Affinage

AKT3

RAC-gamma serine/threonine-protein kinase · UniProt Q9Y243

Length
479 aa
Mass
55.8 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKT3 (PKBγ) is a serine/threonine kinase activated by dual phosphorylation at Thr305 and Ser472 that serves as the brain-predominant AKT isoform and a context-specific driver of cell size, survival, and metabolic signaling (PMID:10491192, PMID:15713641). Its catalytic activity is switched on by insulin and antagonized by PKC through a PH-domain-independent mechanism (PMID:10208883, PMID:9480839), and a distinct layer of regulation operates through direct electrophilic modification of Cys119 by lipid-derived 4-hydroxynonenal, making AKT3 a first-responding redox sensor whose Cys119 is functionally required for downstream phenotypes (PMID:28114274). In the central nervous system AKT3 is the dominant regulator of AKT/mTOR signaling: its loss reduces brain size, cell number, and cell size with attenuated brain mTOR activity, lowers Ser473-AKT phosphorylation and mTORC2 components Rictor and Sin1, and impairs hippocampal protein-synthesis-dependent long-term potentiation and spatial memory (PMID:15713641, PMID:15930105, PMID:28467426, PMID:30053339). Gain-of-function in this same axis is pathogenic: a kinase-domain mutation causes brain overgrowth and seizures via elevated S6 phosphorylation (PMID:21159799), and the activating AKT3(E17K) mutation in neural progenitors drives focal malformations of cortical development through a FOXG1-dependent derepression of reelin that perturbs migration of neighboring cells (PMID:26523971). AKT3 also exerts isoform-specific control over substrates and trafficking: it phosphorylates and degrades WNK1 at Thr58, restraining an SGK1/Cdc42 cascade that otherwise promotes macrophage macropinocytosis, foam-cell formation, and adipogenesis (PMID:29202451, PMID:28389565, PMID:22632897); it stabilizes nuclear PGC-1α by acting on the export receptor CRM-1 to drive mitochondrial biogenesis (PMID:24081905, PMID:33654198); and it phosphorylates V600E B-RAF at Ser364/Ser428 to tune MAPK output during melanoma initiation (PMID:18451171). Across melanoma, glioma, and breast and prostate cancers, AKT3 deregulation through gene amplification, PTEN loss, or the E17K mutation drives survival, proliferation, DNA double-strand break repair via DNA-PKcs, and resistance to BRAF/AKT inhibitors, radiation, and temozolomide (PMID:15466193, PMID:18813315, PMID:25737557, PMID:29090098, PMID:27297869).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1999 High

    Establishing how AKT3 is switched on answered whether the third AKT isoform shares the canonical dual-phosphorylation activation logic of AKT1/AKT2.

    Evidence in vitro kinase assays with site-directed mutagenesis of Thr305/Ser472 and insulin/PKC stimulation in adipocytes

    PMID:10208883 PMID:10491192 PMID:9480839

    Open questions at the time
    • upstream kinase(s) for Thr305/Ser472 not identified
    • structural basis of PKC-mediated PH-domain-independent inhibition unresolved
  2. 1999 Medium

    Linking AKT3 hyperactivity to hormone-independent and PTEN-null cancer cells first implicated it as the dominant active AKT isoform in specific tumor contexts.

    Evidence isoform-specific enzymatic activity assays across breast and prostate cancer cell lines

    PMID:10419456

    Open questions at the time
    • correlative activity measurement without functional dependency test
    • mechanism connecting PTEN loss to selective AKT3 activation unclear
  3. 2004 High

    Isoform-specific knockdown defined AKT3 as a non-redundant survival driver in melanoma, not just an active isoform.

    Evidence AKT3-selective siRNA with apoptosis readout and PTEN re-expression across melanoma lines

    PMID:15466193

    Open questions at the time
    • downstream survival substrates not defined here
    • relative contribution of amplification vs PTEN loss not quantified
  4. 2005 High

    Knockout and compound-allele genetics established AKT3 as the brain-predominant isoform controlling both cell size and number, with dosage-dependent essentiality.

    Evidence Akt3-null and Akt1/Akt3 compound knockout mice with histology, MRI, and brain mTOR analysis

    PMID:15713641 PMID:15930105 PMID:16287854

    Open questions at the time
    • molecular targets mediating brain mTOR regulation not identified
    • cell-type origin of size vs number phenotypes not resolved
  5. 2008 Medium

    Identification of AKT3(E17K) and direct phosphorylation of V600E B-RAF showed how AKT3 both becomes constitutively active and cross-regulates MAPK signaling in melanoma.

    Evidence clinical specimen sequencing, functional expression, and site-specific B-RAF phosphorylation/transformation assays

    PMID:18451171 PMID:18813315

    Open questions at the time
    • physiological frequency and in vivo consequence of Ser364/Ser428 B-RAF phosphorylation not established
    • E17K functional validation in single lab
  6. 2010 Medium

    Constitutively active AKT3 was shown to confer apoptosis resistance to BRAF-mutant melanoma, defining a mechanism of BRAF-inhibitor escape.

    Evidence siRNA, PLX4720 treatment, and ectopic active AKT3 in 3D collagen with BH3-only protein readouts

    PMID:20647317

    Open questions at the time
    • direct AKT3 substrates controlling Bim-EL/Bmf/Mcl-1 not identified
    • single-lab apoptosis assays
  7. 2010 High

    A gain-of-function kinase-domain mutation linked elevated AKT3 catalytic activity to brain overgrowth and epilepsy in vivo.

    Evidence Nmf350 mutant kinase assays, EEG, and S6 phosphorylation immunohistochemistry versus null mice

    PMID:21159799

    Open questions at the time
    • circuit-level basis of seizures not defined
    • whether S6 hyperphosphorylation is causal vs correlative untested
  8. 2012 High

    Macrophage genetics revealed AKT3 as an atheroprotective isoform that limits foam-cell formation by promoting ACAT-1 degradation and reducing lipoprotein uptake.

    Evidence Akt3/ApoE double-knockout mice, cholesterol accumulation assays, ACAT-1 degradation, and macrophage transfer

    PMID:22632897

    Open questions at the time
    • direct AKT3 substrate driving ACAT-1 proteasomal turnover not identified
    • basis of Akt1 vs Akt3 differential localization unknown
  9. 2013 High

    Work in endothelial and cancer cells defined AKT3 as a controller of organelle trafficking and biogenesis through CRM-1/PGC-1α and RCAS1/VEGF axes.

    Evidence knockdown/overexpression with subcellular fractionation, CRM-1 manipulation, VEGF secretion assays, and in vivo angiogenesis

    PMID:21351097 PMID:24081905 PMID:33654198

    Open questions at the time
    • whether AKT3 phosphorylates CRM-1 or PGC-1α directly not shown
    • RCAS1 regulation mechanism downstream of AKT3 incomplete
  10. 2013 High

    Isoform-resolved knockdown distinguished AKT3 from AKT1 functionally in breast cancer, controlling p27 and proliferation rather than invasion.

    Evidence shRNA screen with 3D spheroid and xenograft growth and p27 analysis

    PMID:24335962

    Open questions at the time
    • mechanism linking AKT3 to p27 upregulation not defined
    • opposing migration roles of AKT isoforms only partly explained
  11. 2014 High

    The AKT3-FOXG1-reelin pathway explained how an activating AKT3 mutation produces non-cell-autonomous cortical migration defects underlying focal malformations of cortical development.

    Evidence in utero electroporation of AKT3(E17K), immunoprecipitation, and pharmacological/genetic reelin rescue

    PMID:26523971

    Open questions at the time
    • direct biochemical link between AKT3 and FOXG1 not fully mapped
    • human genotype-phenotype correlation beyond mouse model not established
  12. 2014 Medium

    Migration and metastasis studies showed AKT3 loss can paradoxically increase TNBC cell motility via S100A4, refining its isoform-specific role in tumor progression.

    Evidence isoform-specific shRNA, migration assays, xenograft metastasis, and S100A4 rescue

    PMID:26741489

    Open questions at the time
    • mechanism by which AKT3 suppresses S100A4 unknown
    • single-lab in vivo metastasis data
  13. 2014 Medium

    An AKT3-Rictor-S6K feedback circuit was defined, showing AKT3 restrains vascular tumor endothelial growth opposite to AKT1.

    Evidence isoform manipulation in endothelial cells with S6K and Rictor analysis and S6K inhibition

    PMID:25388284

    Open questions at the time
    • molecular basis of Rictor modulation by AKT3 not shown
    • single-lab functional epistasis
  14. 2015 High

    Amplified AKT3 was shown to drive glioma progression and therapeutic resistance through preferential activation of DNA repair pathways.

    Evidence RCAS/Ntv-a mouse glioma model, expression profiling, and DNA repair/radioresistance assays in human GBM cells

    PMID:25737557

    Open questions at the time
    • direct repair substrates of AKT3 not identified here
    • isoform-selective therapeutic vulnerability not tested clinically
  15. 2015 Medium

    Prostate cancer studies positioned AKT3 as an amplifier of total AKT/mTOR signaling and a determinant of B-Raf inhibitor sensitivity.

    Evidence overexpression/knockdown with pathway western blots and drug sensitivity assays

    PMID:26318033

    Open questions at the time
    • mechanism of TSC1/TSC2 downregulation by AKT3 not defined
    • single-lab correlative pathway data
  16. 2016 Medium

    BET-protein-driven epigenetic upregulation of AKT3 was identified as a mechanism of AKT-inhibitor resistance, linking AKT3 to EMT in breast cancer.

    Evidence stepwise MK2206-resistance model, isoform-specific siRNA, BET inhibition, and EMT marker analysis

    PMID:27297869

    Open questions at the time
    • direct BET target genes regulating AKT3 not mapped
    • single-lab resistance model
  17. 2017 High

    Discovery of Cys119 as a privileged electrophile-sensing residue revealed a redox-dependent activation mode of AKT3 distinct from AKT2 oxidative regulation.

    Evidence redox-targeting screen, MS site identification, C119S mutagenesis, and zebrafish validation

    PMID:28114274

    Open questions at the time
    • physiological electrophile sources in mammalian tissues not defined
    • structural mechanism of Cys119 activation unresolved
  18. 2017 High

    Identification of WNK1 Thr58 phosphorylation and the WNK1/SGK1/Cdc42 axis defined how AKT3 suppresses macrophage macropinocytosis and adipogenesis through a specific substrate.

    Evidence site-specific phosphorylation, ubiquitin-proteasome analysis, stepwise rescue of WNK1/SGK1/Cdc42, and Akt3-KO mice on high-fat diet

    PMID:28389565 PMID:29202451

    Open questions at the time
    • whether AKT3 directly recognizes WNK1 in vivo across all tissues not shown
    • interplay with the parallel ACAT-1 pathway not integrated
  19. 2017 Medium

    AKT3 was shown to be the dominant brain regulator of AKT/mTORC2 signaling and to control GSK3 phosphorylation, hippocampal LTP, and mood/memory behaviors.

    Evidence Akt3 heterozygous/null mice with Ser473-pAKT, Rictor/Sin1, pGSK3 westerns, electrophysiology, behavioral batteries, and lithium rescue

    PMID:28442992 PMID:28467426 PMID:30053339

    Open questions at the time
    • mechanism by which AKT3 sustains mTORC2 component levels not defined
    • single-lab behavioral findings
  20. 2017 Medium

    Physical interaction with DNA-PKcs and a requirement in embryonic stem cell survival expanded AKT3's roles into DNA double-strand break repair and p53-controlled proliferation.

    Evidence reciprocal pull-downs with DNA-PKcs domain mapping, DSB repair/clonogenic assays, and kinase-dead/siRNA ESC studies with p53 rescue

    PMID:28483982 PMID:29090098

    Open questions at the time
    • functional consequence of AKT3-DNA-PKcs binding vs AKT1 unclear
    • whether AKT3 phosphorylates DNA-PKcs not established
  21. 2017 Medium

    Cell-type-specific conditional deletion revealed a T-cell-intrinsic role for AKT3 in iTreg differentiation and CNS autoimmune protection.

    Evidence CD4+ T-cell vs neuronal conditional Akt3 knockout in the EAE model with FOXP3+ Treg flow cytometry

    PMID:31404142

    Open questions at the time
    • AKT3 substrates governing FOXP3 induction not identified
    • single-lab model
  22. 2005 Medium

    Cardiac transgenic overexpression demonstrated AKT3-driven hypertrophy and revealed negative feedback downregulation of other AKT isoforms.

    Evidence cardiac-specific constitutively active AKT3 transgenic mice with echocardiography and AKT1/2 protein analysis

    PMID:15698844

    Open questions at the time
    • mechanism of cross-isoform feedback downregulation not defined
    • single-lab transgenic model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AKT3 achieves isoform-specific substrate selection and tissue-restricted dominance over AKT1/AKT2 across brain, immune, vascular, and tumor contexts remains unresolved.
  • no structural basis for AKT3 substrate specificity
  • upstream signals dictating isoform dominance not defined
  • unified model linking redox, phospho, and PTEN-loss activation modes missing

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 2
Partners
BRAFCRM-1DNA-PKCSFOXG1WNK1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Human AKT3 contains a regulatory serine phosphorylation site (Ser472) in its C-terminal region that is phosphorylated in response to insulin, indicating it is regulated similarly to AKT1 and AKT2. In vitro phosphorylation assay, RT-PCR, sequencing Biochemical and biophysical research communications Medium 10208883
1999 Human AKT3 encodes a serine/threonine kinase with a pleckstrin homology domain and kinase domain; phosphorylation of both Ser472 and Thr305 contributes to activation, as mutation of both to aspartate increased catalytic activity while alanine substitutions inhibited activation. Site-directed mutagenesis, in vitro kinase assay European journal of biochemistry High 10491192
1999 AKT3 enzymatic activity is stimulated ~7-fold by insulin in 3T3-L1 adipocytes; protein kinase C activation inhibits insulin-stimulated AKT3 activity through a mechanism independent of the pleckstrin homology domain. In vitro kinase assay, PKC activation/inhibition, PH-domain deletion mutant Biochemical and biophysical research communications Medium 9480839
1999 AKT3 enzymatic activity is elevated 20–60-fold in estrogen receptor-deficient breast cancer cells and androgen-insensitive prostate cancer cells compared to hormone-responsive lines; in PTEN-null prostate cancer cells, AKT3 is constitutively active and represents the major active AKT isoform. Isoform-specific enzymatic activity assay, RT-PCR, protein quantification The Journal of biological chemistry Medium 10419456
2004 Selective siRNA knockdown of AKT3 (but not AKT1 or AKT2) reduces phosphorylated (active) AKT in melanoma cells and stimulates apoptotic signaling, establishing AKT3 as the predominant active isoform in ~43–60% of nonfamilial melanomas; deregulation occurs via gene copy number increases and PTEN loss. siRNA isoform-specific knockdown, apoptosis assay, active PTEN expression Cancer research High 15466193
2005 Akt3 knockout mice show a selective ~20% reduction in brain size with smaller and fewer cells and attenuated mTOR signaling specifically in the brain, whereas Akt1 knockout reduces cell number; this establishes AKT3 as regulating both cell size and cell number in brain via mTOR. Genetic knockout mouse model, histology, mTOR signaling analysis Molecular and cellular biology High 15713641
2005 Pkbγ (Akt3)-null mice show ~25% reduction in brain weight with smaller cell size and reduced cell number, predominantly affecting white matter (corpus callosum thinning), without affecting glucose metabolism, confirming an essential isoform-specific role in postnatal brain development. Genetic knockout mouse model, in vivo MRI, histological analysis Development (Cambridge, England) High 15930105
2005 Akt1−/−Akt3+/− compound mice die within days after birth with defects in thymus, heart, and skin; Akt1−/−Akt3−/− double knockouts are embryonic lethal ~E11-12 with severe cardiovascular and nervous system defects and increased brain apoptosis, demonstrating dosage-dependent and isoform-specific roles. Compound knockout mouse genetics, histology, apoptosis staining Molecular and cellular biology High 16287854
2005 Cardiac-specific overexpression of a constitutively active AKT3 splice variant (lacking the C-terminal regulatory phosphorylation site) causes marked cardiac hypertrophy that progresses from adaptive to maladaptive with age; endogenous Akt1 and Akt2 protein levels are downregulated in Akt3 transgenic hearts, indicating negative feedback regulation of Akt signaling. Cardiac-specific transgenic mouse, echocardiography, western blot Journal of molecular and cellular cardiology Medium 15698844
2008 An AKT3 E17K mutation, analogous to the activating AKT1 E17K mutation, was identified in melanoma specimens and cell lines; expression of AKT3 E17K in human melanoma cells results in activation of AKT3, establishing this as the first activating AKT3 mutation in cancer. Sequencing of clinical specimens, functional expression in cell lines British journal of cancer Medium 18813315
2008 Active AKT3 phosphorylates V600E B-RAF at Ser364 and Ser428, reducing its kinase activity and downstream MAPK signaling to levels that promote rather than inhibit melanocyte proliferation, thereby cooperating with V600E B-RAF to drive early melanoma development. Site-specific phosphorylation assay, kinase activity assays, anchorage-independent growth assay, melanocyte transformation Cancer research High 18451171
2010 Constitutively active AKT3 protects mutant B-RAF melanoma cells from apoptosis induced by B-RAF knockdown or inhibition (PLX4720) in 3D collagen by preventing upregulation of BH3-only proteins Bim-EL and Bmf and partially protecting Mcl-1-depleted cells. siRNA knockdown, 3D collagen culture, apoptosis assay, ectopic expression of constitutively active AKT3 Cancer research Medium 20647317
2010 A missense mutation in the Akt3 kinase domain (Nmf350) confers higher enzymatic activity in vitro and causes brain enlargement and seizures in mice, with increased phosphorylation of ribosomal protein S6 in the dentate gyrus; Akt3 null mice show elevated seizure threshold, opposite to Akt3(Nmf350). In vitro kinase assay, EEG, immunohistochemistry, genetic mouse model Human molecular genetics High 21159799
2012 Akt3 deficiency in macrophages promotes foam cell formation and atherosclerosis; mechanistically, Akt3 suppresses foam cell formation by reducing lipoprotein uptake and promoting ACAT-1 degradation via the ubiquitin-proteasome pathway; Akt1 and Akt3 show differential subcellular localization in macrophages. Akt3 knockout mouse crossed to ApoE-/-, macrophage cholesterol accumulation assay, ACAT-1 degradation assay, subcellular fractionation Cell metabolism High 22632897
2013 AKT3 controls mitochondrial biogenesis and PGC-1α subcellular localization in endothelial cells by stabilizing CRM-1 (the major nuclear export receptor); AKT3 knockdown causes CRM-1-dependent nuclear export of PGC-1α, ~3-fold reduction in PGC-1α target gene expression, and autophagy induction in a CRM-1-dependent, Akt1/mTOR-independent manner; Akt3-null mice show dose-dependent decreases in angiogenesis. Site-directed mutagenesis, CRM-1 overexpression, siRNA knockdown, autophagosome assay, Matrigel plug angiogenesis in vivo FASEB journal High 24081905
2013 AKT3 silencing, but not AKT1 or AKT2, markedly upregulates p27 cell-cycle inhibitor and inhibits growth of triple-negative breast cancer (TNBC) cells in 3D spheroid cultures and xenograft models; AKT3 does not promote invasion unlike AKT1. shRNA screen, 3D spheroid culture, mouse xenograft, p27 protein analysis Cancer research High 24335962
2013 AKT3 controls VEGF secretion in ovarian cancer cells by regulating expression of the Golgi protein RCAS1; blockade of AKT3 (but not AKT1) reduces RCAS1 expression, retains VEGF in the endoplasmic reticulum, and reduces tumor vascularization in xenografts. shRNA knockdown, AKT3 overexpression, VEGF secretion assay, RCAS1 siRNA, xenograft mouse model International journal of cancer Medium 21351097
2014 AKT3 knockdown in ErbB2+ breast cancer cells reduces ErbB2 and ErbB3 expression and tyrosine phosphorylation, while strongly upregulating ERα expression through decreased phosphorylation of the AKT substrate FOXO3a; AKT3-specific kinase activity (not AKT1 or AKT2) is detected in ErbB2+ and triple-negative tumors. AKT isoform-specific in vitro kinase assay, isoform-specific siRNA knockdown, western blot for ErbB2/ErbB3/ERα/Foxo3a Cellular signalling Medium 24463007
2014 An AKT3-FOXG1-reelin signaling pathway underlies focal malformations of cortical development (FMCD): AKT3(E17K) mutation in neural progenitors causes FOXG1-dependent derepression of reelin transcription, leading to non-cell-autonomous migration defects in neighboring cells; blocking AKT signaling or inactivating reelin restores migration. In utero electroporation in mouse, immunoprecipitation, pathway inhibition, reelin functional rescue Nature medicine High 26523971
2015 Genomically amplified Akt3, but not Akt1, drives progression to high-grade glioma in a mouse model; Akt3-expressing glioma cells show dominant activation of DNA repair pathways, enhanced DNA repair protein activation, and increased resistance to radiation and temozolomide compared to Akt1/Akt2. RCAS/Ntv-a mouse glioma model, gene expression profiling, DNA repair assays, irradiation/drug resistance assays Proceedings of the National Academy of Sciences of the United States of America High 25737557
2014 AKT3 downregulation in triple-negative breast cancer (MDA-MB-231) cells increases migration in vitro and combined AKT2/3 or AKT1/3 knockdown significantly increases metastasis formation in vivo; AKT3 depletion increases S100A4 protein, and S100A4 silencing reverses the increased migration. Isoform-specific shRNA knockdown, live cell imaging, transwell migration, xenograft metastasis model, S100A4 siRNA rescue PloS one Medium 26741489
2015 Akt3 deficiency impairs hippocampal CA1 protein synthesis-dependent long-LTP and long-term spatial memory via inactivation of mTOR; Akt3-KO mice show reduced basal mTOR phosphorylation and failure to activate mTOR-p70S6K-4EBP2-eIF4E signaling cascade and AMPA receptor upregulation after HFS. Akt3 knockout mouse, Morris water maze, electrophysiology (LTP), western blot for mTOR pathway Acta physiologica (Oxford, England) Medium 30053339
2017 AKT3 is a first-responding isoform that preferentially senses native electrophilic lipids (4-hydroxynonenal); electrophile modification occurs at Cys119, and an AKT3 C119S mutant is hypomorphic for all downstream phenotypes, establishing C119 as the privileged electrophile-sensing cysteine distinct from Akt2 oxidative regulation. Redox-targeting screen, digest MS sequencing of modified cysteine, C119S mutagenesis, zebrafish in vivo validation Nature chemical biology High 28114274
2017 Akt3 specifically phosphorylates WNK1 at T58 and promotes its degradation via the ubiquitin-proteasome pathway; loss of Akt3 in adipocytes increases WNK1, activates SGK1, which phosphorylates/inhibits FOXO1 and activates PPARγ transcription to promote adipogenesis. Site-specific phosphorylation assay (T58), ubiquitin-proteasome pathway analysis, Akt3 KO mouse on high-fat diet, SGK1 pharmacological inhibition rescue JCI insight High 29202451
2017 Akt3 suppresses macropinocytosis of LDL in macrophages through a WNK1/SGK1/Cdc42 pathway: Akt3 deficiency increases WNK1 expression → SGK1 activity → Cdc42 expression, promoting actin assembly and pinocytosis; individual suppression of WNK1, SGK1, or Cdc42 in Akt3-deficient macrophages rescues the phenotype. siRNA knockdown of WNK1/SGK1/Cdc42, fluid-phase pinocytosis assay, murine and human macrophages The Journal of biological chemistry High 28389565
2017 AKT3 (but not AKT1 or AKT3) deletion impairs cortical Akt Ser473 phosphorylation in an allele-dose dependent manner and reduces mTORC2 complex proteins Rictor and Sin1, indicating AKT3 is the dominant regulator of AKT/mTOR signaling in brain. Akt3 heterozygous and null mouse model, western blot for Ser473-pAkt, Rictor, Sin1, behavioral testing battery PloS one Medium 28467426
2017 Akt1 and Akt3 (but not Akt2) physically interact with DNA-PKcs and stimulate repair of ionizing radiation-induced DNA double-strand breaks in K-RAS-mutated cancer cells; Akt1 preferentially binds the N-terminal domain of DNA-PKcs while Akt3 interacts with all domains without preference; Akt1 activity correlates with Akt1/DNA-PKcs complex formation. Pull-down with eGFP-tagged DNA-PKcs fragments, mCherry-tagged Akt isoforms, clonogenic survival, DSB repair assays, xenograft tumor growth Cell death discovery Medium 29090098
2017 Akt3 deletion in mice is associated with reduced phosphorylation of GSK3α/β at Ser21/9 in multiple brain regions without affecting Akt1 or Akt2 levels; chronic lithium treatment restores pGSK3α/β levels and rescues depressive and anxiety-like behaviors in Akt3 KO mice. Akt3 knockout mouse, behavioral battery, western blot for pGSK3α/β, lithium pharmacological rescue Frontiers in molecular neuroscience Medium 28442992
2017 Akt3 (but not Akt1 or Akt2) is required for survival and proliferation of mouse embryonic stem cells (ESCs) in a kinase activity-dependent manner; Akt3 depletion leads to G1 cell cycle arrest and nuclear accumulation of p53 with activation of downstream targets (Mdm2, p21, Fas); inhibiting p53 partially rescues Akt3-depletion effects. Isoform-specific inhibition and siRNA in ESCs, kinase-dead mutant, flow cytometry, p53 nuclear fractionation, p53 inhibitor rescue Biology open Medium 28483982
2019 AKT3 promotes PGC-1α nuclear localization through inhibitory effects on CRM-1 (nuclear export protein), driving mitochondrial biogenesis; PPARG overexpression transcriptionally increases AKT3 levels, which elevates nuclear PGC-1α and increases mitochondrial mass and ATP production in prostate cancer. AKT3 overexpression/knockdown, PGC-1α subcellular fractionation, CRM-1 interaction analysis, mitochondrial biogenesis assays Oncogene Medium 33654198
2014 Akt3 inhibits vascular tumor endothelial cell growth and migration by inhibiting S6-Kinase (S6K) activation through modulation of Rictor expression; S6K in turn acts through a negative feedback loop to restrain Akt3 expression; Akt1 and Akt3 have opposing roles in vascular tumor growth. Akt isoform-specific manipulation in endothelial cells, S6K activity assay, Rictor expression analysis, S6K inhibitor, tumor growth assays Cancer research Medium 25388284
2017 AKT3 depletion in T cells (but not neurons) impairs differentiation toward FOXP3+ iTregs and worsens clinical course of EAE; Akt3-enhanced kinase activity mice show increased iTreg efficiency and delayed disease onset, establishing AKT3's role in T-cell-mediated neuroprotection. Conditional Akt3 deletion in CD4+ T-cells (vs. Syn1-CKO in neurons), EAE model, flow cytometry for FOXP3+ Tregs Frontiers in immunology Medium 31404142
2021 AKT3 knockdown in AKT inhibitor (MK2206)-resistant breast cancer cells restores sensitivity to the inhibitor; AKT3 upregulation in resistant cells is regulated epigenetically by bromodomain and extra terminal domain (BET) proteins; AKT3 depletion also diminishes the epithelial-to-mesenchymal transition phenotype in resistant cells. Step-wise drug resistance model, isoform-specific siRNA, BET inhibitor treatment, EMT marker analysis Molecular cancer therapeutics Medium 27297869
2015 AKT3 promotes prostate cancer cell proliferation by increasing total AKT, phospho-AKT (S473/T308), B-Raf expression, and activating mTOR/p70S6K signaling while decreasing TSC1 and TSC2 expression; AKT3 knockdown sensitizes cells to B-Raf inhibitor. Plasmid overexpression, siRNA knockdown, western blot for pathway components, drug sensitivity assay Oncotarget Medium 26318033
2015 Akt3 deficiency in ApoE-/- mice increases atherosclerosis in a macrophage-dependent manner; Akt3 specifically inhibits macrophage cholesteryl ester accumulation and foam cell formation, with Akt1 and Akt3 showing differential subcellular localization in macrophages. Akt3-/- × ApoE-/- mouse genetics, macrophage transfer experiments, subcellular fractionation, cholesterol assay Cell metabolism High 22632897

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature genetics 557 22729224
2005 Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Molecular and cellular biology 494 15713641
2004 Deregulated Akt3 activity promotes development of malignant melanoma. Cancer research 453 15466193
1999 Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. The Journal of biological chemistry 412 10419456
2005 Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development (Cambridge, England) 340 15930105
2019 Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression. Molecular cancer 337 30927924
2019 A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent Kinase-1. Molecular cancer 268 31470874
2008 A novel AKT3 mutation in melanoma tumours and cell lines. British journal of cancer 200 18813315
2005 Dosage-dependent effects of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice. Molecular and cellular biology 193 16287854
2012 In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. The Journal of pathology 174 22262409
2008 Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. Cancer research 163 18451171
2010 Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer research 153 20647317
2019 LncRNA MALAT1 promotes osteoarthritis by modulating miR-150-5p/AKT3 axis. Cell & bioscience 150 31304004
1999 Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site. Biochemical and biophysical research communications 149 10208883
2013 Targeting Akt3 signaling in triple-negative breast cancer. Cancer research 142 24335962
2008 Targeting V600EB-Raf and Akt3 using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer research 139 18794153
1999 AKT3, a phloem-localized K+ channel, is blocked by protons. Proceedings of the National Academy of Sciences of the United States of America 134 10377458
1999 Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3. European journal of biochemistry 132 10491192
2021 HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA. Journal of hematology & oncology 131 33794982
2019 Circ-AKT3 inhibits clear cell renal cell carcinoma metastasis via altering miR-296-3p/E-cadherin signals. Molecular cancer 128 31672157
2009 The PTEN-AKT3 signaling cascade as a therapeutic target in melanoma. Pigment cell & melanoma research 114 19493313
2014 miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocrine-related cancer 103 24781864
2015 An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. Nature medicine 100 26523971
2009 Akt2 and Akt3 play a pivotal role in malignant gliomas. Neuro-oncology 100 20167810
2015 Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression. Proceedings of the National Academy of Sciences of the United States of America 95 25737557
2006 Expression and localisation of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients. British journal of cancer 84 16721361
2005 Akt3 overexpression in the heart results in progression from adaptive to maladaptive hypertrophy. Journal of molecular and cellular cardiology 79 15698844
2012 Akt3 deficiency in macrophages promotes foam cell formation and atherosclerosis in mice. Cell metabolism 75 22632897
2007 AKT1, AKT2 and AKT3-dependent cell survival is cell line-specific and knockdown of all three isoforms selectively induces apoptosis in 20 human tumor cell lines. Cancer biology & therapy 74 17426444
2019 Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR. American journal of medical genetics. Part C, Seminars in medical genetics 73 31441589
2013 miR-122 regulates tumorigenesis in hepatocellular carcinoma by targeting AKT3. PloS one 70 24244539
2015 MicroRNA-29B (mir-29b) regulates the Warburg effect in ovarian cancer by targeting AKT2 and AKT3. Oncotarget 67 26512921
2016 Downregulation of AKT3 Increases Migration and Metastasis in Triple Negative Breast Cancer Cells by Upregulating S100A4. PloS one 66 26741489
2015 miR-582-5p inhibits proliferation of hepatocellular carcinoma by targeting CDK1 and AKT3. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 66 26002580
2015 MicroRNA-424 inhibits Akt3/E2F3 axis and tumor growth in hepatocellular carcinoma. Oncotarget 62 26315541
2019 miR-224-5p inhibits proliferation, migration, and invasion by targeting PIK3R3/AKT3 in uveal melanoma. Journal of cellular biochemistry 57 30825222
2019 MiR-150 attenuates LPS-induced acute lung injury via targeting AKT3. International immunopharmacology 56 31398659
2020 The Circular RNA circHUWE1 Sponges the miR-29b-AKT3 Axis to Regulate Myoblast Development. Molecular therapy. Nucleic acids 55 32045877
2010 A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice. Human molecular genetics 55 21159799
2021 PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer. Oncogene 53 33654198
2017 Akt3 is a privileged first responder in isozyme-specific electrophile response. Nature chemical biology 53 28114274
1998 Protein kinase C modulates the insulin-stimulated increase in Akt1 and Akt3 activity in 3T3-L1 adipocytes. Biochemical and biophysical research communications 53 9480839
2019 A novel lncRNA n384546 promotes thyroid papillary cancer progression and metastasis by acting as a competing endogenous RNA of miR-145-5p to regulate AKT3. Cell death & disease 52 31160577
2015 All Akt isoforms (Akt1, Akt2, Akt3) are involved in normal hearing, but only Akt2 and Akt3 are involved in auditory hair cell survival in the mammalian inner ear. PloS one 51 25811375
2019 MiR-16-5p inhibits breast cancer by reducing AKT3 to restrain NF-κB pathway. Bioscience reports 49 31383783
2016 Upregulation of AKT3 Confers Resistance to the AKT Inhibitor MK2206 in Breast Cancer. Molecular cancer therapeutics 49 27297869
2015 miR-29a suppresses growth and metastasis in papillary thyroid carcinoma by targeting AKT3. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 49 26482618
2018 miR-424 targets AKT3 and PSAT1 and has a tumor-suppressive role in human colorectal cancer. Cancer management and research 48 30555259
2014 MiR-489 modulates cisplatin resistance in human ovarian cancer cells by targeting Akt3. Anti-cancer drugs 48 24686007
2017 PKBγ/AKT3 loss-of-function causes learning and memory deficits and deregulation of AKT/mTORC2 signaling: Relevance for schizophrenia. PloS one 47 28467426
2014 Akt1 and akt3 exert opposing roles in the regulation of vascular tumor growth. Cancer research 47 25388284
2019 Circular RNA circ-PRKCI functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-3680-3p in esophageal squamous cell carcinoma. Journal of cellular biochemistry 45 30659640
2014 MicroRNA-22 induces endothelial progenitor cell senescence by targeting AKT3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 45 25323119
2014 Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia. Molecular genetics and metabolism 45 25523067
2020 circ_0037128/miR-17-3p/AKT3 axis promotes the development of diabetic nephropathy. Gene 44 32860899
2018 MicroRNA-16 functions as a tumor-suppressor gene in oral squamous cell carcinoma by targeting AKT3 and BCL2L2. Journal of cellular physiology 44 30136280
2015 AKT3 promotes prostate cancer proliferation cells through regulation of Akt, B-Raf, and TSC1/TSC2. Oncotarget 43 26318033
2018 Long non-coding RNA CHRF facilitates cardiac hypertrophy through regulating Akt3 via miR-93. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 41 29747050
2017 MiR-15b-5p Regulates Collateral Artery Formation by Targeting AKT3 (Protein Kinase B-3). Arteriosclerosis, thrombosis, and vascular biology 41 28254819
2014 AKT3 regulates ErbB2, ErbB3 and estrogen receptor α expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice. Cellular signalling 41 24463007
2017 Akt1 and Akt3 but not Akt2 through interaction with DNA-PKcs stimulate proliferation and post-irradiation cell survival of K-RAS-mutated cancer cells. Cell death discovery 40 29090098
2019 MALAT1 promotes gastric adenocarcinoma through the MALAT1/miR-181a-5p/AKT3 axis. Open biology 39 31480991
2018 MiR-384 inhibits the proliferation of colorectal cancer by targeting AKT3. Cancer cell international 39 30186040
2021 miR-485-3p regulated by MALAT1 inhibits osteosarcoma glycolysis and metastasis by directly suppressing c-MET and AKT3/mTOR signalling. Life sciences 38 33358903
2020 MicroRNA‑16‑5p regulates cell survival, cell cycle and apoptosis by targeting AKT3 in prostate cancer cells. Oncology reports 36 32705237
2019 Akt3-Mediated Protection Against Inflammatory Demyelinating Disease. Frontiers in immunology 36 31404142
2017 Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling. JCI insight 36 29202451
2013 AKT3 controls mitochondrial biogenesis and autophagy via regulation of the major nuclear export protein CRM-1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 24081905
2021 LINC00680 enhances hepatocellular carcinoma stemness behavior and chemoresistance by sponging miR-568 to upregulate AKT3. Journal of experimental & clinical cancer research : CR 35 33499874
2007 Akt2, but not Akt1 or Akt3 mediates pressure-stimulated serum-opsonized latex bead phagocytosis through activating mTOR and p70 S6 kinase. Journal of cellular biochemistry 35 17372934
2017 Akt3 kinase suppresses pinocytosis of low-density lipoprotein by macrophages via a novel WNK/SGK1/Cdc42 protein pathway. The Journal of biological chemistry 34 28389565
2022 Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells. Journal of medicinal chemistry 33 36173763
2018 The Wnt Signaling Pathway Is Differentially Expressed during the Bovine Herpesvirus 1 Latency-Reactivation Cycle: Evidence That Two Protein Kinases Associated with Neuronal Survival, Akt3 and BMPR2, Are Expressed at Higher Levels during Latency. Journal of virology 33 29321317
2012 AKT3, ANGPTL4, eNOS3, and VEGFA associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau. International journal of hematology 33 22729570
2011 Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells. International journal of cancer 33 21351097
2020 Tanshinone IIA regulates human AML cell proliferation, cell cycle, and apoptosis through miR-497-5p/AKT3 axis. Cancer cell international 32 32782437
2020 circ-AKT3 aggravates renal ischaemia-reperfusion injury via regulating miR-144-5p /Wnt/β-catenin pathway and oxidative stress. Journal of cellular and molecular medicine 32 33200535
2018 MicroRNA-433 targets AKT3 and inhibits cell proliferation and viability in breast cancer. Oncology letters 32 29556282
2020 AKT3 deficiency in M2 macrophages impairs cutaneous wound healing by disrupting tissue remodeling. Aging 31 32291381
2017 miR-217 inhibits proliferation, migration, and invasion via targeting AKT3 in thyroid cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 31 28962076
2016 MiR-20b targets AKT3 and modulates vascular endothelial growth factor-mediated changes in diabetic retinopathy. Acta biochimica et biophysica Sinica 31 27421659
2021 MiR-20b-5p modulates inflammation, apoptosis and angiogenesis in severe acute pancreatitis through autophagy by targeting AKT3. Autoimmunity 30 34402705
2017 Akt3 is responsible for the survival and proliferation of embryonic stem cells. Biology open 30 28483982
2019 MiR-125b-5p and miR-181b-5p inhibit keratinocyte proliferation in skin by targeting Akt3. European journal of pharmacology 29 31518563
2014 Phenotypes of AKT3 deletion: a case report and literature review. American journal of medical genetics. Part A 29 25424989
2021 AKT3 Is a Novel Regulator of Cancer-Associated Fibroblasts in Head and Neck Squamous Cell Carcinoma. Cancers 28 33799788
2021 N6-methyladenosine-modified long non-coding RNA AGAP2-AS1 promotes psoriasis pathogenesis via miR-424-5p/AKT3 axis. Journal of dermatological science 28 34930676
2020 RP11-480I12.5-004 Promotes Growth and Tumorigenesis of Breast Cancer by Relieving miR-29c-3p-Mediated AKT3 and CDK6 Degradation. Molecular therapy. Nucleic acids 28 32810693
2019 Overexpression of miR-1258 inhibits cell proliferation by targeting AKT3 in osteosarcoma. Biochemical and biophysical research communications 27 30737029
2021 Downregulation of microRNA-15b-5p Targeting the Akt3-Mediated GSK-3β/β-Catenin Signaling Pathway Inhibits Cell Apoptosis in Parkinson's Disease. BioMed research international 26 33506036
2017 Genetic Deletion of Akt3 Induces an Endophenotype Reminiscent of Psychiatric Manifestations in Mice. Frontiers in molecular neuroscience 26 28442992
2021 Upregulation of circ_0000142 promotes multiple myeloma progression by adsorbing miR-610 and upregulating AKT3 expression. Journal of biochemistry 25 32970816
2021 AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition. Cancers 25 33673003
2018 Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long-term potentiation through downregulation of mTOR. Acta physiologica (Oxford, England) 25 30053339
2014 Knockdown of AKT3 (PKBγ) and PI3KCA suppresses cell viability and proliferation and induces the apoptosis of glioblastoma multiforme T98G cells. BioMed research international 25 24967401
2018 miR-320b Is Down-Regulated in Psoriasis and Modulates Keratinocyte Proliferation by Targeting AKT3. Inflammation 24 30136020
2020 RHPN1-AS1 promotes cell proliferation and migration via miR-665/Akt3 in ovarian cancer. Cancer gene therapy 23 32457485
2020 LINC02163 promotes colorectal cancer progression via miR-511-3p/AKT3 axis. Artificial cells, nanomedicine, and biotechnology 23 32524841
2017 Targeting protein kinase-b3 (akt3) signaling in melanoma. Expert opinion on therapeutic targets 23 28064546
2021 CircWHSC1 regulates malignancy and glycolysis by the miR-212-5p/AKT3 pathway in triple-negative breast cancer. Experimental and molecular pathology 22 34624276

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