Affinage

SGK2

Serine/threonine-protein kinase Sgk2 · UniProt Q9HBY8

Length
367 aa
Mass
41.2 kDa
Annotated
2026-06-10
16 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SGK2 is a serine/threonine kinase that controls protein stability, subcellular localization, and membrane transporter abundance across epithelial physiology and cancer cell biology (PMID:32848212, PMID:36720852). Its catalytic output reshapes the fate of multiple substrates: it phosphorylates the V-ATPase subunit ATP6V1H to drive lysosomal acidification and autophagic flux (PMID:32848212), phosphorylates FOXO1 at Thr-24/Ser-319 to force its nuclear-to-cytoplasmic translocation, derepressing GPX4 and suppressing ferroptosis (PMID:36720852), phosphorylates PTOV1 at Ser-36 to create a 14-3-3 binding site that sequesters and stabilizes PTOV1 in the cytosol against HUWE1-mediated degradation (PMID:34654719), and phosphorylates EZH2 at Thr-367 to block its ubiquitination, stabilizing EZH2 for H3K27me3-mediated repression of GABARAP and inhibition of autophagy (PMID:39814292). A recurring theme is its control of substrate ubiquitination and turnover, also seen where SGK2 weakens the hOAT4–Nedd4-2 interaction to reduce transporter ubiquitination and increase surface expression (PMID:26740304, PMID:27335683), and where it promotes TSC2 degradation to activate mTOR and suppress protective autophagy during HSV-1 infection (PMID:41851796). SGK2 likewise stimulates ENaC current in a manner independent of direct channel phosphorylation (PMID:12632189), and its own activity is regulated by PXR-scaffolded PP2C dephosphorylation at Thr-193, which couples it to co-activation of gluconeogenic transcription (PMID:26392083), and by transcriptional induction via the β3-adrenergic–PKA–PGC-1α axis (PMID:34899399). An early report of synthetic lethality between SGK2 loss and p53 inactivation (PMID:20616055) was subsequently shown to arise from shRNA off-target effects rather than on-target SGK2 dependence (PMID:25615606).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 Medium

    Established that SGK2, like other SGK family members, can stimulate epithelial Na+ channel activity, but does so without directly phosphorylating the channel consensus site, indicating an indirect regulatory mechanism.

    Evidence Dual-electrode voltage-clamp with αENaC S622A mutagenesis in Xenopus oocytes

    PMID:12632189

    Open questions at the time
    • The intermediary substrate linking SGK2 to ENaC was not identified
    • Heterologous oocyte system may not reflect native epithelial regulation
  2. 2010 Medium

    Proposed that p53 loss creates a selective dependence on SGK2, positioning the kinase as a candidate synthetic-lethal cancer target.

    Evidence shRNA knockdown epistasis screening in primary human epithelial cells with defined p53 inactivation

    PMID:20616055

    Open questions at the time
    • Mechanism connecting p53 status to SGK2 dependence was not defined
    • Reliance on shRNA left open the possibility of off-target killing
  3. 2015 Medium

    Resolved the p53 synthetic-lethality claim by demonstrating that the lethal phenotype in HeLa cells was an shRNA off-target artifact, not on-target SGK2 loss.

    Evidence cDNA rescue failure, single-mismatch knockdown-deficient shRNA, and non-human control shRNAs in HeLa cells

    PMID:25615606

    Open questions at the time
    • Does not exclude a genuine SGK2–p53 relationship in other cell contexts
    • Limited to a single cell line
  4. 2015 Medium

    Linked SGK2 activity to its own regulation and to metabolic transcription by showing PXR scaffolds PP2C to dephosphorylate SGK2 at Thr-193, enabling co-activation of gluconeogenic gene expression.

    Evidence Co-IP, phosphorylation assays, T193 mutagenesis, and reporter assays in human liver cells

    PMID:26392083

    Open questions at the time
    • How dephosphorylated SGK2 mechanistically co-activates PXR transcription is not defined
    • Single-lab finding without in vivo validation
  5. 2016 Medium

    Defined a transporter-regulatory role for SGK2 by showing it increases hOAT4 surface expression through disrupting the hOAT4–Nedd4-2 interaction and reducing ubiquitination.

    Evidence Transport assays, surface biotinylation, ubiquitination assays, and Co-IP with Nedd4-2 manipulation in COS-7 cells

    PMID:26740304

    Open questions at the time
    • Whether SGK2 directly phosphorylates Nedd4-2 was not established
    • Heterologous COS-7 system
  6. 2016 Medium

    Extended SGK2 transporter regulation to hOAT1, showing direct interaction and protein stabilization increase surface transporter levels.

    Evidence Transport assays, biotinylation, Co-IP, and protein-stability assays in COS-7 cells

    PMID:27335683

    Open questions at the time
    • No phosphorylation site on hOAT1 or kinase-dependence was demonstrated
    • Single heterologous system
  7. 2020 Medium

    Identified the first defined SGK2 substrate in autophagy control, ATP6V1H, establishing that SGK2 kinase activity regulates lysosomal acidification and autophagic flux with therapeutic relevance to platinum sensitivity.

    Evidence Loss-of-function screen, knockdown and chemical inhibition, autophagy/lysosomal assays, Co-IP and ATP6V1H phosphorylation assays in ovarian cancer cells

    PMID:32848212

    Open questions at the time
    • The ATP6V1H phosphosite was not mapped
    • Single-lab finding
  8. 2021 Medium

    Showed SGK2 phosphorylation of PTOV1 at Ser-36 controls its localization and stability via a 14-3-3/HUWE1 switch, linking SGK2 to cell-cycle progression.

    Evidence Phosphosite mapping and S36 mutagenesis, Co-IP, fractionation, and proteasome-inhibitor experiments

    PMID:34654719

    Open questions at the time
    • Upstream signals activating SGK2 toward PTOV1 not defined
    • Single-lab finding
  9. 2023 Medium

    Established SGK2 as a ferroptosis regulator by phosphorylating FOXO1 at Thr-24/Ser-319 to drive its cytoplasmic export, derepressing GPX4 and promoting prostate cancer metastasis.

    Evidence Knockdown/overexpression in vitro and in vivo, FOXO1 phosphorylation assays, fractionation, and ferroptosis assays

    PMID:36720852

    Open questions at the time
    • Direct kinase-substrate biochemistry vs. indirect effect not fully separated
    • Single-lab finding
  10. 2025 Medium

    Demonstrated SGK2 phosphorylation of EZH2 at Thr-367 stabilizes EZH2, linking SGK2 to H3K27me3-mediated GABARAP repression and autophagy inhibition in lung cancer.

    Evidence Co-IP, EZH2 T367 phosphorylation and ubiquitination assays, H3K27me3 ChIP, and autophagy flux assays

    PMID:39814292

    Open questions at the time
    • Mechanism by which T367 phosphorylation blocks EZH2 ubiquitination is undefined
    • Single-lab finding
  11. 2026 Medium

    Placed SGK2 upstream of the TSC2/mTOR axis in a viral infection context, showing SGK2 promotes TSC2 degradation to activate mTOR, suppress autophagy, and enhance apoptosis and HSV-1 replication.

    Evidence shRNA and pharmacological inhibition in human corneal epithelial cells with TSC2/mTOR readouts and rapamycin rescue

    PMID:41851796

    Open questions at the time
    • Whether SGK2 directly phosphorylates TSC2 was not shown
    • Single-lab finding in one cell type

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether SGK2's diverse substrate phosphorylation events are governed by a common upstream activation logic or tissue-specific recruitment, and which physiological context defines its core in vivo function.
  • No unifying upstream activator characterized across the substrate set
  • Sgk2 knockout shows no thermogenic phenotype, leaving the essential in vivo role unresolved
  • No structural model of SGK2 substrate selection

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-382551 Transport of small molecules 2 R-HSA-162582 Signal Transduction 1
Partners
ATP6V1HEZH2FOXO1NEDD4-2PP2CPTOV1PXRTSC2

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 SGK2 stimulates the amiloride-sensitive current through epithelial Na+ channel (α,β,γ-ENaC) when expressed in Xenopus oocytes, similarly to SGK1 and SGK3. Site-directed mutagenesis of the SGK consensus phosphorylation site on αENaC (S622A) did not abolish stimulation, indicating SGK2 does not act via direct phosphorylation of ENaC subunits. Dual-electrode voltage-clamp in Xenopus laevis oocytes; site-directed mutagenesis of αENaC S622A Pflugers Archiv : European journal of physiology Medium 12632189
2015 Statin-activated nuclear receptor PXR scaffolds protein phosphatase 2C (PP2C) together with SGK2, stimulating PP2C to dephosphorylate SGK2 at threonine 193. The resulting non-phosphorylated SGK2 co-activates PXR-mediated transcription of gluconeogenic genes (PEPCK1, G6Pase) in human liver cells, enhancing hepatic gluconeogenesis. Co-immunoprecipitation, phosphorylation assays, reporter gene assays, SGK2 T193 mutagenesis, human liver cell overexpression/knockdown experiments Scientific reports Medium 26392083
2015 SGK2 stimulates human organic anion transporter 4 (hOAT4) transport activity by increasing its cell-surface expression (increased Vmax, unchanged Km). This effect is mediated by SGK2 weakening the interaction between hOAT4 and ubiquitin ligase Nedd4-2, thereby reducing hOAT4 ubiquitination and promoting its surface retention. Transport activity assays in COS-7 cells, surface biotinylation, ubiquitination assays, co-immunoprecipitation, Nedd4-2 overexpression and siRNA knockdown Biochemical pharmacology Medium 26740304
2016 SGK2 stimulates human organic anion transporter 1 (hOAT1) transport activity by directly interacting with hOAT1 and enhancing its protein stability, leading to increased cell-surface expression (increased Vmax, unchanged Km) without increased degradation. Transport activity assays in COS-7 cells, surface biotinylation, co-immunoprecipitation, protein stability assays International journal of biochemistry and molecular biology Medium 27335683
2010 SGK2 is synthetically lethal with p53 loss in primary human epithelial cells: loss of p53 function induces a cellular dependence on SGK2, such that combined loss of p53 and SGK2 leads to cell death whereas either loss alone has little effect on viability. shRNA knockdown screening; epistasis analysis in primary human epithelial cells with defined p53 inactivation stages; tested across multiple cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 20616055
2015 The synthetic lethal phenotype observed with SGK2 shRNAs in HPV+ cervical cancer (HeLa) cells could not be rescued by complementary SGK2 cDNA expression, a knockdown-deficient SGK2 shRNA with a single mismatch reproduced the phenotype, and non-human-target shRNAs also killed HeLa cells. This demonstrates that cell death is not caused by on-target SGK2 knockdown but by off-target shRNA effects in this specific cell context. cDNA rescue experiments, mismatch shRNA controls, non-human control shRNAs in HeLa cells PloS one Medium 25615606
2020 SGK2 controls autophagy in a kinase-dependent manner by binding and phosphorylating the V1H subunit (ATP6V1H) of the V-ATPase proton pump, thereby regulating lysosomal acidification and autophagic flux. SGK2 inhibition impairs lysosomal acidification and blocks autophagy, sensitizing epithelial ovarian cancer cells to platinum drugs. Loss-of-function screening (680 genes), SGK2 knockdown and chemical inhibition, autophagy flux assays, lysosomal acidification assays, co-immunoprecipitation of SGK2 with V-ATPase, phosphorylation assays of ATP6V1H Oncogene Medium 32848212
2021 SGK2 phosphorylates PTOV1 at serine 36, which is required for PTOV1 to bind 14-3-3. 14-3-3 binding sequesters PTOV1 in the cytosol, stabilizes it by preventing its interaction with E3 ubiquitin ligase HUWE1, and promotes proteasomal degradation when this interaction is lost. Loss of 14-3-3 binding leads to nuclear accumulation of PTOV1 and its HUWE1-dependent proteasomal degradation. The 14-3-3-stabilized cytosolic PTOV1 promotes cJun expression and cell-cycle progression. Co-immunoprecipitation, phosphorylation site mapping (S36), mutagenesis of S36, subcellular fractionation/localization studies, proteasome inhibitor experiments, HUWE1 interaction assays Molecular cancer research : MCR Medium 34654719
2023 SGK2 promotes prostate cancer metastasis by phosphorylating FOXO1 at Thr-24 and Ser-319, inducing translocation of FOXO1 from the nucleus to the cytoplasm. This relieves FOXO1-mediated transcriptional repression of GPX4, increasing GPX4 expression and thereby inhibiting ferroptosis. SGK2 knockdown and overexpression in prostate cancer cells in vitro and in vivo; phosphorylation assays of FOXO1 at T24/S319; nuclear-cytoplasmic fractionation; GPX4 expression analysis; ferroptosis assays Cell death & disease Medium 36720852
2019 SGK2 promotes ERK1/2 and AKT phosphorylation in renal cell carcinoma cells, and silencing SGK2 inhibited proliferation, migration, colony formation, and invasion. SGK2 knockdown and overexpression in RCC cell lines; Western blot for phospho-ERK1/2 and phospho-AKT European review for medical and pharmacological sciences Low 31002126
2017 SGK2 downregulation in hepatocellular carcinoma cell lines suppresses cell migration/invasion and reduces active (unphosphorylated) GSK-3β levels, leading to decreased dephosphorylation (activation) of β-catenin and preventing its proteasomal degradation. SGK2 knockdown in HCC cell lines; Western blot for GSK-3β and β-catenin phosphorylation status; migration/invasion assays Tumour biology Low 28639896
2021 PGC-1α and NT-PGC-1α, transcriptional coactivators activated by the β3 adrenergic receptor–cAMP–PKA pathway, are recruited to the Sgk2 promoter and drive Sgk2 transcription in response to cold in brown/beige adipocytes. Despite cold-dependent SGK2 activation and increased phosphorylation of RxRxxS/T-motif substrates, Sgk2 knockout mice showed normal thermogenesis and energy expenditure, indicating SGK2 is dispensable for brown adipose tissue thermogenesis. Promoter recruitment assays (ChIP/reporter), Sgk2 knockout mice (cold tolerance, energy expenditure), in vitro loss/gain-of-function in brown adipocytes (thermogenic gene expression, mitochondrial respiration) Frontiers in physiology Medium 34899399
2025 SGK2 physically interacts with EZH2 and phosphorylates EZH2 at threonine 367, increasing EZH2 protein stability and reducing its ubiquitination. This SGK2-mediated EZH2 stabilization promotes H3K27me3-mediated suppression of GABARAP transcription, thereby inhibiting autophagy flux in lung cancer cells. Co-immunoprecipitation (SGK2-EZH2 interaction), phosphorylation assays at EZH2 T367, ubiquitination assays, H3K27me3 ChIP on GABARAP promoter, autophagy flux assays International journal of biological macromolecules Medium 39814292
2026 During HSV-1 infection, SGK2 upregulation activates the mTOR pathway by promoting TSC2 protein degradation, which suppresses protective autophagy and enhances apoptosis. SGK2 inhibition (pharmacological or shRNA) attenuates mTOR activation, restores autophagy, and reduces apoptosis and viral replication. SGK2 knockdown (shRNA) and pharmacological inhibition (GSK 650394) in HCECs; Western blot for TSC2, mTOR pathway components; flow cytometry apoptosis; immunofluorescence; rapamycin rescue experiments Virology journal Medium 41851796
2019 In Shank3-deficient mice, SGK2 expression is diminished in the prefrontal cortex, and blocking SGK family kinase function in wild-type mice attenuates PFC glutamatergic signaling and induces autism-like social deficits. Gq DREADD chemogenetic activation of PFC pyramidal neurons rescued both social behavior and Sgk2 expression in Shank3-deficient mice; blocking Sgk function prevented this rescue. Shank3 knockout mouse model; chemogenetic (DREADD) activation; Sgk2 expression analysis; pharmacological Sgk inhibition with behavioral and electrophysiological readouts iScience Low 31247448

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel alpha,beta,gamma-ENaC. Pflugers Archiv : European journal of physiology 69 12632189
2023 SGK2 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating GPX4. Cell death & disease 59 36720852
2015 Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis. Scientific reports 58 26392083
2010 Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3. Proceedings of the National Academy of Sciences of the United States of America 48 20616055
2019 Chemogenetic Activation of Prefrontal Cortex in Shank3-Deficient Mice Ameliorates Social Deficits, NMDAR Hypofunction, and Sgk2 Downregulation. iScience 40 31247448
2015 Serum- and glucocorticoid-inducible kinase SGK2 regulates human organic anion transporters 4 via ubiquitin ligase Nedd4-2. Biochemical pharmacology 20 26740304
2025 N-acetyltransferase 10 impedes EZH2/H3K27me3/GABARAP axis mediated autophagy and facilitates lung cancer tumorigenesis through enhancing SGK2 mRNA acetylation. International journal of biological macromolecules 15 39814292
2020 Serum- and glucocorticoid- inducible kinase 2, SGK2, is a novel autophagy regulator and modulates platinum drugs response in cancer cells. Oncogene 15 32848212
2019 SGK2 promotes renal cancer progression via enhancing ERK 1/2 and AKT phosphorylation. European review for medical and pharmacological sciences 13 31002126
2017 SGK2 promotes hepatocellular carcinoma progression and mediates GSK-3β/β-catenin signaling in HCC cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 11 28639896
2016 Serum- and glucocorticoid-inducible kinase sgk2 stimulates the transport activity of human organic anion transporters 1 by enhancing the stability of the transporter. International journal of biochemistry and molecular biology 11 27335683
2020 SGK2 is overexpressed in colon cancer and promotes epithelial-mesenchymal transition in colon cancer cells. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 8 32565024
2021 SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1. Molecular cancer research : MCR 7 34654719
2015 Lethality of PAK3 and SGK2 shRNAs to human papillomavirus positive cervical cancer cells is independent of PAK3 and SGK2 knockdown. PloS one 6 25615606
2021 Protein Kinase SGK2 Is Induced by the β3 Adrenergic Receptor-cAMP-PKA-PGC-1α/NT-PGC-1α Axis but Dispensable for Brown/Beige Adipose Tissue Thermogenesis. Frontiers in physiology 3 34899399
2026 SGK2 mediates apoptosis in herpes simplex keratitis by suppressing protective autophagy via the mTOR pathway. Virology journal 0 41851796

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