Affinage

SGK3

Serine/threonine-protein kinase Sgk3 · UniProt Q96BR1

Length
496 aa
Mass
57.1 kDa
Annotated
2026-06-10
80 papers in source corpus 39 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    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

    PMID:12054501

    Open questions at the time
    • Did not establish the cellular/physiological context of the SGK3→GSK3β axis
    • No structural basis for the interaction
  2. 2004 High

    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

    PMID:15240817

    Open questions at the time
    • Did not resolve which SGK3 substrate drives β-catenin accumulation in vivo
    • Redundancy with other kinases unaddressed
  3. 2004 High

    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

    PMID:15166308

    Open questions at the time
    • Heterologous oocyte system may not reflect endogenous epithelial regulation
    • Did not test endogenous SGK3 contribution
  4. 2009 High

    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

    PMID:19433625

    Open questions at the time
    • Did not separate direct vs indirect contributions to β-catenin stabilization
    • Tissue-specific substrate engagement not mapped
  5. 2010 Medium

    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

    PMID:20687898

    Open questions at the time
    • Negative in-cell result limited to one cell type and stimulus
    • Does not exclude a role in other tissues
  6. 2014 High

    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

    PMID:25177796

    Open questions at the time
    • Did not provide structural mechanism of PtdIns(3)P-induced activation
    • Relative contribution of the two lipid pools in physiology unresolved
  7. 2014 High

    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

    PMID:25458846

    Open questions at the time
    • Generality of INPP4B dependence across tumor types untested here
    • Did not define structural NDRG1 recognition determinants
  8. 2016 High

    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

    PMID:27481935

    Open questions at the time
    • Did not identify the transcriptional driver of SGK3 induction
    • Clinical relevance of resistance mechanism not validated in patients here
  9. 2017 Medium

    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

    PMID:28174265

    Open questions at the time
    • Direct SGK3 substrate in the ER stress axis not identified
    • Single-lab cell-line models
  10. 2018 High

    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

    PMID:29150437

    Open questions at the time
    • Did not quantify endosomal pool dynamics over time
    • Crosstalk with other growth-factor inputs unmapped
  11. 2019 High

    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

    PMID:31461270

    Open questions at the time
    • Limited substrate readout beyond NDRG1
    • Did not assess long-term consequences of SGK3 loss
  12. 2019 High

    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

    PMID:31665227

    Open questions at the time
    • Functional impact of STX7/RFIP4/WDR44 phosphorylation not fully resolved
    • Cargo specificity of SGK3-regulated trafficking unknown
  13. 2019 Medium

    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

    PMID:31182914

    Open questions at the time
    • Mechanism of rapamycin-induced SGK3 feedback induction incompletely defined
    • Single-lab in vivo validation
  14. 2023 High

    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

    PMID:37866161

    Open questions at the time
    • Catalase phosphosite and structural effect on tetramerization not fully mapped
    • Physiological/disease context of redox role limited
  15. 2024 High

    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

    PMID:38169564

    Open questions at the time
    • Relative weight of transcriptional vs post-translational mechanisms in vivo unclear
    • Translational targeting not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0008289 lipid binding 3 GO:0016740 transferase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005768 endosome 4
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-382551 Transport of small molecules 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CATALASECDK9GSK3BINPP4BNDRG1NEDD4LPDPK1STX12

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. Selective Vps34 inhibitor (VPS34-IN1), PX domain mutagenesis, class I PI3K inhibitors (GDC-0941, BKM120), phosphorylation assays The Biochemical journal High 25177796
2021 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. Hydrogen-deuterium exchange mass spectrometry, in vitro reconstitution with liposomes, biochemical and biophysical assays The Journal of biological chemistry High 34181950
2018 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. Pharmacological inhibition of Class 1 and Class 3 PI3Ks, endosomal PtdIns(3)P measurement, mTORC2 pathway analysis, Ras pathway dissection The Biochemical journal High 29150437
2016 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. Prolonged PI3K/Akt inhibitor treatment of breast cancer cells, SGK3 phosphorylation and kinase activity assays, TSC2 phosphorylation assays, xenograft tumor model The EMBO journal High 27481935
2014 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. Genetic knockdown/overexpression, co-immunoprecipitation, phosphorylation assays, 3D proliferation and invasion assays, in vivo tumorigenesis Molecular cell High 25458846
2019 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. PROTAC degrader, proteomics, NDRG1 phosphorylation assay, breast cancer cell viability assays ACS chemical biology High 31461270
2019 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. Genetic and pharmacological phosphoproteomic screens, in vitro kinase assays, Phos-tag analysis, Co-IP, SGK3 knockout cells, pan-SGK inhibitor (14H) The Biochemical journal High 31665227
2002 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. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay with phospho-specific antibody Biochemical and biophysical research communications High 12054501
2019 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. SGK3 deletion (CRISPR), phosphoproteomic analysis, pharmacological inhibitors, xenograft model, clinical breast cancer specimens International journal of biological sciences Medium 31182914
2004 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. Xenopus oocyte expression, electrophysiological current measurement, site-directed mutagenesis of Nedd4-2 Obesity research High 15166308
2003 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. Xenopus oocyte dual-electrode voltage-clamp, site-directed mutagenesis of αENaC (S622A) Pflugers Archiv : European journal of physiology Medium 12632189
2004 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. Xenopus oocyte expression, tracer Ca2+ uptake, electrophysiology, cRNA co-injection with NHERF2 Cellular physiology and biochemistry Medium 15319523
2007 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. Xenopus oocyte expression, chemiluminescence for membrane protein abundance, electrophysiology FEBS letters Medium 18005662
2005 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. Xenopus oocyte expression, electrophysiology, chemiluminescence for surface protein abundance Biochemical and biophysical research communications Medium 15737648
2005 SGK3 (but not SGK2 or PKB) stimulates the creatine transporter SLC6A8 by increasing its maximal transport rate in Xenopus oocytes, without significantly altering affinity. Xenopus oocyte expression, electrophysiology, kinetic analysis Biochemical and biophysical research communications Medium 16036218
2013 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. HEK293 stable expression, overexpression, Nedd4-2 phosphorylation assay, dominant-negative Rab11, site-directed mutagenesis of hERG Nedd4-2 binding site The Journal of biological chemistry High 23589291
2006 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. Xenopus oocyte expression, two-electrode voltage clamp, chemiluminescence for membrane abundance, mutagenesis Cellular physiology and biochemistry Medium 17167223
2004 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. Sgk3 knockout mice, histology, BrdU proliferation, immunofluorescence for β-catenin, reporter gene assays in keratinocytes Molecular biology of the cell High 15240817
2005 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. Sgk3 knockout mice, Ussing chamber electrophysiology for glucose transport, plasma glucose measurement Pflugers Archiv : European journal of physiology Medium 15971077
2005 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. Sgk3 knockout mice, proliferation and apoptosis quantification, primary keratinocyte culture, PI3K pathway analysis The Journal of cell biology Medium 16103225
2009 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. Akt2/SGK3 double knockout mice, histology, immunofluorescence, β-catenin-LEF1 reporter assay in keratinocytes FASEB journal High 19433625
2006 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. Immunohistochemistry for p-GSK3β(Ser9) and β-catenin in SGK3-mutant YPC mouse hair follicles The American journal of pathology Medium 16565488
2011 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. Akt2/SGK3 double knockout mice, glucose tolerance tests, plasma insulin/C-peptide, β-cell mass quantification, β-catenin immunostaining in islets Molecular endocrinology Medium 21980074
2010 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. ChIP-seq, promoter reporter assays, siRNA knockdown, apoptosis assays, E2 dose/time-response Molecular endocrinology High 21084382
2014 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. ChIP for AR binding at sgk3 locus, siRNA knockdown, cell cycle analysis, p70S6K and cyclin D1 measurement, ER depletion experiments Molecular endocrinology Medium 24739041
2017 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. SGK3 knockdown/overexpression, ER stress markers, SERCA2b functional analysis, ERα expression analysis, AI-resistant cell models Proceedings of the National Academy of Sciences of the United States of America Medium 28174265
2010 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. In vitro kinase assay with [γ-32P]ATP, SGK3 siRNA knockdown in HEK-293T cells, insulin stimulation assay The Biochemical journal Medium 20687898
2012 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. SGK3 knockout mice, bone marrow-derived DC culture, Ca2+ imaging, patch-clamp, Western blot for STIM2/Orai, chemotaxis assays Cellular physiology and biochemistry Medium 23171960
2015 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. Genetic knockdown, pharmacological inhibition, cell cycle analysis, synthetic lethal screen with pan-PI3K inhibitor Cancer research Medium 25712345
2020 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. Lentiviral shRNA kinome screen, PDPK1 knockdown, SGK3 constitutively active rescue, phosphorylation assays Journal of cellular and molecular medicine Medium 32926495
2018 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. INPP4B knockdown/overexpression, SGK3 phosphorylation assay, PtdIns lipid ELISA, siRNA rescue experiments Journal of experimental & clinical cancer research Medium 29343273
2023 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. Co-immunoprecipitation, in vitro kinase assay for catalase phosphorylation, catalase activity assay, ubiquitination assay, ROS measurement Redox biology High 37866161
2024 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. Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, NF-κB reporter, Nedd4-2 activity assay, SGK3 knockdown in VSMCs, uremic mouse model Theranostics High 38169564
2022 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. Quantitative phosphoproteomics, pulldown assay, Co-immunoprecipitation, CDK9 overexpression/knockdown, in vivo cardiac injury models Frontiers in cardiovascular medicine Medium 36082129
2025 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. Proteomics, ChIP for p-STAT3 at ZMIZ2 promoter, Co-IP for ZMIZ2-β-catenin, lentiviral knockdown/overexpression, ubiquitination assay British journal of pharmacology Medium 39876548
2018 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. Xenopus oocyte expression, two-electrode voltage clamp, immunostaining/confocal imaging, chemiluminescence, brefeldin A decay assay Cellular physiology and biochemistry Medium 24556932
2006 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. Xenopus oocyte expression, electrophysiology, Western blot for membrane protein, cRNA injection timing experiments, mutagenesis Pflugers Archiv : European journal of physiology Medium 16485113
2018 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. SGK3 knockdown/overexpression in podocytes, ubiquitination assay, Co-IP for PC/ezrin interaction, Nedd4-2 knockdown/overexpression Cell death & disease Medium 30385740
2024 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. SGK3-Lyz2-CRE conditional KO mice, Ang II infusion model, RNA sequencing, co-culture system, pathway inhibitor experiments Cellular and molecular life sciences Medium 39158709
2024 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. VPS34-IN1 pharmacological inhibition, SGK3 endosomal localization assay, TLR7 signaling readout in pDCs bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. The Biochemical journal 258 25177796
2004 Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4-2 and kinases SGK1, SGK3, and PKB. Obesity research 150 15166308
2014 SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Molecular cell 128 25458846
2013 AKT-independent PI3-K signaling in cancer - emerging role for SGK3. Cancer management and research 79 24009430
2019 Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader. ACS chemical biology 74 31461270
2003 The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel alpha,beta,gamma-ENaC. Pflugers Archiv : European journal of physiology 69 12632189
2016 The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. The EMBO journal 68 27481935
2004 Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 67 15319523
2010 SGK3 is an estrogen-inducible kinase promoting estrogen-mediated survival of breast cancer cells. Molecular endocrinology (Baltimore, Md.) 63 21084382
2004 Targeted disruption of the protein kinase SGK3/CISK impairs postnatal hair follicle development. Molecular biology of the cell 60 15240817
2012 SGK3 regulates Ca(2+) entry and migration of dendritic cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 55 23171960
2018 LncRNA SNHG5 promotes the progression of osteosarcoma by sponging the miR-212-3p/SGK3 axis. Cancer cell international 53 30250399
2015 PDK1 and SGK3 Contribute to the Growth of BRAF-Mutant Melanomas and Are Potential Therapeutic Targets. Cancer research 50 25712345
2013 The serum- and glucocorticoid-inducible kinases SGK1 and SGK3 regulate hERG channel expression via ubiquitin ligase Nedd4-2 and GTPase Rab11. The Journal of biological chemistry 50 23589291
2018 MiRNA-335-5p negatively regulates granulosa cell proliferation via SGK3 in PCOS. Reproduction (Cambridge, England) 46 30328340
2005 Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3. Biochemical and biophysical research communications 46 16036218
2005 Sgk3 links growth factor signaling to maintenance of progenitor cells in the hair follicle. The Journal of cell biology 46 16103225
2017 MicroRNA-144-3p suppresses tumor growth and angiogenesis by targeting SGK3 in hepatocellular carcinoma. Oncology reports 41 28849156
2015 INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas. Oncotarget 41 26573229
2015 MiR-212-3p inhibits glioblastoma cell proliferation by targeting SGK3. Journal of neuro-oncology 40 25720694
2021 Free CA125 promotes ovarian cancer cell migration and tumor metastasis by binding Mesothelin to reduce DKK1 expression and activate the SGK3/FOXO3 pathway. International journal of biological sciences 35 33613114
2006 Renal function of gene-targeted mice lacking both SGK1 and SGK3. American journal of physiology. Regulatory, integrative and comparative physiology 35 16537821
2006 Upregulation of HERG channels by the serum and glucocorticoid inducible kinase isoform SGK3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 17167223
2016 MiR-155 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells through the activation of PI3K/SGK3/β-catenin signaling pathways. Oncotarget 32 27602769
2014 SGK3 is an androgen-inducible kinase promoting prostate cancer cell proliferation through activation of p70 S6 kinase and up-regulation of cyclin D1. Molecular endocrinology (Baltimore, Md.) 32 24739041
2007 Regulation of the epithelial calcium channel TRPV6 by the serum and glucocorticoid-inducible kinase isoforms SGK1 and SGK3. FEBS letters 31 18005662
2005 Regulation of the excitatory amino acid transporter EAAT5 by the serum and glucocorticoid dependent kinases SGK1 and SGK3. Biochemical and biophysical research communications 31 15737648
2018 Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks. The Biochemical journal 30 29150437
2017 SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis. Proceedings of the National Academy of Sciences of the United States of America 30 28174265
2002 Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction. Biochemical and biophysical research communications 28 12054501
2019 Feedback Activation of SGK3 and AKT Contributes to Rapamycin Resistance by Reactivating mTORC1/4EBP1 Axis via TSC2 in Breast Cancer. International journal of biological sciences 27 31182914
2015 MiR-155 modulates the progression of neuropathic pain through targeting SGK3. International journal of clinical and experimental pathology 27 26823753
2021 Circ_0043532 regulates miR-182/SGK3 axis to promote granulosa cell progression in polycystic ovary syndrome. Reproductive biology and endocrinology : RB&E 25 34740363
2020 Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival. Journal of cellular and molecular medicine 25 32926495
2005 Decreased intestinal glucose transport in the sgk3-knockout mouse. Pflugers Archiv : European journal of physiology 24 15971077
2020 MiR-377-3p inhibits cell metastasis and epithelial-mesenchymal transition in cervical carcinoma through targeting SGK3. European review for medical and pharmacological sciences 23 32432732
2010 Heart 6-phosphofructo-2-kinase activation by insulin requires PKB (protein kinase B), but not SGK3 (serum- and glucocorticoid-induced protein kinase 3). The Biochemical journal 23 20687898
2012 SGK3 is associated with estrogen receptor expression in breast cancer. Breast cancer research and treatment 22 22576469
2018 INPP4B promotes cell survival via SGK3 activation in NPM1-mutated leukemia. Journal of experimental & clinical cancer research : CR 20 29343273
2019 Functional role of SGK3 in PI3K/Pten driven liver tumor development. BMC cancer 19 30975125
1999 Cloning and mapping of a novel human serum/glucocorticoid regulated kinase-like gene, SGKL, to chromosome 8q12.3-q13.1. Genomics 19 10585774
2014 Up-regulation of Kir2.1 (KCNJ2) by the serum & glucocorticoid inducible SGK3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 17 24556932
2009 Akt2 and SGK3 are both determinants of postnatal hair follicle development. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 19433625
2023 The SGK3-Catalase antioxidant signaling axis drives cervical cancer growth and therapy resistance. Redox biology 16 37866161
2019 Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44. The Biochemical journal 16 31665227
2018 Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling. Journal of experimental & clinical cancer research : CR 15 29940988
2020 Mutation of SGK3, a Novel Regulator of Renal Phosphate Transport, Causes Autosomal Dominant Hypophosphatemic Rickets. The Journal of clinical endocrinology and metabolism 13 31821448
2015 SGK3 (CISK) may induce tumor angiogenesis (Hypothesis). Oncology letters 13 26170971
2018 Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds. Acta pharmacologica Sinica 12 30038340
2021 In vitro reconstitution of Sgk3 activation by phosphatidylinositol 3-phosphate. The Journal of biological chemistry 11 34181950
2021 Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma. Cancer biology & medicine 10 33960177
2011 SGK3: a novel regulator of renal phosphate transport? Kidney international 10 21673735
2011 Novel role for SGK3 in glucose homeostasis revealed in SGK3/Akt2 double-null mice. Molecular endocrinology (Baltimore, Md.) 10 21980074
2019 A frameshift insertion in SGK3 leads to recessive hairlessness in Scottish Deerhounds: a candidate gene for human alopecia conditions. Human genetics 9 30927068
2019 MiR-376a functions as tumor suppressor by targeting SGK3 in renal cell carcinoma. European review for medical and pharmacological sciences 9 31114998
2018 The SGK3-triggered ubiquitin-proteasome degradation of podocalyxin (PC) and ezrin in podocytes was associated with the stability of the PC/ezrin complex. Cell death & disease 9 30385740
2006 Additive regulation of GluR1 by stargazin and serum- and glucocorticoid-inducible kinase isoform SGK3. Pflugers Archiv : European journal of physiology 9 16485113
2006 The critical roles of serum/glucocorticoid-regulated kinase 3 (SGK3) in the hair follicle morphogenesis and homeostasis: the allelic difference provides novel insights into hair follicle biology. The American journal of pathology 9 16565488
2024 SGK3 promotes vascular calcification via Pit-1 in chronic kidney disease. Theranostics 8 38169564
2024 SGK3 deficiency in macrophages suppresses angiotensin II-induced cardiac remodeling via regulating Ndufa13-mediated mitochondrial oxidative stress. Cellular and molecular life sciences : CMLS 8 39158709
2023 The role of the SGK3/TOPK signaling pathway in the transition from acute kidney injury to chronic kidney disease. Frontiers in pharmacology 8 37361201
2022 CDK9 binds and activates SGK3 to promote cardiac repair after injury via the GSK-3β/β-catenin pathway. Frontiers in cardiovascular medicine 8 36082129
2021 Hsa-miR-100-3p Controls the Proliferation, DNA Synthesis, and Apoptosis of Human Sertoli Cells by Binding to SGK3. Frontiers in cell and developmental biology 8 34046405
2020 Oxymatrine inhibits the development of non-small cell lung cancer through miR-367-3p upregulation and target gene SGK3 downregulation. American journal of translational research 8 33042436
2022 MicroRNA-92a-3p Regulates Retinal Angiogenesis by Targeting SGK3 in Vascular Endothelial Cells. Investigative ophthalmology & visual science 7 36269185
2022 Contributions of SGK3 to transporter-related diseases. Frontiers in cell and developmental biology 6 36531961
2016 SGK3 Sensitivity of Voltage Gated K+ Channel Kv1.5 (KCNA5). Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 6 26824455
2010 Blunted IgE-mediated activation of mast cells in mice lacking the serum- and glucocorticoid-inducible kinase SGK3. American journal of physiology. Cell physiology 6 20686074
2004 A mutation in the serum and glucocorticoid-inducible kinase-like kinase (Sgkl) gene is associated with defective hair growth in mice. DNA research : an international journal for rapid publication of reports on genes and genomes 6 15871460
2025 Complement C3a promotes the formation of osteoclasts by inhibiting Sirt1 to activate the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma. Journal of translational medicine 4 40091033
2015 Loss of serum and glucocorticoid-regulated kinase 3 (SGK3) does not affect proliferation and survival of multiple myeloma cell lines. PloS one 4 25837824
2010 Regulation of gastric acid secretion by the serum and glucocorticoid inducible kinase isoform SGK3. Journal of gastroenterology 4 21113728
2020 Whole Genome Analysis of a Single Scottish Deerhound Dog Family Provides Independent Corroboration That a SGK3 Coding Variant Leads to Hairlessness. G3 (Bethesda, Md.) 3 31727632
2016 SGK3 Sensitivity of Large-Conductance Ca2+-Activated K+ Channel. Neuro-Signals 3 27898416
2025 The SGK3/GSK3β/β-catenin signaling promotes breast cancer stemness and confers resistance to alpelisib therapy. International journal of biological sciences 2 40303291
2025 SGK3 promotes estrogen receptor-positive breast cancer proliferation by activating STAT3/ZMIZ2 pathway to stabilise β-catenin. British journal of pharmacology 1 39876548
2020 Risk of Nasopharyngeal Carcinoma Associated with Single Nucleotide Polymorphisms in the MicroRNA Binding Site of SGK3. Genetic testing and molecular biomarkers 1 32644852
2026 Semaphorin 7A aggravates abdominal aortic aneurysm through PDK1/SGK3/YTHDC1 axis-mediated phenotypic switching of vascular smooth muscle cells. Cardiovascular research 0 41553434
2026 Inhibition of SGK3 regulates hyperplastic scar development in rats through the MAPK/ERK signaling pathway. Cell cycle (Georgetown, Tex.) 0 41674333
2026 Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice. Nature communications 0 41997967

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