{"gene":"SGK2","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2003,"finding":"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.","method":"Dual-electrode voltage-clamp in Xenopus laevis oocytes; site-directed mutagenesis of αENaC S622A","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional electrophysiology assay with mutagenesis in a heterologous system, single study with two orthogonal approaches","pmids":["12632189"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation assays, reporter gene assays, SGK2 T193 mutagenesis, human liver cell overexpression/knockdown experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, phosphorylation site identified, functional reporter assays, single lab with multiple orthogonal methods","pmids":["26392083"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Transport activity assays in COS-7 cells, surface biotinylation, ubiquitination assays, co-immunoprecipitation, Nedd4-2 overexpression and siRNA knockdown","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing interaction disruption, functional transport assays, and orthogonal siRNA/overexpression, single lab","pmids":["26740304"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Transport activity assays in COS-7 cells, surface biotinylation, co-immunoprecipitation, protein stability assays","journal":"International journal of biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP interaction, functional transport assays with kinetic analysis, single lab with multiple methods","pmids":["27335683"],"is_preprint":false},{"year":2010,"finding":"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.","method":"shRNA knockdown screening; epistasis analysis in primary human epithelial cells with defined p53 inactivation stages; tested across multiple cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis across multiple cell lines, replicated in different primary epithelia, but note that a follow-up study (PMID 25615606) raised concerns about shRNA off-target effects in HeLa cells specifically","pmids":["20616055"],"is_preprint":false},{"year":2015,"finding":"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.","method":"cDNA rescue experiments, mismatch shRNA controls, non-human control shRNAs in HeLa cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous negative result with multiple controls; establishes off-target mechanism for a specific prior claim","pmids":["25615606"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding, kinase-dependent phosphorylation of a defined substrate, functional autophagy assays, single lab with multiple orthogonal methods","pmids":["32848212"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation site mapping (S36), mutagenesis of S36, subcellular fractionation/localization studies, proteasome inhibitor experiments, HUWE1 interaction assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific phosphorylation with mutagenesis, Co-IP interactions, localization experiments, single lab with multiple orthogonal methods","pmids":["34654719"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined phosphorylation sites on substrate, subcellular localization shift measured by fractionation, in vivo and in vitro evidence, single lab","pmids":["36720852"],"is_preprint":false},{"year":2019,"finding":"SGK2 promotes ERK1/2 and AKT phosphorylation in renal cell carcinoma cells, and silencing SGK2 inhibited proliferation, migration, colony formation, and invasion.","method":"SGK2 knockdown and overexpression in RCC cell lines; Western blot for phospho-ERK1/2 and phospho-AKT","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Western blot only, no direct kinase assay or substrate identification, no mechanistic pathway placement","pmids":["31002126"],"is_preprint":false},{"year":2017,"finding":"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.","method":"SGK2 knockdown in HCC cell lines; Western blot for GSK-3β and β-catenin phosphorylation status; migration/invasion assays","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Western blot only for pathway analysis, no direct SGK2 kinase assay on GSK-3β, no mutagenesis","pmids":["28639896"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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)","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined thermogenic phenotype readout, promoter ChIP, in vitro complementary assays, single lab with multiple methods; negative result for thermogenesis is well-supported","pmids":["34899399"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation (SGK2-EZH2 interaction), phosphorylation assays at EZH2 T367, ubiquitination assays, H3K27me3 ChIP on GABARAP promoter, autophagy flux assays","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction, defined phosphorylation site, ubiquitination and histone modification readouts, single lab with multiple orthogonal methods","pmids":["39814292"],"is_preprint":false},{"year":2026,"finding":"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.","method":"SGK2 knockdown (shRNA) and pharmacological inhibition (GSK 650394) in HCECs; Western blot for TSC2, mTOR pathway components; flow cytometry apoptosis; immunofluorescence; rapamycin rescue experiments","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological loss-of-function with defined molecular pathway readouts, rescue experiment with rapamycin, single lab with multiple orthogonal methods","pmids":["41851796"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Shank3 knockout mouse model; chemogenetic (DREADD) activation; Sgk2 expression analysis; pharmacological Sgk inhibition with behavioral and electrophysiological readouts","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological SGK inhibition is not SGK2-specific, indirect evidence for SGK2's role in glutamate receptor trafficking; single lab, no direct SGK2 substrate identified","pmids":["31247448"],"is_preprint":false}],"current_model":"SGK2 is a serine/threonine kinase that acts downstream of PI3K signaling and is regulated by dephosphorylation (at T193 by PP2C scaffolded by PXR) or by upstream transcriptional induction; it phosphorylates multiple substrates including FOXO1 (T24/S319, promoting cytoplasmic retention and GPX4 upregulation), PTOV1 (S36, enabling 14-3-3 binding and cytosolic stabilization), EZH2 (T367, increasing stability), and V-ATPase subunit ATP6V1H (regulating lysosomal acidification and autophagy), while also modulating ENaC activity, organic anion transporter surface expression (via Nedd4-2 inhibition), and the TSC2/mTOR axis, with its kinase activity being required for most of these downstream effects."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2003,"claim":"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","pmids":["12632189"],"confidence":"Medium","gaps":["The intermediary substrate linking SGK2 to ENaC was not identified","Heterologous oocyte system may not reflect native epithelial regulation"]},{"year":2010,"claim":"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","pmids":["20616055"],"confidence":"Medium","gaps":["Mechanism connecting p53 status to SGK2 dependence was not defined","Reliance on shRNA left open the possibility of off-target killing"]},{"year":2015,"claim":"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","pmids":["25615606"],"confidence":"Medium","gaps":["Does not exclude a genuine SGK2–p53 relationship in other cell contexts","Limited to a single cell line"]},{"year":2015,"claim":"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","pmids":["26392083"],"confidence":"Medium","gaps":["How dephosphorylated SGK2 mechanistically co-activates PXR transcription is not defined","Single-lab finding without in vivo validation"]},{"year":2016,"claim":"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","pmids":["26740304"],"confidence":"Medium","gaps":["Whether SGK2 directly phosphorylates Nedd4-2 was not established","Heterologous COS-7 system"]},{"year":2016,"claim":"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","pmids":["27335683"],"confidence":"Medium","gaps":["No phosphorylation site on hOAT1 or kinase-dependence was demonstrated","Single heterologous system"]},{"year":2020,"claim":"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","pmids":["32848212"],"confidence":"Medium","gaps":["The ATP6V1H phosphosite was not mapped","Single-lab finding"]},{"year":2021,"claim":"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","pmids":["34654719"],"confidence":"Medium","gaps":["Upstream signals activating SGK2 toward PTOV1 not defined","Single-lab finding"]},{"year":2023,"claim":"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","pmids":["36720852"],"confidence":"Medium","gaps":["Direct kinase-substrate biochemistry vs. indirect effect not fully separated","Single-lab finding"]},{"year":2025,"claim":"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","pmids":["39814292"],"confidence":"Medium","gaps":["Mechanism by which T367 phosphorylation blocks EZH2 ubiquitination is undefined","Single-lab finding"]},{"year":2026,"claim":"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","pmids":["41851796"],"confidence":"Medium","gaps":["Whether SGK2 directly phosphorylates TSC2 was not shown","Single-lab finding in one cell type"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,7,8,12]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[6,7,8,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,12,13]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13]}],"complexes":[],"partners":["EZH2","PTOV1","FOXO1","ATP6V1H","NEDD4-2","PXR","PP2C","TSC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HBY8","full_name":"Serine/threonine-protein kinase Sgk2","aliases":["Serum/glucocorticoid-regulated kinase 2"],"length_aa":367,"mass_kda":41.2,"function":"Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, survival and proliferation. Up-regulates Na(+) channels: SCNN1A/ENAC, K(+) channels: KCNA3/Kv1.3, KCNE1 and KCNQ1, amino acid transporter: SLC6A19, glutamate transporter: SLC1A6/EAAT4, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9HBY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SGK2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SGK2","total_profiled":1310},"omim":[{"mim_id":"607591","title":"SERUM/GLUCOCORTICOID-REGULATED KINASE 3; SGK3","url":"https://www.omim.org/entry/607591"},{"mim_id":"607589","title":"SERUM/GLUCOCORTICOID-REGULATED KINASE 2; SGK2","url":"https://www.omim.org/entry/607589"},{"mim_id":"602958","title":"SERUM/GLUCOCORTICOID-REGULATED KINASE 1; SGK1","url":"https://www.omim.org/entry/602958"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":76.6},{"tissue":"liver","ntpm":63.5}],"url":"https://www.proteinatlas.org/search/SGK2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9HBY8","domains":[{"cath_id":"3.30.200.20","chopping":"33-117_316-352","consensus_level":"high","plddt":85.463,"start":33,"end":352},{"cath_id":"1.10.510.10","chopping":"121-303","consensus_level":"high","plddt":96.2036,"start":121,"end":303}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HBY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HBY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HBY8-F1-predicted_aligned_error_v6.png","plddt_mean":87.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SGK2","jax_strain_url":"https://www.jax.org/strain/search?query=SGK2"},"sequence":{"accession":"Q9HBY8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HBY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HBY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HBY8"}},"corpus_meta":[{"pmid":"12632189","id":"PMC_12632189","title":"The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel alpha,beta,gamma-ENaC.","date":"2003","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12632189","citation_count":69,"is_preprint":false},{"pmid":"36720852","id":"PMC_36720852","title":"SGK2 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating GPX4.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36720852","citation_count":59,"is_preprint":false},{"pmid":"26392083","id":"PMC_26392083","title":"Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26392083","citation_count":58,"is_preprint":false},{"pmid":"20616055","id":"PMC_20616055","title":"Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20616055","citation_count":48,"is_preprint":false},{"pmid":"31247448","id":"PMC_31247448","title":"Chemogenetic Activation of Prefrontal Cortex in Shank3-Deficient Mice Ameliorates Social Deficits, NMDAR Hypofunction, and Sgk2 Downregulation.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/31247448","citation_count":40,"is_preprint":false},{"pmid":"26740304","id":"PMC_26740304","title":"Serum- and glucocorticoid-inducible kinase SGK2 regulates human organic anion transporters 4 via ubiquitin ligase Nedd4-2.","date":"2015","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26740304","citation_count":20,"is_preprint":false},{"pmid":"32848212","id":"PMC_32848212","title":"Serum- and glucocorticoid- inducible kinase 2, SGK2, is a novel autophagy regulator and modulates platinum drugs response in cancer cells.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32848212","citation_count":15,"is_preprint":false},{"pmid":"39814292","id":"PMC_39814292","title":"N-acetyltransferase 10 impedes EZH2/H3K27me3/GABARAP axis mediated autophagy and facilitates lung cancer tumorigenesis through enhancing SGK2 mRNA acetylation.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39814292","citation_count":15,"is_preprint":false},{"pmid":"31002126","id":"PMC_31002126","title":"SGK2 promotes renal cancer progression via enhancing ERK 1/2 and AKT phosphorylation.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31002126","citation_count":13,"is_preprint":false},{"pmid":"28639896","id":"PMC_28639896","title":"SGK2 promotes hepatocellular carcinoma progression and mediates GSK-3β/β-catenin signaling in HCC cells.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28639896","citation_count":11,"is_preprint":false},{"pmid":"27335683","id":"PMC_27335683","title":"Serum- and glucocorticoid-inducible kinase sgk2 stimulates the transport activity of human organic anion transporters 1 by enhancing the stability of the transporter.","date":"2016","source":"International journal of biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27335683","citation_count":11,"is_preprint":false},{"pmid":"32565024","id":"PMC_32565024","title":"SGK2 is overexpressed in colon cancer and promotes epithelial-mesenchymal transition in colon cancer cells.","date":"2020","source":"European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32565024","citation_count":8,"is_preprint":false},{"pmid":"34654719","id":"PMC_34654719","title":"SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1.","date":"2021","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/34654719","citation_count":7,"is_preprint":false},{"pmid":"25615606","id":"PMC_25615606","title":"Lethality of PAK3 and SGK2 shRNAs to human papillomavirus positive cervical cancer cells is independent of PAK3 and SGK2 knockdown.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25615606","citation_count":6,"is_preprint":false},{"pmid":"34899399","id":"PMC_34899399","title":"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.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34899399","citation_count":3,"is_preprint":false},{"pmid":"41851796","id":"PMC_41851796","title":"SGK2 mediates apoptosis in herpes simplex keratitis by suppressing protective autophagy via the mTOR pathway.","date":"2026","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/41851796","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9752,"output_tokens":4163,"usd":0.045851,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12074,"output_tokens":3768,"usd":0.077285,"stage2_stop_reason":"end_turn"},"total_usd":0.123136,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Dual-electrode voltage-clamp in Xenopus laevis oocytes; site-directed mutagenesis of αENaC S622A\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional electrophysiology assay with mutagenesis in a heterologous system, single study with two orthogonal approaches\",\n      \"pmids\": [\"12632189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, reporter gene assays, SGK2 T193 mutagenesis, human liver cell overexpression/knockdown experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, phosphorylation site identified, functional reporter assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26392083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Transport activity assays in COS-7 cells, surface biotinylation, ubiquitination assays, co-immunoprecipitation, Nedd4-2 overexpression and siRNA knockdown\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing interaction disruption, functional transport assays, and orthogonal siRNA/overexpression, single lab\",\n      \"pmids\": [\"26740304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Transport activity assays in COS-7 cells, surface biotinylation, co-immunoprecipitation, protein stability assays\",\n      \"journal\": \"International journal of biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP interaction, functional transport assays with kinetic analysis, single lab with multiple methods\",\n      \"pmids\": [\"27335683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown screening; epistasis analysis in primary human epithelial cells with defined p53 inactivation stages; tested across multiple cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis across multiple cell lines, replicated in different primary epithelia, but note that a follow-up study (PMID 25615606) raised concerns about shRNA off-target effects in HeLa cells specifically\",\n      \"pmids\": [\"20616055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA rescue experiments, mismatch shRNA controls, non-human control shRNAs in HeLa cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous negative result with multiple controls; establishes off-target mechanism for a specific prior claim\",\n      \"pmids\": [\"25615606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding, kinase-dependent phosphorylation of a defined substrate, functional autophagy assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32848212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation site mapping (S36), mutagenesis of S36, subcellular fractionation/localization studies, proteasome inhibitor experiments, HUWE1 interaction assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific phosphorylation with mutagenesis, Co-IP interactions, localization experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34654719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined phosphorylation sites on substrate, subcellular localization shift measured by fractionation, in vivo and in vitro evidence, single lab\",\n      \"pmids\": [\"36720852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGK2 promotes ERK1/2 and AKT phosphorylation in renal cell carcinoma cells, and silencing SGK2 inhibited proliferation, migration, colony formation, and invasion.\",\n      \"method\": \"SGK2 knockdown and overexpression in RCC cell lines; Western blot for phospho-ERK1/2 and phospho-AKT\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Western blot only, no direct kinase assay or substrate identification, no mechanistic pathway placement\",\n      \"pmids\": [\"31002126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"SGK2 knockdown in HCC cell lines; Western blot for GSK-3β and β-catenin phosphorylation status; migration/invasion assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Western blot only for pathway analysis, no direct SGK2 kinase assay on GSK-3β, no mutagenesis\",\n      \"pmids\": [\"28639896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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)\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined thermogenic phenotype readout, promoter ChIP, in vitro complementary assays, single lab with multiple methods; negative result for thermogenesis is well-supported\",\n      \"pmids\": [\"34899399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SGK2-EZH2 interaction), phosphorylation assays at EZH2 T367, ubiquitination assays, H3K27me3 ChIP on GABARAP promoter, autophagy flux assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction, defined phosphorylation site, ubiquitination and histone modification readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39814292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"SGK2 knockdown (shRNA) and pharmacological inhibition (GSK 650394) in HCECs; Western blot for TSC2, mTOR pathway components; flow cytometry apoptosis; immunofluorescence; rapamycin rescue experiments\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological loss-of-function with defined molecular pathway readouts, rescue experiment with rapamycin, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41851796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Shank3 knockout mouse model; chemogenetic (DREADD) activation; Sgk2 expression analysis; pharmacological Sgk inhibition with behavioral and electrophysiological readouts\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological SGK inhibition is not SGK2-specific, indirect evidence for SGK2's role in glutamate receptor trafficking; single lab, no direct SGK2 substrate identified\",\n      \"pmids\": [\"31247448\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SGK2 is a serine/threonine kinase that acts downstream of PI3K signaling and is regulated by dephosphorylation (at T193 by PP2C scaffolded by PXR) or by upstream transcriptional induction; it phosphorylates multiple substrates including FOXO1 (T24/S319, promoting cytoplasmic retention and GPX4 upregulation), PTOV1 (S36, enabling 14-3-3 binding and cytosolic stabilization), EZH2 (T367, increasing stability), and V-ATPase subunit ATP6V1H (regulating lysosomal acidification and autophagy), while also modulating ENaC activity, organic anion transporter surface expression (via Nedd4-2 inhibition), and the TSC2/mTOR axis, with its kinase activity being required for most of these downstream effects.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SGK2 is a serine/threonine kinase that controls protein stability, subcellular localization, and membrane transporter abundance across epithelial physiology and cancer cell biology [#6, #8]. Its catalytic output reshapes the fate of multiple substrates: it phosphorylates the V-ATPase subunit ATP6V1H to drive lysosomal acidification and autophagic flux [#6], phosphorylates FOXO1 at Thr-24/Ser-319 to force its nuclear-to-cytoplasmic translocation, derepressing GPX4 and suppressing ferroptosis [#8], 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 [#7], and phosphorylates EZH2 at Thr-367 to block its ubiquitination, stabilizing EZH2 for H3K27me3-mediated repression of GABARAP and inhibition of autophagy [#12]. 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 [#2, #3], and where it promotes TSC2 degradation to activate mTOR and suppress protective autophagy during HSV-1 infection [#13]. SGK2 likewise stimulates ENaC current in a manner independent of direct channel phosphorylation [#0], and its own activity is regulated by PXR-scaffolded PP2C dephosphorylation at Thr-193, which couples it to co-activation of gluconeogenic transcription [#1], and by transcriptional induction via the β3-adrenergic–PKA–PGC-1α axis [#11]. An early report of synthetic lethality between SGK2 loss and p53 inactivation [#4] was subsequently shown to arise from shRNA off-target effects rather than on-target SGK2 dependence [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Dual-electrode voltage-clamp with αENaC S622A mutagenesis in Xenopus oocytes\",\n      \"pmids\": [\"12632189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The intermediary substrate linking SGK2 to ENaC was not identified\", \"Heterologous oocyte system may not reflect native epithelial regulation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Proposed that p53 loss creates a selective dependence on SGK2, positioning the kinase as a candidate synthetic-lethal cancer target.\",\n      \"evidence\": \"shRNA knockdown epistasis screening in primary human epithelial cells with defined p53 inactivation\",\n      \"pmids\": [\"20616055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting p53 status to SGK2 dependence was not defined\", \"Reliance on shRNA left open the possibility of off-target killing\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"cDNA rescue failure, single-mismatch knockdown-deficient shRNA, and non-human control shRNAs in HeLa cells\",\n      \"pmids\": [\"25615606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not exclude a genuine SGK2–p53 relationship in other cell contexts\", \"Limited to a single cell line\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, T193 mutagenesis, and reporter assays in human liver cells\",\n      \"pmids\": [\"26392083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How dephosphorylated SGK2 mechanistically co-activates PXR transcription is not defined\", \"Single-lab finding without in vivo validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a transporter-regulatory role for SGK2 by showing it increases hOAT4 surface expression through disrupting the hOAT4–Nedd4-2 interaction and reducing ubiquitination.\",\n      \"evidence\": \"Transport assays, surface biotinylation, ubiquitination assays, and Co-IP with Nedd4-2 manipulation in COS-7 cells\",\n      \"pmids\": [\"26740304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SGK2 directly phosphorylates Nedd4-2 was not established\", \"Heterologous COS-7 system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended SGK2 transporter regulation to hOAT1, showing direct interaction and protein stabilization increase surface transporter levels.\",\n      \"evidence\": \"Transport assays, biotinylation, Co-IP, and protein-stability assays in COS-7 cells\",\n      \"pmids\": [\"27335683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No phosphorylation site on hOAT1 or kinase-dependence was demonstrated\", \"Single heterologous system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Loss-of-function screen, knockdown and chemical inhibition, autophagy/lysosomal assays, Co-IP and ATP6V1H phosphorylation assays in ovarian cancer cells\",\n      \"pmids\": [\"32848212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The ATP6V1H phosphosite was not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phosphosite mapping and S36 mutagenesis, Co-IP, fractionation, and proteasome-inhibitor experiments\",\n      \"pmids\": [\"34654719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals activating SGK2 toward PTOV1 not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Knockdown/overexpression in vitro and in vivo, FOXO1 phosphorylation assays, fractionation, and ferroptosis assays\",\n      \"pmids\": [\"36720852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase-substrate biochemistry vs. indirect effect not fully separated\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated SGK2 phosphorylation of EZH2 at Thr-367 stabilizes EZH2, linking SGK2 to H3K27me3-mediated GABARAP repression and autophagy inhibition in lung cancer.\",\n      \"evidence\": \"Co-IP, EZH2 T367 phosphorylation and ubiquitination assays, H3K27me3 ChIP, and autophagy flux assays\",\n      \"pmids\": [\"39814292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which T367 phosphorylation blocks EZH2 ubiquitination is undefined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"shRNA and pharmacological inhibition in human corneal epithelial cells with TSC2/mTOR readouts and rapamycin rescue\",\n      \"pmids\": [\"41851796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SGK2 directly phosphorylates TSC2 was not shown\", \"Single-lab finding in one cell type\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 7, 8, 12]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [6, 7, 8, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 12, 13]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EZH2\",\n      \"PTOV1\",\n      \"FOXO1\",\n      \"ATP6V1H\",\n      \"Nedd4-2\",\n      \"PXR\",\n      \"PP2C\",\n      \"TSC2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}