{"gene":"SGK3","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2014,"finding":"SGK3 activity requires PtdIns(3)P binding via its N-terminal PX domain; mutations disrupting PtdIns(3)P binding ablated SGK3 kinase activity by suppressing phosphorylation of the T-loop (PDK1 site) and hydrophobic motif (mTOR site). Two pools of PtdIns(3)P control SGK3: one generated by Vps34 class III PI3K at endosomes, and a second derived from dephosphorylation of class I PI3K product PtdIns(3,4,5)P3 via SHIP1/2 and INPP4B.","method":"Selective Vps34 inhibitor (VPS34-IN1), PX domain mutagenesis, class I PI3K inhibitors (GDC-0941, BKM120), phosphorylation assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal pharmacological and mutagenesis approaches in a single rigorous study, replicated by subsequent work","pmids":["25177796"],"is_preprint":false},{"year":2021,"finding":"SGK3 activation by PI3P is mediated by a combination of phosphorylation and allosteric activation. Binding of PI3P to the PX domain induces large conformational changes associated with SGK3 activation; the PI3P-binding pocket of the PX domain is sequestered in the inactive conformation. SGK3 activation was reconstituted in vitro via Vps34-mediated PI3P synthesis on phosphatidylinositol liposomes.","method":"Hydrogen-deuterium exchange mass spectrometry, in vitro reconstitution with liposomes, biochemical and biophysical assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with multiple orthogonal biophysical methods including HDX-MS and functional assays in a single rigorous study","pmids":["34181950"],"is_preprint":false},{"year":2018,"finding":"Endogenous SGK3 is rapidly activated by IGF1 through both Class 1 and Class 3 (hVPS34) PI3Ks. IGF1 enhances endosomal PtdIns(3)P levels via the UV-RAG complex of hVPS34. Class 1 PI3K activates SGK3 through PtdIns(3)P derived from dephosphorylation of PtdIns(3,4,5)P3, and also promotes mTORC2 phosphorylation of SGK3. Oncogenic Ras activates SGK3 solely through the Class 1 PI3K pathway.","method":"Pharmacological inhibition of Class 1 and Class 3 PI3Ks, endosomal PtdIns(3)P measurement, mTORC2 pathway analysis, Ras pathway dissection","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal pharmacological and genetic approaches in a focused mechanistic study","pmids":["29150437"],"is_preprint":false},{"year":2016,"finding":"Under prolonged PI3K/Akt inhibition, SGK3 expression and activation increases and is controlled by hVps34-generated PtdIns(3)P binding to the PX domain, promoting PDK1-dependent phosphorylation and activation. SGK3 substitutes for Akt by phosphorylating TSC2 to activate mTORC1 signaling.","method":"Prolonged PI3K/Akt inhibitor treatment of breast cancer cells, SGK3 phosphorylation and kinase activity assays, TSC2 phosphorylation assays, xenograft tumor model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical, cellular, in vivo xenograft) with defined mechanistic readouts, replicated across contexts","pmids":["27481935"],"is_preprint":false},{"year":2014,"finding":"SGK3 is activated downstream of oncogenic PIK3CA in a manner dependent on the phosphoinositide phosphatase INPP4B. INPP4B expression enhances SGK3 activation and suppresses Akt phosphorylation. SGK3 targets the metastasis suppressor NDRG1 for degradation by the E3 ligase Fbw7.","method":"Genetic knockdown/overexpression, co-immunoprecipitation, phosphorylation assays, 3D proliferation and invasion assays, in vivo tumorigenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including in vivo validation and identification of direct substrate, replicated by subsequent studies","pmids":["25458846"],"is_preprint":false},{"year":2019,"finding":"SGK3-PROTAC1, a PROTAC conjugate targeting SGK3 for VHL-dependent proteasomal degradation, selectively degrades SGK3 (not SGK1/SGK2) and reduces phosphorylation of NDRG1, confirming NDRG1 as an endogenous SGK3 substrate. Proteomic analysis confirmed SGK3 as the only protein selectively degraded.","method":"PROTAC degrader, proteomics, NDRG1 phosphorylation assay, breast cancer cell viability assays","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chemical-genetic approach with proteome-wide selectivity analysis and functional substrate validation","pmids":["31461270"],"is_preprint":false},{"year":2019,"finding":"Phosphoproteomic screens identified novel SGK3-specific substrates at endosomes: STX7 (Ser126), STX12 (Ser139), RFIP4 (Ser527), and WDR44 (Ser346). These were efficiently phosphorylated by SGK3 in vitro and in vivo but poorly by Akt, due to an n+1 residue unfavorable for Akt. SGK3 phosphorylation of STX12 enhanced its interaction with VAMP4/VTI1A/STX6 SNARE complex and promoted plasma membrane localization of STX12.","method":"Genetic and pharmacological phosphoproteomic screens, in vitro kinase assays, Phos-tag analysis, Co-IP, SGK3 knockout cells, pan-SGK inhibitor (14H)","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assays combined with in-cell phosphoproteomic validation, KO controls, and functional SNARE complex interaction assay","pmids":["31665227"],"is_preprint":false},{"year":2002,"finding":"SGK3 (SGKL) phosphorylates GSK-3β at Ser9 through direct physical interaction. GSK-3β was identified as a binding partner of SGK3 by yeast two-hybrid screen, confirmed by co-immunoprecipitation in HEK293 cells; in vitro kinase assay demonstrated SGK3 phosphorylates GSK-3 at Ser21/9.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay with phospho-specific antibody","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus Co-IP confirmation in a single study, later corroborated by multiple downstream studies showing SGK3→GSK3β→β-catenin pathway","pmids":["12054501"],"is_preprint":false},{"year":2019,"finding":"SGK3 phosphorylates TSC2 to reactivate mTORC1/4EBP1 axis during rapamycin treatment. Feedback activation of SGK3 by rapamycin is dependent on hVps34 and mTORC2. SGK3 deletion combined with Akt inhibition nearly abolished rapamycin-induced 4EBP1 re-phosphorylation.","method":"SGK3 deletion (CRISPR), phosphoproteomic analysis, pharmacological inhibitors, xenograft model, clinical breast cancer specimens","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion with pharmacological validation in vitro and in vivo, single lab","pmids":["31182914"],"is_preprint":false},{"year":2004,"finding":"SGK3 stimulates SGLT1 (Na+-coupled glucose transporter) activity by reversing Nedd4-2-mediated inhibition. SGK3 and SGK1 phosphorylate Nedd4-2 at SGK/PKB consensus sites; deletion of these phosphorylation sites in Nedd4-2 blunted the kinase effects on SGLT1.","method":"Xenopus oocyte expression, electrophysiological current measurement, site-directed mutagenesis of Nedd4-2","journal":"Obesity research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional reconstitution in oocytes with mutagenesis of key phosphorylation sites, multiple kinase isoforms tested as controls","pmids":["15166308"],"is_preprint":false},{"year":2003,"finding":"SGK3 stimulates epithelial Na+ channel (ENaC) activity in Xenopus oocytes. The effect is not via direct phosphorylation of αENaC at its SGK consensus site (S622A mutation did not abolish stimulation), indicating an indirect mechanism.","method":"Xenopus oocyte dual-electrode voltage-clamp, site-directed mutagenesis of αENaC (S622A)","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — functional reconstitution with mutagenesis, single lab","pmids":["12632189"],"is_preprint":false},{"year":2004,"finding":"SGK3 upregulates TRPV5 Ca2+ channel activity in Xenopus oocytes, an effect requiring co-expression of the PDZ scaffold protein NHERF2. Constitutively active SGK3 stimulated tracer Ca2+ entry and TRPV5-mediated currents, while inactive SGK3 and SGK2 did not.","method":"Xenopus oocyte expression, tracer Ca2+ uptake, electrophysiology, cRNA co-injection with NHERF2","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional oocyte reconstitution, multiple kinase isoforms as controls, single lab","pmids":["15319523"],"is_preprint":false},{"year":2007,"finding":"SGK3 upregulates TRPV6 Ca2+ channel plasma membrane abundance and activity in Xenopus oocytes. Unlike TRPV5, this effect does not require PDZ-scaffold proteins NHERF1 or NHERF2 and is not dependent on the putative PDZ-binding motif on TRPV6.","method":"Xenopus oocyte expression, chemiluminescence for membrane protein abundance, electrophysiology","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in oocytes with mechanistic comparison to TRPV5, single lab","pmids":["18005662"],"is_preprint":false},{"year":2005,"finding":"SGK3 upregulates excitatory amino acid transporter EAAT5 by increasing its cell surface abundance. Both EAAT5-mediated currents and surface protein levels were increased approximately 1.5–2-fold by SGK1 or SGK3, but not by PKB.","method":"Xenopus oocyte expression, electrophysiology, chemiluminescence for surface protein abundance","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with surface expression measurement, single lab","pmids":["15737648"],"is_preprint":false},{"year":2005,"finding":"SGK3 (but not SGK2 or PKB) stimulates the creatine transporter SLC6A8 by increasing its maximal transport rate in Xenopus oocytes, without significantly altering affinity.","method":"Xenopus oocyte expression, electrophysiology, kinetic analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with kinetic analysis and isoform selectivity controls, single lab","pmids":["16036218"],"is_preprint":false},{"year":2013,"finding":"SGK3 increases mature hERG channel expression and current in HEK293 cells by two mechanisms: (1) inhibiting Nedd4-2 via phosphorylation, and (2) promoting Rab11-mediated hERG channel recycling to the plasma membrane. Disrupting both Nedd4-2 binding sites and Rab11 eliminated the SGK3-mediated increase in hERG expression.","method":"HEK293 stable expression, overexpression, Nedd4-2 phosphorylation assay, dominant-negative Rab11, site-directed mutagenesis of hERG Nedd4-2 binding site","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent mechanisms identified and validated by mutagenesis and dominant-negative approaches in a single study","pmids":["23589291"],"is_preprint":false},{"year":2006,"finding":"SGK3 (but not SGK1) increases HERG channel plasma membrane protein abundance and current in Xenopus oocytes without affecting channel gating kinetics. Alanine substitution at both SGK consensus sites in HERG decreased baseline current but did not abolish SGK3-mediated stimulation.","method":"Xenopus oocyte expression, two-electrode voltage clamp, chemiluminescence for membrane abundance, mutagenesis","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with surface expression measurement and mutagenesis, single lab","pmids":["17167223"],"is_preprint":false},{"year":2004,"finding":"SGK3 null mice display defective postnatal hair follicle morphogenesis, with reduced proliferation and impaired nuclear β-catenin accumulation in hair bulb keratinocytes. In cultured keratinocytes, SGK3 potently modulates β-catenin/Lef-1-mediated gene transcription.","method":"Sgk3 knockout mice, histology, BrdU proliferation, immunofluorescence for β-catenin, reporter gene assays in keratinocytes","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype plus mechanistic reporter assay, replicated by multiple subsequent studies","pmids":["15240817"],"is_preprint":false},{"year":2005,"finding":"SGK3 is required for adequate intestinal Na+-coupled glucose transport in vivo. Sgk3 knockout mice show significantly reduced glucose-induced currents in jejunal segments, lower fasting plasma glucose, and enhanced food intake.","method":"Sgk3 knockout mice, Ussing chamber electrophysiology for glucose transport, plasma glucose measurement","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined transport phenotype in intact tissue, single lab","pmids":["15971077"],"is_preprint":false},{"year":2005,"finding":"SGK3 loss in hair follicle leads to reduced proliferation, increased apoptosis, and premature regression of follicles. Using primary keratinocytes, SGK3 functions by negatively regulating PI3K signaling in this context.","method":"Sgk3 knockout mice, proliferation and apoptosis quantification, primary keratinocyte culture, PI3K pathway analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype and mechanistic pathway placement, single lab","pmids":["16103225"],"is_preprint":false},{"year":2009,"finding":"SGK3 and Akt2 both regulate postnatal hair follicle morphogenesis through redundant control of β-catenin-dependent transcription. Akt2/SGK3 double knockout mice have a markedly worse hair growth defect than SGK3 single KO, with profound failure to accumulate nuclear β-catenin in follicle matrix cells. Transfected Akt2 and SGK3 both stimulate a β-catenin-LEF1 reporter in keratinocytes.","method":"Akt2/SGK3 double knockout mice, histology, immunofluorescence, β-catenin-LEF1 reporter assay in keratinocytes","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double KO, reporter assay mechanistic validation, replicated findings on β-catenin pathway","pmids":["19433625"],"is_preprint":false},{"year":2006,"finding":"SGK3 phosphorylation of GSK3β at Ser9 and reduced nuclear β-catenin accumulation are observed in SGK3-mutant (YPC) mouse hair follicles, implicating the SGK3→GSK3β→β-catenin/WNT pathway in hair follicle development.","method":"Immunohistochemistry for p-GSK3β(Ser9) and β-catenin in SGK3-mutant YPC mouse hair follicles","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunohistochemical pathway analysis in genetic model, corroborated by multiple independent studies","pmids":["16565488"],"is_preprint":false},{"year":2011,"finding":"SGK3 plays a role in pancreatic β-cell function. Akt2/SGK3 double knockout mice show worse glucose homeostasis than Akt2 single nulls, with lower plasma insulin, reduced β-cell mass, impaired glucose-stimulated insulin secretion, and dramatically lower β-catenin in islets.","method":"Akt2/SGK3 double knockout mice, glucose tolerance tests, plasma insulin/C-peptide, β-cell mass quantification, β-catenin immunostaining in islets","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in double KO with multiple metabolic and cellular readouts, single lab","pmids":["21980074"],"is_preprint":false},{"year":2010,"finding":"SGK3 is transcriptionally regulated by estrogen receptor α (ERα) in breast cancer cells. ERα binds two regions at the sgk3 locus (identified by ChIP-seq) and stimulates sgk3 promoter activity. SGK3 is required for estrogen-mediated cell survival of MCF-7 cells, and SGK3 overexpression partially protects against apoptosis induced by antiestrogen ICI 182,780.","method":"ChIP-seq, promoter reporter assays, siRNA knockdown, apoptosis assays, E2 dose/time-response","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq identification of ERα binding sites combined with promoter reporter and functional KD assays, multiple orthogonal methods","pmids":["21084382"],"is_preprint":false},{"year":2014,"finding":"SGK3 is an androgen receptor (AR) transcriptional target in prostate cancer. SGK3 expression is induced by DHT/AR, requiring co-expression of estrogen receptor. SGK3 promotes G1-S cell cycle progression by activating p70 S6 kinase and upregulating cyclin D1.","method":"ChIP for AR binding at sgk3 locus, siRNA knockdown, cell cycle analysis, p70S6K and cyclin D1 measurement, ER depletion experiments","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional knockdown with defined downstream readouts, single lab","pmids":["24739041"],"is_preprint":false},{"year":2017,"finding":"SGK3 promotes endoplasmic reticulum (EnR) homeostasis by preserving SERCA2b function in aromatase inhibitor (AI)-resistant breast cancer cells, thereby sustaining ERα signaling. SGK3 prevents excessive EnR stress-induced suppression of ERα expression through the PERK arm of the UPR. This creates a feed-forward loop between SGK3 and ERα.","method":"SGK3 knockdown/overexpression, ER stress markers, SERCA2b functional analysis, ERα expression analysis, AI-resistant cell models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation with mechanistic pathway dissection, single lab","pmids":["28174265"],"is_preprint":false},{"year":2010,"finding":"SGK3 in vitro phosphorylates heart PFK-2 at Ser466 and Ser483, activating the enzyme. However, SGK3 is NOT required for insulin-induced PFK-2 activation in cells (siRNA knockdown had no effect on insulin response), establishing a negative result for this in vivo pathway.","method":"In vitro kinase assay with [γ-32P]ATP, SGK3 siRNA knockdown in HEK-293T cells, insulin stimulation assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus cellular siRNA experiment; negative in-cell result well-controlled","pmids":["20687898"],"is_preprint":false},{"year":2012,"finding":"SGK3 regulates store-operated Ca2+ (SOC) entry and migration of dendritic cells. SGK3 knockout DCs show reduced SOC entry triggered by thapsigargin, reduced LPS- and CXCL12-induced Ca2+ increases, reduced SOC channel currents, and lower STIM2 protein levels. Migration of both immature and LPS-matured DCs was reduced in SGK3 KO.","method":"SGK3 knockout mice, bone marrow-derived DC culture, Ca2+ imaging, patch-clamp, Western blot for STIM2/Orai, chemotaxis assays","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple orthogonal cellular readouts, single lab","pmids":["23171960"],"is_preprint":false},{"year":2015,"finding":"SGK3 is a downstream effector of PDK1 in BRAF-mutant melanoma cells. Genetic or pharmacologic inhibition of PDK1 or SGK3 attenuates melanoma growth by inducing G1 phase cell cycle arrest.","method":"Genetic knockdown, pharmacological inhibition, cell cycle analysis, synthetic lethal screen with pan-PI3K inhibitor","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological inhibition with defined cell cycle phenotype, single lab","pmids":["25712345"],"is_preprint":false},{"year":2020,"finding":"PDPK1 (PDK1) mediates prostate cancer cell survival predominantly through activation/phosphorylation of SGK3, not through SGK1 or AKT. Ectopic expression of constitutively active SGK3 completely abrogated apoptosis induced by PDPK1 knockdown.","method":"Lentiviral shRNA kinome screen, PDPK1 knockdown, SGK3 constitutively active rescue, phosphorylation assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by rescue experiment with constitutively active SGK3, single lab","pmids":["32926495"],"is_preprint":false},{"year":2018,"finding":"INPP4B promotes leukemia cell survival via SGK3 activation (not Akt). INPP4B overexpression enhanced phosphorylated SGK3 status and increased PtdIns(3)P and PtdIns(3,4)P2 levels. SGK3 knockdown was required to eliminate INPP4B-induced proliferation in OCI-AML3 NPM1-mutated leukemia cells.","method":"INPP4B knockdown/overexpression, SGK3 phosphorylation assay, PtdIns lipid ELISA, siRNA rescue experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with lipid measurements and functional rescue, single lab","pmids":["29343273"],"is_preprint":false},{"year":2023,"finding":"SGK3 maintains redox homeostasis by directly interacting with and phosphorylating catalase, promoting its tetrameric state and enzymatic activity. SGK3 also phosphorylates GSK3β to protect catalase from GSK3β-β-TrCP-mediated ubiquitination and proteasomal degradation.","method":"Co-immunoprecipitation, in vitro kinase assay for catalase phosphorylation, catalase activity assay, ubiquitination assay, ROS measurement","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with substrate identification plus Co-IP and functional enzyme activity measurement, single lab with multiple orthogonal methods","pmids":["37866161"],"is_preprint":false},{"year":2024,"finding":"SGK3 promotes vascular calcification in CKD by enhancing expression and activity of the sodium-dependent phosphate cotransporter Pit-1. Mechanistically, SGK3 activates Pit-1 mRNA transcription via NF-κB, inhibits Nedd4-2-mediated Pit-1 ubiquitin-proteasome degradation, and directly interacts with and phosphorylates Pit-1 at Thr468 in loop7 to enhance phosphate uptake.","method":"Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, NF-κB reporter, Nedd4-2 activity assay, SGK3 knockdown in VSMCs, uremic mouse model","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay with specific phosphorylation site identification, Co-IP, functional assays in cells and in vivo, multiple orthogonal mechanisms","pmids":["38169564"],"is_preprint":false},{"year":2022,"finding":"CDK9 binds and directly activates SGK3 to promote cardiomyocyte proliferation and cardiac repair. CDK9-SGK3 interaction was identified by quantitative phosphoproteomics and confirmed by pulldown and Co-IP. CDK9 promotes cardiac repair via SGK3 and the downstream GSK-3β/β-catenin pathway.","method":"Quantitative phosphoproteomics, pulldown assay, Co-immunoprecipitation, CDK9 overexpression/knockdown, in vivo cardiac injury models","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmation of direct binding plus functional in vivo epistasis, single lab","pmids":["36082129"],"is_preprint":false},{"year":2025,"finding":"SGK3 promotes breast cancer cell proliferation and stemness via the STAT3/ZMIZ2/β-catenin signaling pathway. Proteomics identified ZMIZ2 as a downstream target of SGK3; SGK3 activates STAT3, which drives ZMIZ2 transcription. ZMIZ2 binds and stabilizes β-catenin; SGK3 knockdown causes β-catenin polyubiquitination and degradation that is reversed by ZMIZ2 overexpression.","method":"Proteomics, ChIP for p-STAT3 at ZMIZ2 promoter, Co-IP for ZMIZ2-β-catenin, lentiviral knockdown/overexpression, ubiquitination assay","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-based substrate identification with ChIP, Co-IP, and functional rescue, single lab","pmids":["39876548"],"is_preprint":false},{"year":2018,"finding":"SGK3 upregulates the inward rectifier K+ channel Kir2.1 by increasing channel protein abundance in the cell membrane (insertion rather than reduced retrieval), as the rate of current decay following brefeldin A treatment was similar with or without SGK3. Kinase-inactive SGK3 had no effect, and the SGK inhibitor EMD638683 abrogated the effect.","method":"Xenopus oocyte expression, two-electrode voltage clamp, immunostaining/confocal imaging, chemiluminescence, brefeldin A decay assay","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with mechanistic trafficking dissection using brefeldin A, single lab","pmids":["24556932"],"is_preprint":false},{"year":2006,"finding":"SGK3 and stargazin regulate GluR1 (AMPA receptor) surface expression independently and additively. SGK3 increases GluR1 plasma membrane abundance at late timepoints (6 days post-injection), while stargazin accelerates membrane insertion earlier (2 days). Mutagenesis of the SGK consensus site in stargazin did not prevent SGK3-mediated stimulation.","method":"Xenopus oocyte expression, electrophysiology, Western blot for membrane protein, cRNA injection timing experiments, mutagenesis","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution with mutagenesis and mechanistic timing experiments, single lab","pmids":["16485113"],"is_preprint":false},{"year":2018,"finding":"SGK3 triggers ubiquitin-proteasome degradation of podocalyxin (PC) and ezrin in podocytes. The SGK3/Nedd4-2 signaling pathway specifically regulates ezrin ubiquitination but not PC ubiquitination directly. Downregulation of SGK3 activity decreased PC and ezrin protein expression and increased their ubiquitin-proteasome degradation; upregulation mostly reversed PAN-induced decrease.","method":"SGK3 knockdown/overexpression in podocytes, ubiquitination assay, Co-IP for PC/ezrin interaction, Nedd4-2 knockdown/overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays including ubiquitination and Co-IP, with gain/loss of function, single lab","pmids":["30385740"],"is_preprint":false},{"year":2024,"finding":"SGK3 deficiency in macrophages attenuates angiotensin II-induced cardiac remodeling by inhibiting the NLRP3/Caspase-1/IL-1β pathway, reducing IL-1β secretion, and consequently suppressing Ndufa13 expression and mitochondrial oxidative stress in cardiomyocytes and fibroblasts.","method":"SGK3-Lyz2-CRE conditional KO mice, Ang II infusion model, RNA sequencing, co-culture system, pathway inhibitor experiments","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with RNA-seq pathway identification and mechanistic co-culture validation, single lab","pmids":["39158709"],"is_preprint":false},{"year":2024,"finding":"SGK3 recruitment to endosomes (via PX domain/PtdIns(3)P) is necessary for TLR7 signaling in plasmacytoid dendritic cells. VPS34-IN1 blocks SGK3 endosomal recruitment and impairs TLR7-dependent innate signaling.","method":"VPS34-IN1 pharmacological inhibition, SGK3 endosomal localization assay, TLR7 signaling readout in pDCs","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, pharmacological only (no SGK3-specific genetic control confirmed), single lab","pmids":[],"is_preprint":true}],"current_model":"SGK3 is a PX domain-containing AGC serine/threonine kinase that is recruited to endosomal membranes by binding PtdIns(3)P — generated by both class III PI3K (Vps34/hVPS34) and by dephosphorylation of class I PI3K products (PtdIns(3,4,5)P3 → PtdIns(3)P via SHIP1/2 and INPP4B); PtdIns(3)P binding induces allosteric conformational changes and promotes PDK1 (T-loop) and mTORC2 (hydrophobic motif) phosphorylation to fully activate the kinase. Active SGK3 phosphorylates multiple substrates including TSC2 (activating mTORC1), NDRG1 (targeting it for Fbw7-mediated degradation), GSK3β (Ser9, suppressing it to stabilize β-catenin), catalase (promoting its tetrameric active state and protecting it from GSK3β/β-TrCP-mediated degradation), endosomal SNARE proteins (STX7, STX12, RFIP4, WDR44), Nedd4-2 (inhibiting this E3 ubiquitin ligase to increase surface abundance of ENaC, SGLT1, hERG, TRPV5/6, and other ion channels/transporters), and Pit-1 (enhancing phosphate uptake). SGK3 thus mediates Akt-independent PI3K oncogenic signaling, confers resistance to PI3K/Akt inhibitors by substituting for Akt in activating mTORC1, regulates endosomal membrane trafficking, maintains endoplasmic reticulum homeostasis, controls hair follicle morphogenesis via β-catenin/LEF1 transcription, and governs intestinal nutrient absorption, dendritic cell Ca2+ signaling and migration, and cardiac remodeling."},"narrative":{"mechanistic_narrative":"SGK3 is a PX-domain-containing AGC serine/threonine kinase that couples endosomal phosphoinositide signaling to cell growth, survival, membrane trafficking, and ion-transport control [PMID:25177796, PMID:25458846]. Its activation is gated by PtdIns(3)P binding to the N-terminal PX domain: this lipid is supplied both by class III PI3K (Vps34, including via the UVRAG/IGF1 axis) at endosomes and by dephosphorylation of class I PI3K-derived PtdIns(3,4,5)P3 through INPP4B and SHIP, and the resulting allosteric conformational change permits PDK1 (T-loop) and mTORC2 (hydrophobic motif) phosphorylation to fully activate the kinase [PMID:25177796, PMID:34181950, PMID:29150437]. This wiring lets SGK3 act as an Akt-independent arm of oncogenic PI3K signaling, and under prolonged PI3K/Akt or rapamycin treatment it is induced and substitutes for Akt by phosphorylating TSC2 to reactivate mTORC1 [PMID:27481935, PMID:31182914]. SGK3 phosphorylates a defined substrate set: NDRG1, targeting it for Fbw7-mediated degradation [PMID:25458846, PMID:31461270]; GSK3β at Ser9, suppressing it to stabilize β-catenin and drive β-catenin/LEF1-dependent transcription required for hair follicle morphogenesis [PMID:12054501, PMID:15240817, PMID:19433625]; endosomal SNARE and trafficking proteins STX7, STX12, RFIP4 and WDR44, with STX12 phosphorylation enhancing its SNARE-complex interaction and surface delivery [PMID:31665227]; and catalase, promoting its active tetrameric state and protecting it from degradation to maintain redox homeostasis [PMID:37866161]. Through phosphorylation of the E3 ligase Nedd4-2, SGK3 raises the surface abundance and activity of numerous channels and transporters, including SGLT1, ENaC, TRPV5/TRPV6, hERG and Pit-1 [PMID:15166308, PMID:23589291, PMID:38169564]. Genetically, SGK3 governs hair follicle development, intestinal Na+-coupled glucose absorption, and dendritic-cell store-operated Ca2+ entry and migration [PMID:15240817, PMID:15971077, PMID:23171960]. SGK3 is itself a transcriptional target of estrogen receptor α and androgen receptor, embedding it in hormone-driven cancer survival programs [PMID:21084382, PMID:24739041].","teleology":[{"year":2002,"claim":"Established the first direct SGK3 substrate and a route into Wnt signaling by showing SGK3 binds and phosphorylates GSK3β at Ser9.","evidence":"Yeast two-hybrid, Co-IP in HEK293, and in vitro kinase assay with phospho-specific antibody","pmids":["12054501"],"confidence":"High","gaps":["Did not establish the cellular/physiological context of the SGK3→GSK3β axis","No structural basis for the interaction"]},{"year":2004,"claim":"Linked SGK3 to in vivo development by showing SGK3-null mice fail in hair follicle morphogenesis through impaired β-catenin/LEF1 transcription, connecting the kinase to a defined developmental program.","evidence":"Sgk3 knockout mice, histology, BrdU proliferation, β-catenin immunofluorescence, keratinocyte reporter assays","pmids":["15240817"],"confidence":"High","gaps":["Did not resolve which SGK3 substrate drives β-catenin accumulation in vivo","Redundancy with other kinases unaddressed"]},{"year":2004,"claim":"Defined a mechanism by which SGK3 controls membrane transporters, showing it phosphorylates the E3 ligase Nedd4-2 to relieve Nedd4-2-mediated inhibition of SGLT1.","evidence":"Xenopus oocyte electrophysiology with site-directed mutagenesis of Nedd4-2 phosphorylation sites","pmids":["15166308"],"confidence":"High","gaps":["Heterologous oocyte system may not reflect endogenous epithelial regulation","Did not test endogenous SGK3 contribution"]},{"year":2009,"claim":"Resolved kinase redundancy in development, showing Akt2 and SGK3 jointly control β-catenin-dependent hair follicle morphogenesis with a more severe double-knockout phenotype.","evidence":"Akt2/SGK3 double knockout mice, histology, β-catenin-LEF1 reporter in keratinocytes","pmids":["19433625"],"confidence":"High","gaps":["Did not separate direct vs indirect contributions to β-catenin stabilization","Tissue-specific substrate engagement not mapped"]},{"year":2010,"claim":"Tested and excluded a candidate metabolic pathway, showing SGK3 phosphorylates PFK-2 in vitro but is dispensable for insulin-induced PFK-2 activation in cells.","evidence":"In vitro kinase assay and SGK3 siRNA knockdown with insulin stimulation in HEK-293T","pmids":["20687898"],"confidence":"Medium","gaps":["Negative in-cell result limited to one cell type and stimulus","Does not exclude a role in other tissues"]},{"year":2014,"claim":"Established the core activation mechanism, demonstrating SGK3 kinase activity strictly requires PtdIns(3)P binding via its PX domain, sourced from both Vps34 and class-I-derived dephosphorylation routes.","evidence":"Selective Vps34 inhibitor, PX-domain mutagenesis, class I PI3K inhibitors, phosphorylation assays","pmids":["25177796"],"confidence":"High","gaps":["Did not provide structural mechanism of PtdIns(3)P-induced activation","Relative contribution of the two lipid pools in physiology unresolved"]},{"year":2014,"claim":"Placed SGK3 as the Akt-independent effector of oncogenic PIK3CA, showing INPP4B-dependent activation and identification of NDRG1 as a degradation substrate via Fbw7.","evidence":"Knockdown/overexpression, Co-IP, phosphorylation assays, 3D invasion and in vivo tumorigenesis","pmids":["25458846"],"confidence":"High","gaps":["Generality of INPP4B dependence across tumor types untested here","Did not define structural NDRG1 recognition determinants"]},{"year":2016,"claim":"Explained drug resistance, showing prolonged PI3K/Akt inhibition upregulates SGK3 which substitutes for Akt by phosphorylating TSC2 to sustain mTORC1.","evidence":"Prolonged inhibitor treatment of breast cancer cells, kinase and TSC2 phosphorylation assays, xenografts","pmids":["27481935"],"confidence":"High","gaps":["Did not identify the transcriptional driver of SGK3 induction","Clinical relevance of resistance mechanism not validated in patients here"]},{"year":2017,"claim":"Extended SGK3's pro-survival role to ER homeostasis, showing it preserves SERCA2b and limits PERK-arm UPR suppression of ERα in endocrine-resistant breast cancer.","evidence":"SGK3 knockdown/overexpression, ER stress markers, SERCA2b and ERα analysis in AI-resistant cells","pmids":["28174265"],"confidence":"Medium","gaps":["Direct SGK3 substrate in the ER stress axis not identified","Single-lab cell-line models"]},{"year":2018,"claim":"Defined the upstream lipid-supply logic, showing IGF1 activates SGK3 via both class I and class III (UVRAG-hVPS34) PI3K, while oncogenic Ras signals solely through the class I route.","evidence":"Class-specific PI3K inhibition, endosomal PtdIns(3)P measurement, mTORC2 and Ras pathway dissection","pmids":["29150437"],"confidence":"High","gaps":["Did not quantify endosomal pool dynamics over time","Crosstalk with other growth-factor inputs unmapped"]},{"year":2019,"claim":"Confirmed substrate selectivity in cells using a degrader, with SGK3-PROTAC1 selectively eliminating SGK3 and reducing NDRG1 phosphorylation.","evidence":"VHL-recruiting PROTAC, proteome-wide selectivity analysis, NDRG1 phospho-assay","pmids":["31461270"],"confidence":"High","gaps":["Limited substrate readout beyond NDRG1","Did not assess long-term consequences of SGK3 loss"]},{"year":2019,"claim":"Defined SGK3's endosomal trafficking function by identifying SGK3-selective substrates STX7, STX12, RFIP4 and WDR44, with STX12 phosphorylation modulating SNARE assembly and surface delivery.","evidence":"Phosphoproteomic screens, in vitro kinase assays, Phos-tag, Co-IP, SGK3 knockout cells","pmids":["31665227"],"confidence":"High","gaps":["Functional impact of STX7/RFIP4/WDR44 phosphorylation not fully resolved","Cargo specificity of SGK3-regulated trafficking unknown"]},{"year":2019,"claim":"Showed SGK3 confers rapamycin resistance by reactivating mTORC1/4EBP1 through TSC2, in an hVps34/mTORC2-dependent feedback loop.","evidence":"CRISPR SGK3 deletion, phosphoproteomics, inhibitors, xenografts, clinical specimens","pmids":["31182914"],"confidence":"Medium","gaps":["Mechanism of rapamycin-induced SGK3 feedback induction incompletely defined","Single-lab in vivo validation"]},{"year":2023,"claim":"Identified a redox-regulatory function, showing SGK3 directly phosphorylates catalase to stabilize its active tetramer and protects it via GSK3β suppression.","evidence":"Co-IP, in vitro kinase assay, catalase activity and ubiquitination assays, ROS measurement","pmids":["37866161"],"confidence":"High","gaps":["Catalase phosphosite and structural effect on tetramerization not fully mapped","Physiological/disease context of redox role limited"]},{"year":2024,"claim":"Extended Nedd4-2/transporter control to disease, showing SGK3 promotes vascular calcification by transcriptionally inducing, stabilizing, and directly phosphorylating (Thr468) the phosphate cotransporter Pit-1.","evidence":"Co-IP, in vitro kinase assay, ubiquitination and NF-κB reporter assays, VSMC knockdown, uremic mouse model","pmids":["38169564"],"confidence":"High","gaps":["Relative weight of transcriptional vs post-translational mechanisms in vivo unclear","Translational targeting not tested"]},{"year":null,"claim":"How SGK3's distinct substrate programs (mTORC1 growth, β-catenin transcription, endosomal SNARE trafficking, Nedd4-2/transporter regulation, redox control) are spatially and contextually partitioned from a single endosomal PtdIns(3)P-gated activation event remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking lipid-pool source to substrate selection","Endogenous, tissue-specific substrate hierarchy not established","Structural basis of PX-domain allostery in cells not directly visualized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,6,7,31,32]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,15,32]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,2,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,4]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,15]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[9,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[17,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,32]}],"complexes":[],"partners":["GSK3B","NEDD4L","CATALASE","NDRG1","PDPK1","CDK9","STX12","INPP4B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96BR1","full_name":"Serine/threonine-protein kinase Sgk3","aliases":["Cytokine-independent survival kinase","Serum/glucocorticoid-regulated kinase 3","Serum/glucocorticoid-regulated kinase-like"],"length_aa":496,"mass_kda":57.1,"function":"Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, proliferation, survival and migration. Up-regulates Na(+) channels: SCNN1A/ENAC and SCN5A, K(+) channels: KCNA3/KV1.3, KCNE1, KCNQ1 and KCNH2/HERG, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channel: BSND, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, amino acid transporters: SLC1A5/ASCT2 and SLC6A19, glutamate transporters: SLC1A3/EAAT1, SLC1A6/EAAT4 and SLC1A7/EAAT5, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase. Plays a role in the regulation of renal tubular phosphate transport and bone density. Phosphorylates NEDD4L and GSK3B. Positively regulates ER transcription activity through phosphorylation of FLII. Negatively regulates the function of ITCH/AIP4 via its phosphorylation and thereby prevents CXCR4 from being efficiently sorted to lysosomes","subcellular_location":"Cytoplasmic vesicle; Early endosome; Recycling endosome","url":"https://www.uniprot.org/uniprotkb/Q96BR1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SGK3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SGK3","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"},{"mim_id":"300036","title":"SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, CREATINE), MEMBER 8; SLC6A8","url":"https://www.omim.org/entry/300036"},{"mim_id":"193100","title":"HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL DOMINANT; ADHR","url":"https://www.omim.org/entry/193100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SGK3"},"hgnc":{"alias_symbol":[],"prev_symbol":["SGK2","SGKL"]},"alphafold":{"accession":"Q96BR1","domains":[{"cath_id":"3.30.1520.10","chopping":"13-121","consensus_level":"high","plddt":87.1906,"start":13,"end":121},{"cath_id":"3.30.200.20","chopping":"158-242_453-480","consensus_level":"high","plddt":83.6299,"start":158,"end":480},{"cath_id":"1.10.510.10","chopping":"247-428","consensus_level":"high","plddt":95.0426,"start":247,"end":428}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BR1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BR1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96BR1-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SGK3","jax_strain_url":"https://www.jax.org/strain/search?query=SGK3"},"sequence":{"accession":"Q96BR1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96BR1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96BR1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96BR1"}},"corpus_meta":[{"pmid":"25177796","id":"PMC_25177796","title":"Characterization 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Two pools of PtdIns(3)P control SGK3: one generated by Vps34 class III PI3K at endosomes, and a second derived from dephosphorylation of class I PI3K product PtdIns(3,4,5)P3 via SHIP1/2 and INPP4B.\",\n      \"method\": \"Selective Vps34 inhibitor (VPS34-IN1), PX domain mutagenesis, class I PI3K inhibitors (GDC-0941, BKM120), phosphorylation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal pharmacological and mutagenesis approaches in a single rigorous study, replicated by subsequent work\",\n      \"pmids\": [\"25177796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SGK3 activation by PI3P is mediated by a combination of phosphorylation and allosteric activation. Binding of PI3P to the PX domain induces large conformational changes associated with SGK3 activation; the PI3P-binding pocket of the PX domain is sequestered in the inactive conformation. SGK3 activation was reconstituted in vitro via Vps34-mediated PI3P synthesis on phosphatidylinositol liposomes.\",\n      \"method\": \"Hydrogen-deuterium exchange mass spectrometry, in vitro reconstitution with liposomes, biochemical and biophysical assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with multiple orthogonal biophysical methods including HDX-MS and functional assays in a single rigorous study\",\n      \"pmids\": [\"34181950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Endogenous SGK3 is rapidly activated by IGF1 through both Class 1 and Class 3 (hVPS34) PI3Ks. IGF1 enhances endosomal PtdIns(3)P levels via the UV-RAG complex of hVPS34. Class 1 PI3K activates SGK3 through PtdIns(3)P derived from dephosphorylation of PtdIns(3,4,5)P3, and also promotes mTORC2 phosphorylation of SGK3. Oncogenic Ras activates SGK3 solely through the Class 1 PI3K pathway.\",\n      \"method\": \"Pharmacological inhibition of Class 1 and Class 3 PI3Ks, endosomal PtdIns(3)P measurement, mTORC2 pathway analysis, Ras pathway dissection\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal pharmacological and genetic approaches in a focused mechanistic study\",\n      \"pmids\": [\"29150437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Under prolonged PI3K/Akt inhibition, SGK3 expression and activation increases and is controlled by hVps34-generated PtdIns(3)P binding to the PX domain, promoting PDK1-dependent phosphorylation and activation. SGK3 substitutes for Akt by phosphorylating TSC2 to activate mTORC1 signaling.\",\n      \"method\": \"Prolonged PI3K/Akt inhibitor treatment of breast cancer cells, SGK3 phosphorylation and kinase activity assays, TSC2 phosphorylation assays, xenograft tumor model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical, cellular, in vivo xenograft) with defined mechanistic readouts, replicated across contexts\",\n      \"pmids\": [\"27481935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SGK3 is activated downstream of oncogenic PIK3CA in a manner dependent on the phosphoinositide phosphatase INPP4B. INPP4B expression enhances SGK3 activation and suppresses Akt phosphorylation. SGK3 targets the metastasis suppressor NDRG1 for degradation by the E3 ligase Fbw7.\",\n      \"method\": \"Genetic knockdown/overexpression, co-immunoprecipitation, phosphorylation assays, 3D proliferation and invasion assays, in vivo tumorigenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including in vivo validation and identification of direct substrate, replicated by subsequent studies\",\n      \"pmids\": [\"25458846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGK3-PROTAC1, a PROTAC conjugate targeting SGK3 for VHL-dependent proteasomal degradation, selectively degrades SGK3 (not SGK1/SGK2) and reduces phosphorylation of NDRG1, confirming NDRG1 as an endogenous SGK3 substrate. Proteomic analysis confirmed SGK3 as the only protein selectively degraded.\",\n      \"method\": \"PROTAC degrader, proteomics, NDRG1 phosphorylation assay, breast cancer cell viability assays\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chemical-genetic approach with proteome-wide selectivity analysis and functional substrate validation\",\n      \"pmids\": [\"31461270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phosphoproteomic screens identified novel SGK3-specific substrates at endosomes: STX7 (Ser126), STX12 (Ser139), RFIP4 (Ser527), and WDR44 (Ser346). These were efficiently phosphorylated by SGK3 in vitro and in vivo but poorly by Akt, due to an n+1 residue unfavorable for Akt. SGK3 phosphorylation of STX12 enhanced its interaction with VAMP4/VTI1A/STX6 SNARE complex and promoted plasma membrane localization of STX12.\",\n      \"method\": \"Genetic and pharmacological phosphoproteomic screens, in vitro kinase assays, Phos-tag analysis, Co-IP, SGK3 knockout cells, pan-SGK inhibitor (14H)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assays combined with in-cell phosphoproteomic validation, KO controls, and functional SNARE complex interaction assay\",\n      \"pmids\": [\"31665227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SGK3 (SGKL) phosphorylates GSK-3β at Ser9 through direct physical interaction. GSK-3β was identified as a binding partner of SGK3 by yeast two-hybrid screen, confirmed by co-immunoprecipitation in HEK293 cells; in vitro kinase assay demonstrated SGK3 phosphorylates GSK-3 at Ser21/9.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay with phospho-specific antibody\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus Co-IP confirmation in a single study, later corroborated by multiple downstream studies showing SGK3→GSK3β→β-catenin pathway\",\n      \"pmids\": [\"12054501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGK3 phosphorylates TSC2 to reactivate mTORC1/4EBP1 axis during rapamycin treatment. Feedback activation of SGK3 by rapamycin is dependent on hVps34 and mTORC2. SGK3 deletion combined with Akt inhibition nearly abolished rapamycin-induced 4EBP1 re-phosphorylation.\",\n      \"method\": \"SGK3 deletion (CRISPR), phosphoproteomic analysis, pharmacological inhibitors, xenograft model, clinical breast cancer specimens\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion with pharmacological validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"31182914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SGK3 stimulates SGLT1 (Na+-coupled glucose transporter) activity by reversing Nedd4-2-mediated inhibition. SGK3 and SGK1 phosphorylate Nedd4-2 at SGK/PKB consensus sites; deletion of these phosphorylation sites in Nedd4-2 blunted the kinase effects on SGLT1.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiological current measurement, site-directed mutagenesis of Nedd4-2\",\n      \"journal\": \"Obesity research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution in oocytes with mutagenesis of key phosphorylation sites, multiple kinase isoforms tested as controls\",\n      \"pmids\": [\"15166308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SGK3 stimulates epithelial Na+ channel (ENaC) activity in Xenopus oocytes. The effect is not via direct phosphorylation of αENaC at its SGK consensus site (S622A mutation did not abolish stimulation), indicating an indirect mechanism.\",\n      \"method\": \"Xenopus oocyte dual-electrode voltage-clamp, site-directed mutagenesis of αENaC (S622A)\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution with mutagenesis, single lab\",\n      \"pmids\": [\"12632189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SGK3 upregulates TRPV5 Ca2+ channel activity in Xenopus oocytes, an effect requiring co-expression of the PDZ scaffold protein NHERF2. Constitutively active SGK3 stimulated tracer Ca2+ entry and TRPV5-mediated currents, while inactive SGK3 and SGK2 did not.\",\n      \"method\": \"Xenopus oocyte expression, tracer Ca2+ uptake, electrophysiology, cRNA co-injection with NHERF2\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional oocyte reconstitution, multiple kinase isoforms as controls, single lab\",\n      \"pmids\": [\"15319523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SGK3 upregulates TRPV6 Ca2+ channel plasma membrane abundance and activity in Xenopus oocytes. Unlike TRPV5, this effect does not require PDZ-scaffold proteins NHERF1 or NHERF2 and is not dependent on the putative PDZ-binding motif on TRPV6.\",\n      \"method\": \"Xenopus oocyte expression, chemiluminescence for membrane protein abundance, electrophysiology\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in oocytes with mechanistic comparison to TRPV5, single lab\",\n      \"pmids\": [\"18005662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SGK3 upregulates excitatory amino acid transporter EAAT5 by increasing its cell surface abundance. Both EAAT5-mediated currents and surface protein levels were increased approximately 1.5–2-fold by SGK1 or SGK3, but not by PKB.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiology, chemiluminescence for surface protein abundance\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with surface expression measurement, single lab\",\n      \"pmids\": [\"15737648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SGK3 (but not SGK2 or PKB) stimulates the creatine transporter SLC6A8 by increasing its maximal transport rate in Xenopus oocytes, without significantly altering affinity.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiology, kinetic analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with kinetic analysis and isoform selectivity controls, single lab\",\n      \"pmids\": [\"16036218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SGK3 increases mature hERG channel expression and current in HEK293 cells by two mechanisms: (1) inhibiting Nedd4-2 via phosphorylation, and (2) promoting Rab11-mediated hERG channel recycling to the plasma membrane. Disrupting both Nedd4-2 binding sites and Rab11 eliminated the SGK3-mediated increase in hERG expression.\",\n      \"method\": \"HEK293 stable expression, overexpression, Nedd4-2 phosphorylation assay, dominant-negative Rab11, site-directed mutagenesis of hERG Nedd4-2 binding site\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent mechanisms identified and validated by mutagenesis and dominant-negative approaches in a single study\",\n      \"pmids\": [\"23589291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SGK3 (but not SGK1) increases HERG channel plasma membrane protein abundance and current in Xenopus oocytes without affecting channel gating kinetics. Alanine substitution at both SGK consensus sites in HERG decreased baseline current but did not abolish SGK3-mediated stimulation.\",\n      \"method\": \"Xenopus oocyte expression, two-electrode voltage clamp, chemiluminescence for membrane abundance, mutagenesis\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with surface expression measurement and mutagenesis, single lab\",\n      \"pmids\": [\"17167223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SGK3 null mice display defective postnatal hair follicle morphogenesis, with reduced proliferation and impaired nuclear β-catenin accumulation in hair bulb keratinocytes. In cultured keratinocytes, SGK3 potently modulates β-catenin/Lef-1-mediated gene transcription.\",\n      \"method\": \"Sgk3 knockout mice, histology, BrdU proliferation, immunofluorescence for β-catenin, reporter gene assays in keratinocytes\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype plus mechanistic reporter assay, replicated by multiple subsequent studies\",\n      \"pmids\": [\"15240817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SGK3 is required for adequate intestinal Na+-coupled glucose transport in vivo. Sgk3 knockout mice show significantly reduced glucose-induced currents in jejunal segments, lower fasting plasma glucose, and enhanced food intake.\",\n      \"method\": \"Sgk3 knockout mice, Ussing chamber electrophysiology for glucose transport, plasma glucose measurement\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined transport phenotype in intact tissue, single lab\",\n      \"pmids\": [\"15971077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SGK3 loss in hair follicle leads to reduced proliferation, increased apoptosis, and premature regression of follicles. Using primary keratinocytes, SGK3 functions by negatively regulating PI3K signaling in this context.\",\n      \"method\": \"Sgk3 knockout mice, proliferation and apoptosis quantification, primary keratinocyte culture, PI3K pathway analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype and mechanistic pathway placement, single lab\",\n      \"pmids\": [\"16103225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SGK3 and Akt2 both regulate postnatal hair follicle morphogenesis through redundant control of β-catenin-dependent transcription. Akt2/SGK3 double knockout mice have a markedly worse hair growth defect than SGK3 single KO, with profound failure to accumulate nuclear β-catenin in follicle matrix cells. Transfected Akt2 and SGK3 both stimulate a β-catenin-LEF1 reporter in keratinocytes.\",\n      \"method\": \"Akt2/SGK3 double knockout mice, histology, immunofluorescence, β-catenin-LEF1 reporter assay in keratinocytes\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double KO, reporter assay mechanistic validation, replicated findings on β-catenin pathway\",\n      \"pmids\": [\"19433625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SGK3 phosphorylation of GSK3β at Ser9 and reduced nuclear β-catenin accumulation are observed in SGK3-mutant (YPC) mouse hair follicles, implicating the SGK3→GSK3β→β-catenin/WNT pathway in hair follicle development.\",\n      \"method\": \"Immunohistochemistry for p-GSK3β(Ser9) and β-catenin in SGK3-mutant YPC mouse hair follicles\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunohistochemical pathway analysis in genetic model, corroborated by multiple independent studies\",\n      \"pmids\": [\"16565488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SGK3 plays a role in pancreatic β-cell function. Akt2/SGK3 double knockout mice show worse glucose homeostasis than Akt2 single nulls, with lower plasma insulin, reduced β-cell mass, impaired glucose-stimulated insulin secretion, and dramatically lower β-catenin in islets.\",\n      \"method\": \"Akt2/SGK3 double knockout mice, glucose tolerance tests, plasma insulin/C-peptide, β-cell mass quantification, β-catenin immunostaining in islets\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in double KO with multiple metabolic and cellular readouts, single lab\",\n      \"pmids\": [\"21980074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SGK3 is transcriptionally regulated by estrogen receptor α (ERα) in breast cancer cells. ERα binds two regions at the sgk3 locus (identified by ChIP-seq) and stimulates sgk3 promoter activity. SGK3 is required for estrogen-mediated cell survival of MCF-7 cells, and SGK3 overexpression partially protects against apoptosis induced by antiestrogen ICI 182,780.\",\n      \"method\": \"ChIP-seq, promoter reporter assays, siRNA knockdown, apoptosis assays, E2 dose/time-response\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq identification of ERα binding sites combined with promoter reporter and functional KD assays, multiple orthogonal methods\",\n      \"pmids\": [\"21084382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SGK3 is an androgen receptor (AR) transcriptional target in prostate cancer. SGK3 expression is induced by DHT/AR, requiring co-expression of estrogen receptor. SGK3 promotes G1-S cell cycle progression by activating p70 S6 kinase and upregulating cyclin D1.\",\n      \"method\": \"ChIP for AR binding at sgk3 locus, siRNA knockdown, cell cycle analysis, p70S6K and cyclin D1 measurement, ER depletion experiments\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional knockdown with defined downstream readouts, single lab\",\n      \"pmids\": [\"24739041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SGK3 promotes endoplasmic reticulum (EnR) homeostasis by preserving SERCA2b function in aromatase inhibitor (AI)-resistant breast cancer cells, thereby sustaining ERα signaling. SGK3 prevents excessive EnR stress-induced suppression of ERα expression through the PERK arm of the UPR. This creates a feed-forward loop between SGK3 and ERα.\",\n      \"method\": \"SGK3 knockdown/overexpression, ER stress markers, SERCA2b functional analysis, ERα expression analysis, AI-resistant cell models\",\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 manipulation with mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"28174265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SGK3 in vitro phosphorylates heart PFK-2 at Ser466 and Ser483, activating the enzyme. However, SGK3 is NOT required for insulin-induced PFK-2 activation in cells (siRNA knockdown had no effect on insulin response), establishing a negative result for this in vivo pathway.\",\n      \"method\": \"In vitro kinase assay with [γ-32P]ATP, SGK3 siRNA knockdown in HEK-293T cells, insulin stimulation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus cellular siRNA experiment; negative in-cell result well-controlled\",\n      \"pmids\": [\"20687898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SGK3 regulates store-operated Ca2+ (SOC) entry and migration of dendritic cells. SGK3 knockout DCs show reduced SOC entry triggered by thapsigargin, reduced LPS- and CXCL12-induced Ca2+ increases, reduced SOC channel currents, and lower STIM2 protein levels. Migration of both immature and LPS-matured DCs was reduced in SGK3 KO.\",\n      \"method\": \"SGK3 knockout mice, bone marrow-derived DC culture, Ca2+ imaging, patch-clamp, Western blot for STIM2/Orai, chemotaxis assays\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple orthogonal cellular readouts, single lab\",\n      \"pmids\": [\"23171960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SGK3 is a downstream effector of PDK1 in BRAF-mutant melanoma cells. Genetic or pharmacologic inhibition of PDK1 or SGK3 attenuates melanoma growth by inducing G1 phase cell cycle arrest.\",\n      \"method\": \"Genetic knockdown, pharmacological inhibition, cell cycle analysis, synthetic lethal screen with pan-PI3K inhibitor\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological inhibition with defined cell cycle phenotype, single lab\",\n      \"pmids\": [\"25712345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDPK1 (PDK1) mediates prostate cancer cell survival predominantly through activation/phosphorylation of SGK3, not through SGK1 or AKT. Ectopic expression of constitutively active SGK3 completely abrogated apoptosis induced by PDPK1 knockdown.\",\n      \"method\": \"Lentiviral shRNA kinome screen, PDPK1 knockdown, SGK3 constitutively active rescue, phosphorylation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by rescue experiment with constitutively active SGK3, single lab\",\n      \"pmids\": [\"32926495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"INPP4B promotes leukemia cell survival via SGK3 activation (not Akt). INPP4B overexpression enhanced phosphorylated SGK3 status and increased PtdIns(3)P and PtdIns(3,4)P2 levels. SGK3 knockdown was required to eliminate INPP4B-induced proliferation in OCI-AML3 NPM1-mutated leukemia cells.\",\n      \"method\": \"INPP4B knockdown/overexpression, SGK3 phosphorylation assay, PtdIns lipid ELISA, siRNA rescue experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with lipid measurements and functional rescue, single lab\",\n      \"pmids\": [\"29343273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SGK3 maintains redox homeostasis by directly interacting with and phosphorylating catalase, promoting its tetrameric state and enzymatic activity. SGK3 also phosphorylates GSK3β to protect catalase from GSK3β-β-TrCP-mediated ubiquitination and proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay for catalase phosphorylation, catalase activity assay, ubiquitination assay, ROS measurement\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with substrate identification plus Co-IP and functional enzyme activity measurement, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37866161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SGK3 promotes vascular calcification in CKD by enhancing expression and activity of the sodium-dependent phosphate cotransporter Pit-1. Mechanistically, SGK3 activates Pit-1 mRNA transcription via NF-κB, inhibits Nedd4-2-mediated Pit-1 ubiquitin-proteasome degradation, and directly interacts with and phosphorylates Pit-1 at Thr468 in loop7 to enhance phosphate uptake.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, NF-κB reporter, Nedd4-2 activity assay, SGK3 knockdown in VSMCs, uremic mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay with specific phosphorylation site identification, Co-IP, functional assays in cells and in vivo, multiple orthogonal mechanisms\",\n      \"pmids\": [\"38169564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDK9 binds and directly activates SGK3 to promote cardiomyocyte proliferation and cardiac repair. CDK9-SGK3 interaction was identified by quantitative phosphoproteomics and confirmed by pulldown and Co-IP. CDK9 promotes cardiac repair via SGK3 and the downstream GSK-3β/β-catenin pathway.\",\n      \"method\": \"Quantitative phosphoproteomics, pulldown assay, Co-immunoprecipitation, CDK9 overexpression/knockdown, in vivo cardiac injury models\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmation of direct binding plus functional in vivo epistasis, single lab\",\n      \"pmids\": [\"36082129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SGK3 promotes breast cancer cell proliferation and stemness via the STAT3/ZMIZ2/β-catenin signaling pathway. Proteomics identified ZMIZ2 as a downstream target of SGK3; SGK3 activates STAT3, which drives ZMIZ2 transcription. ZMIZ2 binds and stabilizes β-catenin; SGK3 knockdown causes β-catenin polyubiquitination and degradation that is reversed by ZMIZ2 overexpression.\",\n      \"method\": \"Proteomics, ChIP for p-STAT3 at ZMIZ2 promoter, Co-IP for ZMIZ2-β-catenin, lentiviral knockdown/overexpression, ubiquitination assay\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-based substrate identification with ChIP, Co-IP, and functional rescue, single lab\",\n      \"pmids\": [\"39876548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SGK3 upregulates the inward rectifier K+ channel Kir2.1 by increasing channel protein abundance in the cell membrane (insertion rather than reduced retrieval), as the rate of current decay following brefeldin A treatment was similar with or without SGK3. Kinase-inactive SGK3 had no effect, and the SGK inhibitor EMD638683 abrogated the effect.\",\n      \"method\": \"Xenopus oocyte expression, two-electrode voltage clamp, immunostaining/confocal imaging, chemiluminescence, brefeldin A decay assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with mechanistic trafficking dissection using brefeldin A, single lab\",\n      \"pmids\": [\"24556932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SGK3 and stargazin regulate GluR1 (AMPA receptor) surface expression independently and additively. SGK3 increases GluR1 plasma membrane abundance at late timepoints (6 days post-injection), while stargazin accelerates membrane insertion earlier (2 days). Mutagenesis of the SGK consensus site in stargazin did not prevent SGK3-mediated stimulation.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiology, Western blot for membrane protein, cRNA injection timing experiments, mutagenesis\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution with mutagenesis and mechanistic timing experiments, single lab\",\n      \"pmids\": [\"16485113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SGK3 triggers ubiquitin-proteasome degradation of podocalyxin (PC) and ezrin in podocytes. The SGK3/Nedd4-2 signaling pathway specifically regulates ezrin ubiquitination but not PC ubiquitination directly. Downregulation of SGK3 activity decreased PC and ezrin protein expression and increased their ubiquitin-proteasome degradation; upregulation mostly reversed PAN-induced decrease.\",\n      \"method\": \"SGK3 knockdown/overexpression in podocytes, ubiquitination assay, Co-IP for PC/ezrin interaction, Nedd4-2 knockdown/overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays including ubiquitination and Co-IP, with gain/loss of function, single lab\",\n      \"pmids\": [\"30385740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SGK3 deficiency in macrophages attenuates angiotensin II-induced cardiac remodeling by inhibiting the NLRP3/Caspase-1/IL-1β pathway, reducing IL-1β secretion, and consequently suppressing Ndufa13 expression and mitochondrial oxidative stress in cardiomyocytes and fibroblasts.\",\n      \"method\": \"SGK3-Lyz2-CRE conditional KO mice, Ang II infusion model, RNA sequencing, co-culture system, pathway inhibitor experiments\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with RNA-seq pathway identification and mechanistic co-culture validation, single lab\",\n      \"pmids\": [\"39158709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SGK3 recruitment to endosomes (via PX domain/PtdIns(3)P) is necessary for TLR7 signaling in plasmacytoid dendritic cells. VPS34-IN1 blocks SGK3 endosomal recruitment and impairs TLR7-dependent innate signaling.\",\n      \"method\": \"VPS34-IN1 pharmacological inhibition, SGK3 endosomal localization assay, TLR7 signaling readout in pDCs\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, pharmacological only (no SGK3-specific genetic control confirmed), single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SGK3 is a PX domain-containing AGC serine/threonine kinase that is recruited to endosomal membranes by binding PtdIns(3)P — generated by both class III PI3K (Vps34/hVPS34) and by dephosphorylation of class I PI3K products (PtdIns(3,4,5)P3 → PtdIns(3)P via SHIP1/2 and INPP4B); PtdIns(3)P binding induces allosteric conformational changes and promotes PDK1 (T-loop) and mTORC2 (hydrophobic motif) phosphorylation to fully activate the kinase. Active SGK3 phosphorylates multiple substrates including TSC2 (activating mTORC1), NDRG1 (targeting it for Fbw7-mediated degradation), GSK3β (Ser9, suppressing it to stabilize β-catenin), catalase (promoting its tetrameric active state and protecting it from GSK3β/β-TrCP-mediated degradation), endosomal SNARE proteins (STX7, STX12, RFIP4, WDR44), Nedd4-2 (inhibiting this E3 ubiquitin ligase to increase surface abundance of ENaC, SGLT1, hERG, TRPV5/6, and other ion channels/transporters), and Pit-1 (enhancing phosphate uptake). SGK3 thus mediates Akt-independent PI3K oncogenic signaling, confers resistance to PI3K/Akt inhibitors by substituting for Akt in activating mTORC1, regulates endosomal membrane trafficking, maintains endoplasmic reticulum homeostasis, controls hair follicle morphogenesis via β-catenin/LEF1 transcription, and governs intestinal nutrient absorption, dendritic cell Ca2+ signaling and migration, and cardiac remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SGK3 is a PX-domain-containing AGC serine/threonine kinase that couples endosomal phosphoinositide signaling to cell growth, survival, membrane trafficking, and ion-transport control [#0, #4]. Its activation is gated by PtdIns(3)P binding to the N-terminal PX domain: this lipid is supplied both by class III PI3K (Vps34, including via the UVRAG/IGF1 axis) at endosomes and by dephosphorylation of class I PI3K-derived PtdIns(3,4,5)P3 through INPP4B and SHIP, and the resulting allosteric conformational change permits PDK1 (T-loop) and mTORC2 (hydrophobic motif) phosphorylation to fully activate the kinase [#0, #1, #2]. This wiring lets SGK3 act as an Akt-independent arm of oncogenic PI3K signaling, and under prolonged PI3K/Akt or rapamycin treatment it is induced and substitutes for Akt by phosphorylating TSC2 to reactivate mTORC1 [#3, #8]. SGK3 phosphorylates a defined substrate set: NDRG1, targeting it for Fbw7-mediated degradation [#4, #5]; GSK3\\u03b2 at Ser9, suppressing it to stabilize \\u03b2-catenin and drive \\u03b2-catenin/LEF1-dependent transcription required for hair follicle morphogenesis [#7, #17, #20]; endosomal SNARE and trafficking proteins STX7, STX12, RFIP4 and WDR44, with STX12 phosphorylation enhancing its SNARE-complex interaction and surface delivery [#6]; and catalase, promoting its active tetrameric state and protecting it from degradation to maintain redox homeostasis [#31]. Through phosphorylation of the E3 ligase Nedd4-2, SGK3 raises the surface abundance and activity of numerous channels and transporters, including SGLT1, ENaC, TRPV5/TRPV6, hERG and Pit-1 [#9, #15, #32]. Genetically, SGK3 governs hair follicle development, intestinal Na+-coupled glucose absorption, and dendritic-cell store-operated Ca2+ entry and migration [#17, #18, #27]. SGK3 is itself a transcriptional target of estrogen receptor \\u03b1 and androgen receptor, embedding it in hormone-driven cancer survival programs [#23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first direct SGK3 substrate and a route into Wnt signaling by showing SGK3 binds and phosphorylates GSK3\\u03b2 at Ser9.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP in HEK293, and in vitro kinase assay with phospho-specific antibody\",\n      \"pmids\": [\"12054501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the cellular/physiological context of the SGK3\\u2192GSK3\\u03b2 axis\", \"No structural basis for the interaction\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked SGK3 to in vivo development by showing SGK3-null mice fail in hair follicle morphogenesis through impaired \\u03b2-catenin/LEF1 transcription, connecting the kinase to a defined developmental program.\",\n      \"evidence\": \"Sgk3 knockout mice, histology, BrdU proliferation, \\u03b2-catenin immunofluorescence, keratinocyte reporter assays\",\n      \"pmids\": [\"15240817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which SGK3 substrate drives \\u03b2-catenin accumulation in vivo\", \"Redundancy with other kinases unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a mechanism by which SGK3 controls membrane transporters, showing it phosphorylates the E3 ligase Nedd4-2 to relieve Nedd4-2-mediated inhibition of SGLT1.\",\n      \"evidence\": \"Xenopus oocyte electrophysiology with site-directed mutagenesis of Nedd4-2 phosphorylation sites\",\n      \"pmids\": [\"15166308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heterologous oocyte system may not reflect endogenous epithelial regulation\", \"Did not test endogenous SGK3 contribution\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved kinase redundancy in development, showing Akt2 and SGK3 jointly control \\u03b2-catenin-dependent hair follicle morphogenesis with a more severe double-knockout phenotype.\",\n      \"evidence\": \"Akt2/SGK3 double knockout mice, histology, \\u03b2-catenin-LEF1 reporter in keratinocytes\",\n      \"pmids\": [\"19433625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate direct vs indirect contributions to \\u03b2-catenin stabilization\", \"Tissue-specific substrate engagement not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tested and excluded a candidate metabolic pathway, showing SGK3 phosphorylates PFK-2 in vitro but is dispensable for insulin-induced PFK-2 activation in cells.\",\n      \"evidence\": \"In vitro kinase assay and SGK3 siRNA knockdown with insulin stimulation in HEK-293T\",\n      \"pmids\": [\"20687898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative in-cell result limited to one cell type and stimulus\", \"Does not exclude a role in other tissues\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the core activation mechanism, demonstrating SGK3 kinase activity strictly requires PtdIns(3)P binding via its PX domain, sourced from both Vps34 and class-I-derived dephosphorylation routes.\",\n      \"evidence\": \"Selective Vps34 inhibitor, PX-domain mutagenesis, class I PI3K inhibitors, phosphorylation assays\",\n      \"pmids\": [\"25177796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not provide structural mechanism of PtdIns(3)P-induced activation\", \"Relative contribution of the two lipid pools in physiology unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed SGK3 as the Akt-independent effector of oncogenic PIK3CA, showing INPP4B-dependent activation and identification of NDRG1 as a degradation substrate via Fbw7.\",\n      \"evidence\": \"Knockdown/overexpression, Co-IP, phosphorylation assays, 3D invasion and in vivo tumorigenesis\",\n      \"pmids\": [\"25458846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of INPP4B dependence across tumor types untested here\", \"Did not define structural NDRG1 recognition determinants\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Explained drug resistance, showing prolonged PI3K/Akt inhibition upregulates SGK3 which substitutes for Akt by phosphorylating TSC2 to sustain mTORC1.\",\n      \"evidence\": \"Prolonged inhibitor treatment of breast cancer cells, kinase and TSC2 phosphorylation assays, xenografts\",\n      \"pmids\": [\"27481935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the transcriptional driver of SGK3 induction\", \"Clinical relevance of resistance mechanism not validated in patients here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended SGK3's pro-survival role to ER homeostasis, showing it preserves SERCA2b and limits PERK-arm UPR suppression of ER\\u03b1 in endocrine-resistant breast cancer.\",\n      \"evidence\": \"SGK3 knockdown/overexpression, ER stress markers, SERCA2b and ER\\u03b1 analysis in AI-resistant cells\",\n      \"pmids\": [\"28174265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SGK3 substrate in the ER stress axis not identified\", \"Single-lab cell-line models\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the upstream lipid-supply logic, showing IGF1 activates SGK3 via both class I and class III (UVRAG-hVPS34) PI3K, while oncogenic Ras signals solely through the class I route.\",\n      \"evidence\": \"Class-specific PI3K inhibition, endosomal PtdIns(3)P measurement, mTORC2 and Ras pathway dissection\",\n      \"pmids\": [\"29150437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not quantify endosomal pool dynamics over time\", \"Crosstalk with other growth-factor inputs unmapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed substrate selectivity in cells using a degrader, with SGK3-PROTAC1 selectively eliminating SGK3 and reducing NDRG1 phosphorylation.\",\n      \"evidence\": \"VHL-recruiting PROTAC, proteome-wide selectivity analysis, NDRG1 phospho-assay\",\n      \"pmids\": [\"31461270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Limited substrate readout beyond NDRG1\", \"Did not assess long-term consequences of SGK3 loss\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined SGK3's endosomal trafficking function by identifying SGK3-selective substrates STX7, STX12, RFIP4 and WDR44, with STX12 phosphorylation modulating SNARE assembly and surface delivery.\",\n      \"evidence\": \"Phosphoproteomic screens, in vitro kinase assays, Phos-tag, Co-IP, SGK3 knockout cells\",\n      \"pmids\": [\"31665227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional impact of STX7/RFIP4/WDR44 phosphorylation not fully resolved\", \"Cargo specificity of SGK3-regulated trafficking unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed SGK3 confers rapamycin resistance by reactivating mTORC1/4EBP1 through TSC2, in an hVps34/mTORC2-dependent feedback loop.\",\n      \"evidence\": \"CRISPR SGK3 deletion, phosphoproteomics, inhibitors, xenografts, clinical specimens\",\n      \"pmids\": [\"31182914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of rapamycin-induced SGK3 feedback induction incompletely defined\", \"Single-lab in vivo validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a redox-regulatory function, showing SGK3 directly phosphorylates catalase to stabilize its active tetramer and protects it via GSK3\\u03b2 suppression.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, catalase activity and ubiquitination assays, ROS measurement\",\n      \"pmids\": [\"37866161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalase phosphosite and structural effect on tetramerization not fully mapped\", \"Physiological/disease context of redox role limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended Nedd4-2/transporter control to disease, showing SGK3 promotes vascular calcification by transcriptionally inducing, stabilizing, and directly phosphorylating (Thr468) the phosphate cotransporter Pit-1.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, ubiquitination and NF-\\u03baB reporter assays, VSMC knockdown, uremic mouse model\",\n      \"pmids\": [\"38169564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weight of transcriptional vs post-translational mechanisms in vivo unclear\", \"Translational targeting not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SGK3's distinct substrate programs (mTORC1 growth, \\u03b2-catenin transcription, endosomal SNARE trafficking, Nedd4-2/transporter regulation, redox control) are spatially and contextually partitioned from a single endosomal PtdIns(3)P-gated activation event remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking lipid-pool source to substrate selection\", \"Endogenous, tissue-specific substrate hierarchy not established\", \"Structural basis of PX-domain allostery in cells not directly visualized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 6, 7, 31, 32]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 15, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 15]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [9, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GSK3B\", \"NEDD4L\", \"CATALASE\", \"NDRG1\", \"PDPK1\", \"CDK9\", \"STX12\", \"INPP4B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}