Affinage

AKT3

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

Length
479 aa
Mass
55.8 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKT3 is a PI3K/mTORC2-activated serine/threonine kinase that functions as the dominant AKT isoform in the brain and exerts non-redundant, tissue-specific roles in cell growth, mitochondrial biogenesis, lipid metabolism, immune regulation, and platelet activation. AKT3 is activated by phosphorylation at Thr305 and Ser472, with mTORC2 serving as its principal upstream activator in cortex, and signals through mTOR/p70S6K to control brain size, cell number, cell size, and protein synthesis–dependent synaptic plasticity; loss of Akt3 in mice causes selective microcephaly, impaired long-term potentiation, and psychiatric-relevant behavioral deficits rescued by GSK-3 inhibition (PMID:15713641, PMID:30053339, PMID:28442992, PMID:28467426). In non-neuronal contexts, AKT3 promotes mitochondrial biogenesis by stabilizing CRM-1 to retain PGC-1α in the nucleus, suppresses adipogenesis by phosphorylating WNK1 at T58 to target it for proteasomal degradation, limits macrophage foam cell formation by degrading ACAT-1 via the ubiquitin–proteasome pathway, promotes FOXP3+ iTreg differentiation in CD4+ T cells, and facilitates platelet activation through GSK-3β Ser9 phosphorylation (PMID:24081905, PMID:29202451, PMID:22632897, PMID:31404142, PMID:21821713). Activating AKT3 mutations—including PH-domain variants with enhanced phospholipid binding—cause constitutive PI3K/AKT pathway signaling and underlie megalencephaly syndromes (PMID:28969385).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Defining AKT3's activation mechanism resolved whether this third AKT isoform used the same phosphorylation-dependent switch as AKT1/2: phosphorylation at both Ser472 and Thr305 is required for full catalytic activation, and constitutively elevated AKT3 activity was found to dominate in PTEN-null and hormone-insensitive cancer cells.

    Evidence Molecular cloning, site-directed mutagenesis with in vitro kinase assays, and kinase activity profiling across cancer cell panels

    PMID:10419456 PMID:10491192

    Open questions at the time
    • Upstream kinase(s) responsible for each phosphorylation site not yet identified in this work
    • No structural basis for isoform-selective activation
  2. 2001 High

    Establishing that membrane recruitment converts AKT3 from weakly transforming to strongly oncogenic demonstrated that subcellular localization gates its kinase-dependent oncogenicity.

    Evidence Myristylated vs. wild-type AKT3 retroviral expression in chicken embryo fibroblasts; focus formation and hemangiosarcoma induction in vivo

    PMID:11466625

    Open questions at the time
    • Endogenous membrane-targeting mechanism not defined
    • Identity of critical substrates mediating transformation unclear
  3. 2005 High

    The discovery that Akt3 knockout mice have selectively smaller brains—with both reduced cell size and number, and attenuated mTOR signaling—established AKT3 as a non-redundant, isoform-specific regulator of brain growth acting through the mTOR pathway.

    Evidence Akt3 KO mouse model with brain size, cell number, cell size, and mTOR pathway activity measurements

    PMID:15713641

    Open questions at the time
    • Specific mTOR effectors mediating cell size vs. cell number effects not separated
    • Developmental timing of AKT3 requirement not resolved
  4. 2006 High

    Akt2/Akt3 double knockout mice demonstrated that AKT3 has non-redundant whole-organism roles beyond the brain, contributing to body weight, testis size, and metabolic homeostasis.

    Evidence Double KO mouse model with metabolic and organ measurements

    PMID:16923958

    Open questions at the time
    • Relative contributions of Akt2 vs. Akt3 to metabolic phenotypes not individually resolved
  5. 2008 High

    Identification of AKT3 as selectively required for VEGF-induced mitochondrial biogenesis in endothelial cells—and its regulation of PGC-1α nuclear retention—revealed a novel isoform-specific function in organelle biogenesis distinct from canonical AKT survival signaling.

    Evidence Akt3 vs. Akt1 siRNA/shRNA in endothelial cells, mtDNA/O₂ consumption quantification, PGC-1α localization, Akt3 KO mouse brain mitochondria

    PMID:18524868

    Open questions at the time
    • Molecular mechanism by which AKT3 retains PGC-1α in the nucleus not yet defined
    • Direct AKT3 substrate linking kinase activity to mitochondrial gene program unknown
  6. 2011 High

    Two studies established context-dependent roles: AKT3 promotes platelet activation by phosphorylating GSK-3β at Ser9, while in ovarian cancer it isoform-specifically controls VEGF secretion via RCAS1/Golgi-dependent trafficking.

    Evidence Akt3 KO mouse platelets with aggregation assays and GSK-3β inhibitor rescue; isoform-specific shRNA in ovarian cancer with VEGF secretion and ER retention imaging

    PMID:21351097 PMID:21821713

    Open questions at the time
    • How AKT3 activates RCAS1 expression mechanistically unknown
    • Platelet AKT3 substrate specificity beyond GSK-3β not explored
  7. 2012 High

    AKT3 was shown to restrict macrophage foam cell formation by promoting ACAT-1 ubiquitin-proteasome degradation, and separately to suppress N-cadherin–driven breast cancer cell migration, consolidating its role as a cell-type–specific negative regulator in both atherosclerosis and metastasis.

    Evidence Akt3 KO in ApoE−/− mice with macrophage cholesterol/ACAT-1 degradation assays; N-cadherin/Akt3 bidirectional manipulation in mammary tumor cells with motility assays

    PMID:22410780 PMID:22632897

    Open questions at the time
    • Direct phosphorylation target linking AKT3 to ACAT-1 ubiquitination not identified
    • N-cadherin mechanism of AKT3 transcriptional/translational suppression unclear
  8. 2013 High

    Identification of CRM-1 stabilization as the mechanism by which AKT3 retains PGC-1α in the nucleus resolved how AKT3 controls mitochondrial biogenesis, and revealed a CRM-1–dependent, mTOR-independent autophagy pathway.

    Evidence Akt3 knockdown with CRM-1 protein stability analysis, PGC-1α nuclear export assay, autophagosome quantification, Matrigel angiogenesis in Akt3 KO mice

    PMID:24081905

    Open questions at the time
    • Whether AKT3 directly phosphorylates CRM-1 or acts indirectly not resolved
    • Autophagy pathway downstream effectors not identified
  9. 2015 High

    AKT3 was established as an isoform-specific suppressor of breast cancer cell migration acting through S100A4, with combined AKT isoform depletion increasing metastasis in vivo.

    Evidence Isoform-specific shRNA, S100A4 siRNA rescue of migration, in vivo xenograft metastasis model

    PMID:26741489

    Open questions at the time
    • How AKT3 loss upregulates S100A4 protein mechanistically unknown
    • Whether S100A4 is a direct or indirect target not determined
  10. 2017 High

    Multiple 2017 studies converged to define AKT3's upstream activation and disease relevance: mTORC2 (Rictor/Sin1) was identified as the dominant upstream activator in brain, megalencephaly-associated mutations were shown to constitutively activate kinase activity (PH domain mutants via enhanced phospholipid binding), and AKT3 was linked to adipogenesis suppression by phosphorylating WNK1 at T58.

    Evidence Allele dose-dependent Rictor/Sin1 reduction in Akt3 KO cortex; ex vivo kinase and phospholipid binding assays on patient mutations; Akt3 KO adipocyte model with WNK1 T58 phosphorylation, SGK1 inhibitor rescue in vivo

    PMID:28467426 PMID:28969385 PMID:29202451

    Open questions at the time
    • Structural basis for PH domain mutation-driven phospholipid selectivity not solved
    • Whether mTORC2 dependence extends to non-brain tissues not tested
    • WNK1 T58 phosphorylation not confirmed as direct in reconstituted system
  11. 2018 High

    AKT3's neurological roles were extended to synaptic plasticity and behavior: Akt3 KO impairs protein synthesis–dependent LTP via mTOR/p70S6K/4EBP2 and produces psychiatric-like behaviors rescued by lithium-mediated GSK-3 inhibition.

    Evidence Akt3 KO mice with electrophysiological LTP recordings, Morris water maze, p-mTOR/p-p70S6K/p-4EBP2 western blots; behavioral battery with lithium rescue and GSK-3α/β phosphorylation analysis

    PMID:28442992 PMID:30053339

    Open questions at the time
    • Whether LTP and behavioral phenotypes share a single downstream mechanism or represent parallel pathways unclear
    • Cell-type specificity of AKT3 function in adult brain circuits not resolved
  12. 2019 High

    Cell-type–specific conditional knockout revealed that AKT3 protects against neuroinflammation by promoting FOXP3+ iTreg differentiation specifically in CD4+ T cells, not neurons, resolving the cellular origin of AKT3-dependent neuroprotection.

    Evidence CD4-Cre and Syn1-Cre conditional Akt3 KO mice in EAE model, FOXP3 flow cytometry

    PMID:31404142

    Open questions at the time
    • Direct substrate linking AKT3 kinase activity to FOXP3 induction not identified
    • Whether this mechanism operates in other autoimmune contexts untested
  13. 2022 High

    Development of an AKT3-selective PROTAC degrader validated that AKT3 protein, specifically, sustains survival signaling in drug-resistant NSCLC, confirming isoform-selective dependency.

    Evidence PROTAC-mediated selective AKT3 degradation with isoform selectivity profiling, cell viability, and in vivo xenograft

    PMID:36173763

    Open questions at the time
    • AKT3-specific substrates mediating drug resistance not identified
    • Whether selective AKT3 degradation has therapeutic utility in other resistance contexts unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis for AKT3 isoform selectivity toward its substrates, the identity of direct phosphorylation targets mediating CRM-1 stabilization and ACAT-1 degradation, and whether the diverse tissue-specific functions reflect distinct substrate repertoires or context-dependent signaling scaffolds.
  • No crystal structure of AKT3 in complex with isoform-specific substrates
  • Direct kinase–substrate relationships for CRM-1, ACAT-1, and S100A4 regulation unresolved
  • Systems-level substrate atlas comparing AKT1/2/3 phosphoproteomes lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2 R-HSA-109582 Hemostasis 1 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
ACAT1CRM1GSK3BPGC1APRAS40RICTORS100A4WNK1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Akt3 knockout mice display a selective 20% decrease in brain size with smaller and fewer cells (reduced cell size and cell number), distinct from Akt1 knockout which reduces cell number only; mTOR signaling is specifically attenuated in Akt3-/- but not Akt1-/- brains, indicating isoform-specific regulation of cell growth via mTOR. Akt3 knockout mouse model with organ size measurements, cell counting, cell size analysis, and mTOR pathway activity assessment Molecular and cellular biology High 15713641
1999 Human AKT3 encodes a serine/threonine kinase with a pleckstrin homology domain and kinase domain; phosphorylation of both Ser472 and Thr305 contributes to kinase activation, as mutation of both to aspartate increased catalytic activity and mutation to alanine inhibited activation; the kinase is inhibited by staurosporine and Ro 31-8220. Molecular cloning, site-directed mutagenesis, in vitro kinase assay European journal of biochemistry High 10491192
1999 Akt3 enzymatic activity is 20–60-fold elevated in estrogen receptor-deficient breast cancer cells and androgen-insensitive prostate cancer cells compared to hormone-responsive cells; in PTEN-null prostate cancer cells, Akt3 constitutive activity represents the dominant active Akt isoform. In vitro kinase activity assay across multiple cancer cell lines The Journal of biological chemistry High 10419456
2001 Membrane-targeted (myristylated) Akt3 is strongly oncogenic in chicken embryo fibroblasts, inducing multilayered foci and hemangiosarcomas in animals, with enhanced kinase activity; wild-type Akt3 is only weakly transforming, demonstrating that membrane localization and kinase activation are required for full oncogenic potential. RCAS retroviral expression in chicken embryo fibroblasts, focus formation assay, animal tumor model Oncogene High 11466625
2006 Akt2-/-Akt3-/- double knockout mice survive but exhibit glucose and insulin intolerance, ~25% reduced body weight, and substantial reductions in brain and testis size, demonstrating non-redundant in vivo roles of Akt2 and Akt3 in whole-animal size and individual organ size determination. Double knockout mouse model with metabolic, weight, and organ size measurements Molecular and cellular biology High 16923958
2008 Akt3, but not Akt1, is specifically required for VEGF-induced mitochondrial biogenesis in endothelial cells; Akt3 silencing decreases mitochondrial gene expression, mtDNA content, nuclear-encoded mitochondrial gene transcripts, O2 consumption, and TOM70 expression; Akt3 knockdown causes cytoplasmic accumulation of PGC-1α (master regulator of mitochondrial biogenesis); Akt3 knockout mice show an abnormal mitochondrial phenotype in brain tissue. Akt3 gene silencing by siRNA/shRNA with comparison to Akt1 silencing, mitochondrial gene/mtDNA quantification, O2 consumption measurement, PGC-1α localization, Akt3 KO mouse tissue analysis FASEB journal High 18524868
2011 Akt3 is expressed in platelets and Akt3-/- mouse platelets exhibit impaired aggregation and secretion in response to low concentrations of thrombin receptor agonists and thromboxane A2 (but not collagen or VWF); Akt3 promotes platelet activation by phosphorylating and inhibiting GSK-3β at Ser9; pharmacological rescue of GSK-3β inhibition restores Akt3-/- platelet aggregation defect; Akt3-/- mice show retarded FeCl3-induced carotid artery thrombosis in vivo. Akt3 KO mouse platelets, platelet aggregation/secretion assays, GSK-3β phosphorylation analysis, GSK-3β inhibitor rescue, in vivo thrombosis model Blood High 21821713
2012 Akt3 deficiency in macrophages promotes foam cell formation and atherosclerosis; Akt3 specifically inhibits cholesteryl ester accumulation by reducing lipoprotein uptake and promoting ACAT-1 degradation via the ubiquitin-proteasome pathway; Akt1 and Akt3 show differential subcellular localization in macrophages. Akt3 KO in hyperlipidemic ApoE-/- mice, macrophage cholesteryl ester assays, lipoprotein uptake measurements, ACAT-1 protein degradation analysis with ubiquitin-proteasome pathway assessment, subcellular fractionation Cell metabolism High 22632897
2013 Akt3 controls mitochondrial biogenesis and autophagy via regulation of CRM-1 (chromosome maintenance region-1), the major nuclear export receptor; Akt3 knockdown destabilizes CRM-1, causing PGC-1α nuclear export in a CRM-1-dependent manner; Akt3 knockdown induces autophagosome formation via a CRM-1-dependent, Akt1/mTOR-independent pathway; Akt3-null and heterozygous mice show dose-dependent decreases in angiogenesis in vivo. Akt3 knockdown, site-directed mutagenesis, co-immunoprecipitation/association analyses, autophagosome assay, PGC-1α localization, Matrigel angiogenesis assay in Akt3 KO mice FASEB journal High 24081905
2011 Akt3, but not Akt1, controls VEGF secretion in ovarian cancer cells; Akt3 blockade reduces VEGF secretion and causes retention of VEGF protein in the endoplasmic reticulum; Akt3 regulates expression of Golgi protein RCAS1, which in turn controls VEGF secretion; Akt3 overexpression increases RCAS1 expression and VEGF secretion. shRNA knockdown of Akt3 vs Akt1, VEGF secretion assay, ER retention imaging, RCAS1 siRNA, xenograft mouse model International journal of cancer High 21351097
2014 Akt3 and Akt1 exert opposing roles in vascular tumor growth: Akt1 promotes and Akt3 inhibits vascular tumor growth; Akt3 inhibits tumor endothelial cell growth and migration by suppressing S6-Kinase (S6K) activation through modulation of Rictor expression; S6K in turn suppresses Akt3 expression via negative feedback. Gain- and loss-of-function of individual Akt isoforms, in vivo vascular tumor model, S6K pathway analysis, Rictor expression measurement Cancer research High 25388284
2012 N-cadherin expression in mammary tumor cells selectively inhibits Akt3 expression and phosphorylation, leading to increased cell motility; Akt3 knockdown increases cell motility; Akt3 overexpression inhibits motility promoted by N-cadherin, establishing Akt3 as a downstream suppressor of N-cadherin-driven cell migration. N-cadherin overexpression in PyMT and MCF-7 cells, Akt3 knockdown and overexpression, motility assays, phosphorylation analysis Oncogene High 22410780
2017 AKT3 mutations identified in megalencephaly patients all increase kinase activity as measured by ex vivo kinase assays; pleckstrin homology domain mutants (including p.E17K) exhibit enhanced phospholipid binding, explaining constitutive membrane recruitment and activation. Ex vivo kinase assays on engineered patient-mutation AKT3 constructs, phospholipid binding assay for PH domain mutants Brain : a journal of neurology High 28969385
2017 Akt3 loss-of-function in mice dramatically impairs cortical Akt Ser473 phosphorylation in an allele dose-dependent manner with concomitant reduction of mTORC2 complex proteins Rictor and Sin1, identifying mTORC2 as the dominant upstream activator of Akt3 in brain and Akt3 as the primary regulator of Akt/mTOR signaling in brain. Akt3 heterozygous and null mice, western blot quantification of Akt Ser473, Rictor, and Sin1 in cortex PloS one High 28467426
2017 Akt3 deficiency in adipocytes increases WNK1 protein levels (by loss of Akt3-mediated phosphorylation of WNK1 at T58 and ubiquitin-proteasome degradation), leading to SGK1 activation; SGK1 then phosphorylates and inhibits FOXO1, activating PPARγ transcription and promoting adipogenesis; pharmacological blockade of SGK1 rescues the obesity phenotype in Akt3-deficient mice. Akt3 KO mouse model, phosphorylation site identification (WNK1 T58), ubiquitin-proteasome pathway analysis, SGK1 inhibitor treatment in vivo, adipogenesis assays JCI insight High 29202451
2021 PPAR-γ overexpression drives increased AKT3 expression; AKT3 promotes nuclear localization of PGC-1α by inhibiting CRM1 (nuclear export protein), driving mitochondrial biogenesis and elevated ATP production that fuels epithelial-to-mesenchymal transition in prostate cancer. PPAR-γ overexpression, AKT3 expression analysis, PGC-1α nuclear localization assay, CRM1 inhibition experiments, mitochondrial mass and ATP measurements Oncogene Medium 33654198
2015 AKT3 knockdown in triple-negative breast cancer cells increases migration in vitro, which is mediated by upregulation of S100A4 protein; siRNA knockdown of S100A4 reverses the increased migration caused by AKT3 depletion; combined AKT2/AKT3 or AKT1/AKT3 depletion increases metastasis in vivo, establishing AKT3 as an isoform-specific suppressor of migration/metastasis acting through S100A4. isoform-specific shRNA knockdown, live-cell imaging and transwell migration assays, S100A4 siRNA rescue, in vivo xenograft metastasis model PloS one High 26741489
2016 AKT3 upregulation in breast cancer cells confers resistance to the allosteric AKT inhibitor MK2206; knockdown of AKT3 (but not AKT1 or AKT2) in resistant cells restores MK2206 sensitivity; AKT3 induction in resistant cells is regulated epigenetically by bromodomain and extra terminal domain (BET) proteins. Step-wise drug resistance model, isoform-specific siRNA knockdown, BET inhibitor treatment, cell viability assays Molecular cancer therapeutics High 27297869
2018 Akt3 deletion in mice reduces GSK3α/β phosphorylation at Ser21/9 in multiple brain regions; this leads to behavioral phenotypes resembling schizophrenia, anxiety, and depression; chronic lithium treatment (which inhibits GSK3) restores GSK3α/β phosphorylation and rescues the behavioral deficits, placing GSK3 phosphorylation as a key downstream mechanism of Akt3 in psychiatric-relevant behavior. Akt3 KO mice, western blot of p-GSK3α/β, behavioral test battery, lithium rescue treatment Frontiers in molecular neuroscience High 28442992
2018 Akt3 deficiency in mice impairs protein synthesis-dependent long-LTP (HFS×4-induced) and long-term spatial memory; Akt3 KO reduces basal mTOR phosphorylation; HFS×4 fails to trigger mTOR-p70S6K signaling cascade or increase 4EBP2/eIF4E phosphorylation in Akt3 KO mice, indicating Akt3 regulates protein synthesis-dependent plasticity via mTOR-p70S6K pathway. Akt3 KO mice, Morris water maze, electrophysiological LTP recordings, western blot of mTOR/p70S6K/4EBP2/eIF4E pathway components Acta physiologica High 30053339
2015 AKT3 overexpression increases total AKT, phospho-AKT (S473 and T308), B-Raf, and downstream mTOR/p70S6K signaling while decreasing TSC1 and TSC2 proteins in prostate cancer cells; AKT3 knockdown sensitizes cells to B-Raf inhibitor treatment. Plasmid overexpression and siRNA knockdown of AKT3 in prostate cancer cell lines, western blot pathway analysis, drug sensitivity assay Oncotarget Medium 26318033
2017 Akt3 specifically controls embryonic stem cell survival and proliferation; Akt3 inhibition causes nuclear accumulation of p53 and activation of downstream targets Mdm2, p21, and Fas; inhibiting p53 and its downstream targets partially rescues the effects of Akt3 depletion, identifying the Akt3-p53 axis as isoform-specific in ESC survival. Akt3 knockdown in mouse ESCs, p53 nuclear localization (western/fractionation), p53 inhibitor rescue, cell cycle and apoptosis assays Biology open Medium 28483982
2019 M2-polarized tumor-associated macrophages activate the AKT3/PRAS40 signaling pathway in cholangiocarcinoma cells (via secreted cytokines), promoting EMT; AKT3 silencing (but not AKT1 or AKT2 silencing) markedly inhibits phosphorylation of AKT and PRAS40 and inhibits EMT in co-culture with M2-TAMs. Macrophage-cancer cell co-culture, isoform-specific AKT siRNA knockdown, p-AKT and p-PRAS40 western blot, EMT marker analysis Journal of cellular biochemistry Medium 31692069
2019 Akt3-mediated protection against inflammatory demyelinating disease is specifically mediated by Akt3 in CD4+ T-cells (not neurons); conditional deletion of Akt3 in CD4+ T-cells worsens EAE, decreases FOXP3+ Treg cells, and increases CNS inflammation; enhanced Akt3 kinase activity increases FOXP3+ iTreg differentiation efficiency. Cell-type specific conditional Akt3 knockout mice (CD4-CKO and Syn1-CKO), EAE model, FOXP3 expression, flow cytometry Frontiers in immunology High 31404142
2010 IL-13 suppresses MMP-13 expression in human dermal fibroblasts via the PI3K/Akt3 pathway; Akt3-specific siRNA knockdown upregulates MMP-13 in IL-13-treated fibroblasts, indicating Akt3 negatively controls MMP-13 expression downstream of IL-13/PI3K signaling. Akt3-specific siRNA knockdown, cDNA microarray, MMP-13 mRNA and protein measurement, PI3K inhibitor treatment The Journal of investigative dermatology Medium 21191416
2009 In malignant glioma cells, Akt2 and Akt3 (not Akt1) knockdown reduces phosphorylated Bad and induces caspase-dependent apoptosis; overexpression of Akt2 or Akt3 cross-suppresses expression of the other isoform; endogenous Akt3 shows high kinase activity in U87MG cells. Isoform-specific RNA interference and plasmid overexpression in glioma cell lines, Bad phosphorylation analysis, caspase-dependent apoptosis assay, kinase activity measurement Neuro-oncology Medium 20167810
2021 AKT3 controls expression of the cell cycle regulator p27KIP1 in CMS4 mesenchymal colorectal cancer cells; chemical inhibition or knockout of AKT3 hampers CMS4 cell outgrowth by regulating p27KIP1 levels; high AKT3 expression is associated with high EMT gene expression. AKT3 CRISPR knockout and chemical inhibition in CMS4 CRC cell lines and PDX models, p27KIP1 protein quantification, in vitro and in vivo growth assays Cancers Medium 33673003
2022 Isoform-selective AKT3 PROTAC degrader (12l) induces proteasomal degradation of AKT3 but not AKT1/2 in vitro and in vivo; selective AKT3 degradation suppresses growth of osimertinib-resistant NSCLC cells, validating a non-canonical, AKT3-specific survival function in drug-resistant cells. PROTAC-mediated targeted protein degradation, isoform selectivity profiling, cell viability assays, in vivo xenograft model Journal of medicinal chemistry High 36173763

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 554 22729224
2005 Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Molecular and cellular biology 493 15713641
1999 Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. The Journal of biological chemistry 412 10419456
2019 Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression. Molecular cancer 336 30927924
2006 Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Molecular and cellular biology 221 16923958
2019 LncRNA MALAT1 promotes osteoarthritis by modulating miR-150-5p/AKT3 axis. Cell & bioscience 149 31304004
2008 Targeting V600EB-Raf and Akt3 using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer research 139 18794153
1999 Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3. European journal of biochemistry 131 10491192
2019 Circ-AKT3 inhibits clear cell renal cell carcinoma metastasis via altering miR-296-3p/E-cadherin signals. Molecular cancer 128 31672157
2021 HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA. Journal of hematology & oncology 127 33794982
2009 The PTEN-AKT3 signaling cascade as a therapeutic target in melanoma. Pigment cell & melanoma research 114 19493313
2017 MiRNA-29b suppresses tumor growth through simultaneously inhibiting angiogenesis and tumorigenesis by targeting Akt3. Cancer letters 106 28365400
2014 miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocrine-related cancer 103 24781864
2008 VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 103 18524868
2009 Akt2 and Akt3 play a pivotal role in malignant gliomas. Neuro-oncology 99 20167810
2017 Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. Brain : a journal of neurology 97 28969385
2011 An important role for Akt3 in platelet activation and thrombosis. Blood 97 21821713
2001 Oncogenic transformation induced by membrane-targeted Akt2 and Akt3. Oncogene 92 11466625
2006 Expression and localisation of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients. British journal of cancer 83 16721361
2012 Akt3 deficiency in macrophages promotes foam cell formation and atherosclerosis in mice. Cell metabolism 75 22632897
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 71 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
2006 Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas. Oncology 58 17047397
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
2019 miR-224-5p inhibits proliferation, migration, and invasion by targeting PIK3R3/AKT3 in uveal melanoma. Journal of cellular biochemistry 55 30825222
2021 PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer. Oncogene 53 33654198
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
2019 M2-polarized tumor-associated macrophages promote epithelial-mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma. Journal of cellular biochemistry 51 31692069
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
2010 Expression of matrix metalloproteinase-13 is controlled by IL-13 via PI3K/Akt3 and PKC-δ in normal human dermal fibroblasts. The Journal of investigative dermatology 49 21191416
2017 MicroRNA-338-3p inhibits thyroid cancer progression through targeting AKT3. American journal of cancer research 48 28560065
2015 Flotillin-2 promotes metastasis of nasopharyngeal carcinoma by activating NF-κB and PI3K/Akt3 signaling pathways. Scientific reports 48 26206082
2014 MiR-489 modulates cisplatin resistance in human ovarian cancer cells by targeting Akt3. Anti-cancer drugs 48 24686007
2018 miR-424 targets AKT3 and PSAT1 and has a tumor-suppressive role in human colorectal cancer. Cancer management and research 47 30555259
2017 MiR-145 ameliorates neuropathic pain via inhibiting inflammatory responses and mTOR signaling pathway by targeting Akt3 in a rat model. Neuroscience research 47 29162479
2014 Akt1 and akt3 exert opposing roles in the regulation of vascular tumor growth. Cancer research 47 25388284
2017 PKBγ/AKT3 loss-of-function causes learning and memory deficits and deregulation of AKT/mTORC2 signaling: Relevance for schizophrenia. PloS one 45 28467426
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
2020 circ_0037128/miR-17-3p/AKT3 axis promotes the development of diabetic nephropathy. Gene 44 32860899
2014 Focal dysplasia of the cerebral cortex and infantile spasms associated with somatic 1q21.1-q44 duplication including the AKT3 gene. Clinical genetics 44 25091978
2012 N-cadherin regulates mammary tumor cell migration through Akt3 suppression. Oncogene 44 22410780
2020 Propofol suppresses proliferation and metastasis of colorectal cancer cells by regulating miR-124-3p.1/AKT3. Biotechnology letters 43 31894425
2015 AKT3 promotes prostate cancer proliferation cells through regulation of Akt, B-Raf, and TSC1/TSC2. Oncotarget 43 26318033
2014 Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia. Molecular genetics and metabolism 43 25523067
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
2010 Molecular alterations in AKT1, AKT2 and AKT3 detected in breast and prostatic cancer by FISH. Histopathology 40 20102399
2019 MALAT1 promotes gastric adenocarcinoma through the MALAT1/miR-181a-5p/AKT3 axis. Open biology 39 31480991
2018 Long non-coding RNA FEZF1-AS1 promotes cell growth in multiple myeloma via miR-610/Akt3 axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 39 29864963
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
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
2001 The AKT3 potassium channel protein interacts with the AtPP2CA protein phosphatase 2C. Journal of experimental botany 34 11181729
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 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
2019 MiR-15a attenuates peripheral nerve injury-induced neuropathic pain by targeting AKT3 to regulate autophagy. Genes & genomics 32 31736006
2018 miRNA‑145 inhibits myocardial infarction‑induced apoptosis through autophagy via Akt3/mTOR signaling pathway in vitro and in vivo. International journal of molecular medicine 32 29956747
2014 Amplification of Chromosome 1q Genes Encoding the Phosphoinositide Signalling Enzymes PI4KB, AKT3, PIP5K1A and PI3KC2B in Breast Cancer. Journal of Cancer 32 25368680
2011 Uncommon GNAQ, MMP8, AKT3, EGFR, and PIK3R1 mutations in thyroid cancers. Endocrine pathology 32 21487925
2022 Discovery of Isoform-Selective Akt3 Degraders Overcoming Osimertinib-Induced Resistance in Non-Small Cell Lung Cancer Cells. Journal of medicinal chemistry 31 36173763
2019 MiR-20b-5p relieves neuropathic pain by targeting Akt3 in a chronic constriction injury rat model. Synapse (New York, N.Y.) 31 31381191
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
2017 Akt3 is responsible for the survival and proliferation of embryonic stem cells. Biology open 30 28483982
2021 MiR-20b-5p modulates inflammation, apoptosis and angiogenesis in severe acute pancreatitis through autophagy by targeting AKT3. Autoimmunity 29 34402705
2016 MicroRNA-150 negatively regulates the function of CD4(+) T cells through AKT3/Bim signaling pathway. Cellular immunology 29 27329362
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 MiR-125b-5p and miR-181b-5p inhibit keratinocyte proliferation in skin by targeting Akt3. European journal of pharmacology 28 31518563
2014 Phenotypes of AKT3 deletion: a case report and literature review. American journal of medical genetics. Part A 28 25424989
2021 AKT3 Is a Novel Regulator of Cancer-Associated Fibroblasts in Head and Neck Squamous Cell Carcinoma. Cancers 27 33799788
2021 N6-methyladenosine-modified long non-coding RNA AGAP2-AS1 promotes psoriasis pathogenesis via miR-424-5p/AKT3 axis. Journal of dermatological science 27 34930676
2019 Overexpression of miR-1258 inhibits cell proliferation by targeting AKT3 in osteosarcoma. Biochemical and biophysical research communications 27 30737029
2018 Upregulation of miR-582-5p regulates cell proliferation and apoptosis by targeting AKT3 in human endometrial carcinoma. Saudi journal of biological sciences 27 30108448
2017 MicroRNA-582-5p suppressed gastric cancer cell proliferation via targeting AKT3. European review for medical and pharmacological sciences 27 29228422
2016 The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression. Journal of neuro-oncology 27 27422127
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
2019 Inhibition of miR-181b-5p protects cardiomyocytes against ischemia/reperfusion injury by targeting AKT3 and PI3KR3. Journal of cellular biochemistry 25 31297863
2019 LINC00565 promotes proliferation and inhibits apoptosis of gastric cancer by targeting miR-665/AKT3 axis. OncoTargets and therapy 25 31576144
2018 Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long-term potentiation through downregulation of mTOR. Acta physiologica (Oxford, England) 24 30053339
2018 miR-320b Is Down-Regulated in Psoriasis and Modulates Keratinocyte Proliferation by Targeting AKT3. Inflammation 24 30136020
2020 LncRNA DSCAM-AS1 promotes colorectal cancer progression by acting as a molecular sponge of miR-384 to modulate AKT3 expression. Aging 23 32453706
2020 RHPN1-AS1 promotes cell proliferation and migration via miR-665/Akt3 in ovarian cancer. Cancer gene therapy 23 32457485
2017 Targeting protein kinase-b3 (akt3) signaling in melanoma. Expert opinion on therapeutic targets 23 28064546
2014 MicroRNA-207 enhances radiation-induced apoptosis by directly targeting Akt3 in cochlea hair cells. Cell death & disease 23 25275594
2020 LINC02163 promotes colorectal cancer progression via miR-511-3p/AKT3 axis. Artificial cells, nanomedicine, and biotechnology 22 32524841
2016 Combination Therapy with AKT3 and PI3KCA siRNA Enhances the Antitumor Effect of Temozolomide and Carmustine in T98G Glioblastoma Multiforme Cells. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 22 26902608