI3K-dependent manner; PI3K inhibition blocks both SGK phosphorylation and mineralocorticoid-induced Na+ transport. In vitro-translated SGK1 directly interacts with ENaC subunits expressed as GST fusion proteins. Insulin augments SGK1 phosphorylation and synergizes with mineralocorticoids in stimulating Na+ transport. PI3K inhibitor studies in A6 kidney cells and Xenopus oocytes, in vitro pulldown with GST-ENaC subunits, electrophysiology American journal of physiology. Renal physiology High 11208606
2009 SGK1 activates MDM2-dependent p53 ubiquitylation (mono- and polyubiquitylation), thereby reducing p53 levels and contributing to cell survival, cell-cycle progression, and epithelial de-differentiation. SGK1 silencing prevents MDM2-mediated p53 ubiquitylation; dominant-negative SGK1 blocks these effects. RNA silencing, dominant-negative and wild-type SGK1 stable transfection, ubiquitylation assays, mouse model Journal of molecular medicine (Berlin, Germany) Medium 19756449
2006 ERK directly phosphorylates SGK1 at Ser78 in vitro; inhibition of ERK (PD98059) decreases SGK phosphorylation at Ser78, Thr256, and Ser422 in vivo following spatial training. ERK activation of SGK1 (via SGK1 Thr256 phosphorylation) is involved in spatial memory formation in rats. In vitro kinase assay (ERK phosphorylating SGK), pharmacological ERK inhibition (PD98059), phospho-specific immunoblot, site-directed mutagenesis (S78A, T256A), hippocampal DNA transfection in rats The European journal of neuroscience High 16553792
2001 SGK1 mediates glucocorticoid-induced upregulation of Kv1.5 channel activity, leading to increased repolarizing K+ current, reduced Ca2+ oscillations, and decreased glucose-induced insulin secretion. This pathway is absent in SGK1 knockout mouse islets, confirming SGK1 as the required intermediary. Xenopus oocyte co-expression electrophysiology, INS-1 cell patch-clamp, K+ channel blockers, SGK1 knockout mouse islets Diabetes High 15793248
2003 SGK1 contains a nuclear localization signal (NLS) that binds to the importin-α nuclear import receptor, controlling nuclear-cytoplasmic shuttling. This NLS is located at an external surface of the kinase domain based on 3D structural modeling. Importin-α binding assay, NLS identification, structural modeling Cellular physiology and biochemistry Low 12649597
2006 SGK1 increases GLUT1 plasma membrane abundance and maximal glucose transport rate without altering substrate affinity; constitutively active SGK1 (S422D) stimulates GLUT1 transport while kinase-inactive SGK1 (K127N) does not. The effect is due to increased transporter plasma membrane abundance, not de novo protein synthesis. Tracer-flux studies in Xenopus oocytes and HEK-293 cells, constitutively active and kinase-dead SGK1 mutants, kinetic analysis Diabetes Medium 16443776
2009 SGK1 regulates adipocyte differentiation by directly phosphorylating Foxo1, changing its localization from nucleus to cytosol. SGK1-/- cells cannot relocalize Foxo1 to the cytosol in response to dexamethasone, and SGK1 knockdown diminishes adipogenesis while SGK1 overexpression promotes it. siRNA knockdown, ectopic SGK1 expression, Foxo1 localization (nuclear/cytosolic fractionation), SGK1-/- cells, immunofluorescence Molecular endocrinology (Baltimore, Md.) Medium 19965929
2002 SGK1 (and also SGK2 and SGK3) activates voltage-gated K+ channels (Kv1 family) when expressed in HEK293 cells or Xenopus oocytes, as measured by patch-clamp. The current increase is blocked by TEA and partially by the Kv1-specific blocker margatoxin. Patch-clamp electrophysiology, transfection of SGK isoforms, Xenopus oocyte dual-electrode voltage clamp Pflugers Archiv : European journal of physiology Medium 12397388
2013 SGK1 potentiates glucocorticoid receptor (GR) function by increasing GR phosphorylation and GR nuclear translocation, even after cortisol withdrawal. SGK1 also acts downstream of GR to regulate Hedgehog pathway-dependent neurogenesis. Pharmacological SGK1 inhibition (GSK650394) blocks cortisol-induced reduction of neurogenesis. Small molecule inhibitor (GSK650394), GR antagonist (RU486), gene expression and pathway analysis, phospho-GR immunoblot, nuclear translocation assays in human hippocampal progenitor cells Proceedings of the National Academy of Sciences of the United States of America Medium 23650397
2019 SGK directly phosphorylates both Cdc25 (activating phosphatase) and Myt1 (inhibitory kinase) to trigger cyclin B-Cdk1 activation at the meiotic G2/M transition in starfish oocytes. SGK is activated by cooperation between the Gβγ-PI3K pathway and an additional atypical Gβγ pathway upon hormonal stimulation. In vitro kinase assay with purified SGK, phosphosite identification on Cdc25 and Myt1, rescue experiments in starfish oocytes, pathway inhibitor studies The Journal of cell biology High 31537708
2022 YAP-dependent regulation of SGK1 is required to activate mTORC1/SREBP signaling and stimulate de novo lipogenesis to support cell proliferation and tissue growth. Loss-of-function experiments (sgk1 knockdown/knockout), mTORC1 signaling assays, lipogenesis measurements, epistasis between YAP and SGK1 Developmental cell Medium 35216681
2017 SGK1 inhibition (GSK650394 or shRNA) in prostate cancer cells induces G2/M arrest, autophagy, and apoptosis. Autophagy precedes and is required for apoptosis (3-MA inhibition of autophagy attenuates apoptosis). The mechanism involves suppression of mTOR- and Foxo3a-phosphorylation; pFoxo3a(S253) interacts with LC3 and p27. Flow cytometry, western blotting, immunofluorescence, transmission electron microscopy, SGK1 shRNA, ectopic SGK1 overexpression, xenograft model British journal of cancer Medium 29017179
2018 SGK1 in Treg cells prevents Foxo1 nuclear retention, thereby limiting Foxp3 expression and suppressive function of Tregs while promoting Th17 development. SGK1 mediates IL-23R-dependent inhibition of Treg and development of Th17 cells. Treg cell-specific SGK1 deletion (conditional knockout), Foxo1 nuclear/cytoplasmic localization assays, Foxp3 CNS1 binding assays, T cell differentiation assays Cell reports Medium 29346764
2017 Loss of T cell SGK1 blunts hypertensive response to angiotensin II and DOCA-salt, reduces renal and vascular inflammation, prevents endothelial dysfunction and renal injury. The Na+-K+-2Cl- cotransporter NKCC1 is upregulated in Th17 cells and is required for salt-induced increase in SGK1 and IL-23 receptor expression. T cell-specific SGK1 knockout mice, blood pressure measurement, vascular and renal inflammation quantification, NKCC1 expression analysis JCI insight Medium 28679951
2010 SGK1 knockout in the C57BL/6J background causes embryonic lethality at E10.5-11.5 due to angiogenic defects, increased apoptosis of endothelial and vascular smooth muscle cells, impaired myocardial trabeculation, and reduced Notch signaling (Efnb2, Nrp1 markers). SGK1 knockout mouse (C57BL/6J background), histology, apoptosis assays, gene expression analysis Developmental dynamics Medium 20568246
2012 SGK1 promotes platelet migration by enhancing WASP phosphorylation and reducing vinculin phosphorylation. Platelets from SGK1 knockout mice show reduced SDF-1-stimulated migration and WASP phosphorylation, and less transmigration into inflamed vessel walls in vivo. SGK1 knockout mouse platelets, phospho-WASP/vinculin immunoblot, migration assay, in vivo intestinal inflammation model with immunohistochemistry Cellular physiology and biochemistry Medium 22759972
2021 SGK1 promotes glucose uptake (via elevated GLUT1 transcription) and channels carbon flux into the pentose phosphate pathway to support ATP production and cell survival during ECM-detached conditions; SGK1 activation is necessary and sufficient for ATP generation during ECM detachment. SGK1 knockdown/overexpression, glucose uptake assays, metabolic flux analysis (PPP), anchorage-independent growth assays Cell reports Medium 33730592
2012 SGK1 upregulates Orai1 abundance by phosphorylating Nedd4-2, which then binds to 14-3-3 protein and cannot ubiquitinate Orai1, preventing Orai1 degradation. SGK1 also increases Orai1 and STIM1 protein levels by activating NF-κB. Overexpression of active vs. inactive SGK1 mutants, Nedd4-2 phosphorylation assay, co-immunoprecipitation (Nedd4-2/14-3-3), store-operated Ca2+ entry measurements Cell calcium Medium 22682960
2006 SGK protein kinase activity (phosphorylation at Ser422) facilitates expression of long-term potentiation (LTP) in hippocampal neurons. Constitutively active SGK (S422D) upregulates postsynaptic density-95 expression; dominant-negative SGK (S422A) impairs LTP expression but not induction. Hippocampal slice electrophysiology (LTP recording), dominant-negative and constitutively active SGK mutant transfection, PSD-95 western blot Learning & memory (Cold Spring Harbor, N.Y.) Medium 16585788
2015 SGK1 mediates the mTORC2-dependent regulation of ENaC; the mTOR catalytic site inhibitor PP242 (not rapamycin) inhibits ENaC and induces natriuresis in wild-type mice but does not further impair Na+ reabsorption in sgk1-/- mice, placing mTORC2 upstream of SGK1 in ENaC regulation. mTOR inhibitors (PP242, rapamycin) in wild-type and SGK1 knockout mice, isolated perfused tubules, Na+ flux measurements, in vivo natriuresis Nephrology, dialysis, transplantation Medium 26163195
2021 Herbacetin (HBT) directly binds SGK1 and inhibits its activity (IC50 752 nmol); site-specific mutation of Asp177 in SGK1 completely abolishes HBT's inhibitory activity, identifying Asp177 as a critical binding residue. HBT decreases SGK1 phosphorylation and downstream FoxO1 signaling, suppressing cardiomyocyte hypertrophy. Mass spectrometry-based kinase inhibitory assay, thermal shift assay, KINOMEscan in vitro assay, molecular docking, SGK1 Asp177 site-directed mutagenesis, cardiomyocyte hypertrophy assays Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 34761560
2019 EPO/EPO-R ligation on CD4+ T cells abrogates SGK1 gene upregulation and blocks p38-mediated SGK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL-17 and IL-23 receptor genes and preventing Th17 differentiation. In vitro T cell differentiation assays, SGK1 gene expression and phosphorylation assays, p38 inhibition, EPO-R conditional knockout mice, murine kidney disease models JCI insight Medium 31013255
2015 SGK1 inhibition in the rat medial prefrontal cortex causes helplessness- and anhedonic-like behaviors accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Pharmacological SGK1 inhibition in rat PFC, behavioral tests (helplessness, anhedonia), dendritic spine morphology analysis, electrophysiology PLoS biology Medium 26506154
2014 In C. elegans, SGK-1 loss-of-function recapitulates the lifespan extension phenotype of daf-2 mutants upon prohibitin depletion; mTORC2 (via RICT-1) regulates SGK-1 for mitochondrial homeostasis (UPRmt) in a pathway parallel to DAF-2/insulin signaling. Genetic epistasis places SGK-1 downstream of both DAF-2 and mTORC2 (RICT-1). C. elegans genetic epistasis, loss-of-function mutants, UPRmt reporter assays, lifespan assays PloS one Medium 25265021

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Molecular and cellular biology 727 11154281
1999 Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. The EMBO journal 475 10357815
2013 Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis. Proceedings of the National Academy of Sciences of the United States of America 259 23650397
2003 Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 232 12649597
1999 Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast. Current biology : CB 225 10074427
2004 cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2. The Journal of biological chemistry 186 15328345
2001 SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport. American journal of physiology. Renal physiology 180 11208606
2012 Regulation of ion channels by the serum- and glucocorticoid-inducible kinase SGK1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 161 23012321
2000 Regulation of sgk by aldosterone and its effects on the epithelial Na(+) channel. American journal of physiology. Renal physiology 161 10751222
2002 Concerted action of ENaC, Nedd4-2, and Sgk1 in transepithelial Na(+) transport. American journal of physiology. Renal physiology 156 12167587
2005 Serum- and glucocorticoid-inducible kinase 1 (SGK1) mediates glucocorticoid-induced inhibition of insulin secretion. Diabetes 146 15793248
2012 Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder. Translational psychiatry 145 22832853
2010 Significance of SGK1 in the regulation of neuronal function. The Journal of physiology 140 20530112
2010 Second AKT: the rise of SGK in cancer signalling. Growth factors (Chur, Switzerland) 137 20919962
2003 SGK1 regulation of epithelial sodium transport. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 136 12649598
1999 h-sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology 126 10220500
2006 Sgk kinases and their role in epithelial transport. Annual review of physiology 125 16460280
2001 IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflugers Archiv : European journal of physiology 117 11907830
2003 SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 108 12649599
2002 sgk: an essential convergence point for peptide and steroid hormone regulation of ENaC-mediated Na+ transport. American journal of physiology. Cell physiology 106 11832334
2011 EMD638683, a novel SGK inhibitor with antihypertensive potency. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 104 21865856
2017 A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage. JCI insight 100 28679951
2009 Targeting SGK1 in diabetes. Expert opinion on therapeutic targets 92 19764891
2009 Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation. Journal of molecular medicine (Berlin, Germany) 91 19756449
2017 SGK1 inhibition induces autophagy-dependent apoptosis via the mTOR-Foxo3a pathway. British journal of cancer 90 29017179
2018 SGK1 Governs the Reciprocal Development of Th17 and Regulatory T Cells. Cell reports 89 29346764
2021 SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models. EMBO molecular medicine 88 33646633
2002 Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1). The Journal of biological chemistry 88 12218062
2001 Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf. The Journal of biological chemistry 88 11410590
2016 SGK1: The Dark Side of PI3K Signaling. Current topics in developmental biology 86 28236975
2017 JNK, p38, ERK, and SGK1 Inhibitors in Cancer. Cancers 84 29267206
2005 WNK1 activates SGK1 by a phosphatidylinositol 3-kinase-dependent and non-catalytic mechanism. The Journal of biological chemistry 83 16081417
2004 Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. The Journal of biological chemistry 80 15576372
2010 Colorectal carcinoma cells--regulation of survival and growth by SGK1. The international journal of biochemistry & cell biology 76 20541034
2003 Enrichment enhances the expression of sgk, a glucocorticoid-induced gene, and facilitates spatial learning through glutamate AMPA receptor mediation. The European journal of neuroscience 73 14656333
2016 SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 72 27771704
2000 The sgk, an aldosterone-induced gene in mineralocorticoid target cells, regulates the epithelial sodium channel. Kidney international 71 10760056
2001 The role of SGK1 in hormone-regulated sodium transport. Trends in endocrinology and metabolism: TEM 69 11551807
2015 Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress. PLoS biology 68 26506154
2009 Serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates adipocyte differentiation via forkhead box O1. Molecular endocrinology (Baltimore, Md.) 68 19965929
2010 Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. The Journal of biological chemistry 67 20525693
2018 Aldosterone, SGK1, and ion channels in the kidney. Clinical science (London, England : 1979) 61 29352074
2002 K+ channel activation by all three isoforms of serum- and glucocorticoid-dependent protein kinase SGK. Pflugers Archiv : European journal of physiology 61 12397388
2012 Regulation of Orai1/STIM1 by the kinases SGK1 and AMPK. Cell calcium 60 22682960
2021 SGK1 in Human Cancer: Emerging Roles and Mechanisms. Frontiers in oncology 58 33542904
2007 Salt, sodium channels, and SGK1. The Journal of clinical investigation 58 17332888
2015 Regulation of the epithelial Na+ channel by the mTORC2/SGK1 pathway. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 56 26163195
2015 Baicalin decreases SGK1 expression in the hippocampus and reverses depressive-like behaviors induced by corticosterone. Neuroscience 56 26480816
2006 SGK1 kinase upregulates GLUT1 activity and plasma membrane expression. Diabetes 56 16443776
1998 Cloning of sgk serine-threonine protein kinase from shark rectal gland – a gene induced by hypertonicity and secretagogues. Pflugers Archiv : European journal of physiology 56 9683731
2007 IL-2 signals through Sgk1 and inhibits proliferation and apoptosis in kidney cancer cells. Journal of molecular medicine (Berlin, Germany) 53 17571248
2005 Role of Sgk1 in salt and potassium homeostasis. American journal of physiology. Regulatory, integrative and comparative physiology 53 15590995
2013 The cell survival kinase SGK1 and its targets FOXO3a and NDRG1 in aged human brain. Neuropathology and applied neurobiology 51 23363009
2000 Expression of cell volume-regulated kinase h-sgk in pancreatic tissue. American journal of physiology. Gastrointestinal and liver physiology 51 11052997
2000 Role of SGK in mineralocorticoid-regulated sodium transport. Kidney international 49 10760055
2022 YAP regulates an SGK1/mTORC1/SREBP-dependent lipogenic program to support proliferation and tissue growth. Developmental cell 48 35216681
2006 High glucose up-regulates ENaC and SGK1 expression in HCD-cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 47 17170520
2020 The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star. Therapeutic advances in medical oncology 45 32728395
2008 The role of SGK and CFTR in acute adaptation to seawater in Fundulus heteroclitus. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 45 18769033
2008 Regulation of epithelial Na+ channels by aldosterone: role of Sgk1. Clinical and experimental pharmacology & physiology 44 18197893
2021 Discovery of Herbacetin as a Novel SGK1 Inhibitor to Alleviate Myocardial Hypertrophy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 43 34761560
2006 SGK protein kinase facilitates the expression of long-term potentiation in hippocampal neurons. Learning & memory (Cold Spring Harbor, N.Y.) 42 16585788
2018 INPP4B restrains cell proliferation and metastasis via regulation of the PI3K/AKT/SGK pathway. Journal of cellular and molecular medicine 41 29516642
2018 Targeting of SGK1 by miR-576-3p Inhibits Lung Adenocarcinoma Migration and Invasion. Molecular cancer research : MCR 41 30257988
2014 Sodium chloride, SGK1, and Th17 activation. Pflugers Archiv : European journal of physiology 40 25471348
2020 HPV E7-mediated NCAPH ectopic expression regulates the carcinogenesis of cervical carcinoma via PI3K/AKT/SGK pathway. Cell death & disease 38 33311486
2012 SGK regulation of renal sodium transport. Current opinion in nephrology and hypertension 38 22691875
2021 SGK1 signaling promotes glucose metabolism and survival in extracellular matrix detached cells. Cell reports 37 33730592
2017 Therapeutic inhibition of SGK1 suppresses colorectal cancer. Experimental & molecular medicine 37 29170478
2015 SGK1 inhibits cellular apoptosis and promotes proliferation via the MEK/ERK/p53 pathway in colitis. World journal of gastroenterology 37 26034353
2012 SGK1 sensitivity of platelet migration. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 22759972
2010 Serum and glucocorticoid-inducible kinase 1 (SGK1) is necessary for vascular remodeling during angiogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 37 20568246
2006 Ubiquitin-proteasome degradation of serum- and glucocorticoid-regulated kinase-1 (SGK-1) is mediated by the chaperone-dependent E3 ligase CHIP. The Biochemical journal 36 16895519
2024 Dexamethasone upregulates macrophage PIEZO1 via SGK1, suppressing inflammation and increasing ROS and apoptosis. Biochemical pharmacology 35 38354960
2006 Renal function of gene-targeted mice lacking both SGK1 and SGK3. American journal of physiology. Regulatory, integrative and comparative physiology 35 16537821
2019 Erythropoietin inhibits SGK1-dependent TH17 induction and TH17-dependent kidney disease. JCI insight 34 31013255
2000 SGK is a primary glucocorticoid-induced gene in the human. The Journal of steroid biochemistry and molecular biology 34 11179908
2014 Prohibitin-mediated lifespan and mitochondrial stress implicate SGK-1, insulin/IGF and mTORC2 in C. elegans. PloS one 33 25265021
2020 SGK1 activation exacerbates diet-induced obesity, metabolic syndrome and hypertension. The Journal of endocrinology 32 31600722
2019 SGK phosphorylates Cdc25 and Myt1 to trigger cyclin B-Cdk1 activation at the meiotic G2/M transition. The Journal of cell biology 32 31537708
2019 SGK1 Mediates Hypoxic Pulmonary Hypertension through Promoting Macrophage Infiltration and Activation. Analytical cellular pathology (Amsterdam) 32 31815093
2014 Mineralocorticoid and SGK1-sensitive inflammation and tissue fibrosis. Nephron. Physiology 32 25377230
2006 Serum- and glucocorticoid-inducible kinase (SGK) is a target of the MAPK/ERK signaling pathway that mediates memory formation in rats. The European journal of neuroscience 32 16553792
2023 Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3. Journal of translational medicine 31 36788538
2019 Estradiol promotes trophoblast viability and invasion by activating SGK1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 31 31203134
2018 Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity. Neurotoxicity research 31 29882004
2018 SGK1/FOXO3 Signaling in Hypothalamic POMC Neurons Mediates Glucocorticoid-Increased Adiposity. Diabetes 29 29321171
1998 Genomic organization and chromosomal localization of the human SGK protein kinase gene. Genomics 29 9722955
2023 Role of Serum/Glucocorticoid-Regulated Kinase 1 (SGK1) in Immune and Inflammatory Diseases. Inflammation 27 37353719
2001 Tissue-specific expression of the transcriptionally regulated serum and glucocorticoid-inducible protein kinase (Sgk) during mouse embryogenesis. Mechanisms of development 27 11335130
2022 SGK1 in Cancer: Biomarker and Drug Target. Cancers 26 35625991
2019 Akt and SGK protein kinases are required for efficient feeding by macropinocytosis. Journal of cell science 26 30617109
2019 Inhibition of SGK1 confers vulnerability to redox dysregulation in cervical cancer. Redox biology 26 31136958
2015 Roles of Akt and SGK1 in the Regulation of Renal Tubular Transport. BioMed research international 26 26491696
2020 GR, Sgk1, and NDRG1 in esophageal squamous cell carcinoma: their correlation with therapeutic outcome of neoadjuvant chemotherapy. BMC cancer 25 32106831
2015 SGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-α. Cell death & disease 25 26379195
2014 SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart: pressure-related effects. American journal of hypertension 25 24429675
2019 Review about the multi-target profile of resveratrol and its implication in the SGK1 inhibition. European journal of medicinal chemistry 24 31539779
2018 To die or not to die SGK1-sensitive ORAI/STIM in cell survival. Cell calcium 24 29807219
2013 TGFβ1 and SGK1-sensitive store-operated Ca2+ entry and Orai1 expression in endometrial Ishikawa cells. Molecular human reproduction 23 24043696

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