Affinage

AKT2

RAC-beta serine/threonine-protein kinase · UniProt P31751

Length
481 aa
Mass
55.8 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 42 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

AKT2 (PKBβ) is a plasma membrane-recruited serine/threonine kinase that executes isoform-specific functions in insulin/growth-factor signaling, metabolic control, cell migration, and immune polarization, distinct from its paralog AKT1 (PMID:10523666, PMID:16365168). Its maximal catalytic output requires hydrophobic-motif phosphorylation at Ser474, which drives phosphorylation of canonical substrates (TSC2, PRAS40, FOXO1/3a, AS160), mTORC1 activation, FOXO nuclear exclusion, and GLUT4 translocation (PMID:31548312); AKT2 is selectively inactivated by the phosphatase PHLPP1, whereas linker-residue phosphorylation differences (lack of Ser131 modification) restrict its substrate range relative to AKT1 (PMID:22044669, PMID:24769357). In insulin-responsive tissues, insulin selectively recruits AKT2 to the plasma membrane to drive GLUT4 trafficking, acting through direct phosphorylation of myosin 5a at Ser1650 and through the AS160 node, and is required for insulin-stimulated glucose uptake in muscle, fat, and heart (PMID:10523666, PMID:17515613, PMID:16950770, PMID:29170369). AKT2 directly phosphorylates additional substrates to control diverse outputs: ezrin at Thr567 to trigger NHE3 translocation, Pitx2 to destabilize Cyclin D1 mRNA and initiate myogenic differentiation, and the de novo pyrimidine-synthesis enzyme CAD at S1406/S1859 to potentiate nucleotide synthesis in liver cancer (PMID:15531580, PMID:20019746, PMID:36122209). AKT2 also governs cytoskeletal dynamics and migration—through isoform-specific interaction with PKCζ to drive LIMK/cofilin signaling and chemotaxis, and conversely by suppressing Rac/PAK1 signaling—and controls transcriptional programs by regulating FOXO1 occupancy at target promoters (MMP-9/TIMP-1, CLDN5, gluconeogenic genes) and by phosphorylating CREB to maintain basal hepatic gluconeogenic gene expression (PMID:17012749, PMID:18353613, PMID:23250987, PMID:30574832, PMID:32096546). In innate immunity, AKT2 directs neutrophil αMβ2 integrin translocation and macrophage M1/M2 polarization via a miR-155/C/EBPβ axis (PMID:24642468, PMID:22647600). Activating lesions—the E17K mutation and a recurrent BCAM-AKT2 fusion—drive constitutive membrane association and stimulus-independent kinase activity, causing severe hypoglycemia and oncogenic transformation respectively (PMID:21979934, PMID:25733895).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 High

    Established that AKT2 is the insulin-selective AKT isoform in adipocytes, answering whether the two AKT isoforms have distinct upstream regulation and tissue roles.

    Evidence Subcellular fractionation and isoform-specific phosphorylation assays with substrate antibody microinjection in 3T3-L1 adipocytes

    PMID:10523666

    Open questions at the time
    • Did not identify the direct AKT2 substrates mediating GLUT4 translocation
    • Did not resolve why insulin but not PDGF recruits AKT2
  2. 2000 High

    Showed AKT2 has an isoform-specific nuclear role in muscle differentiation, distinguishing it functionally from AKT1.

    Evidence Cell fractionation, isoform-specific antibody microinjection, and transactivation assays in myotubes

    PMID:11087731

    Open questions at the time
    • Did not identify nuclear AKT2 substrates
    • Mechanism of isoform-specific nuclear localization unknown
  3. 2002 High

    Defined a positive feedback loop in which MyoD transcriptionally drives Akt2 and Akt2 reinforces MyoD-MEF2 activity, linking AKT2 to a transcriptional differentiation circuit.

    Evidence Promoter cloning, EMSA, reporter assays, and anti-Akt2 antibody microinjection

    PMID:11948187

    Open questions at the time
    • Direct AKT2 substrate within the MyoD-MEF2 program not defined here
  4. 2004 High

    Identified ezrin Thr567 as a direct AKT2 substrate, providing the molecular link between AKT2 and NHE3 trafficking in epithelial transport.

    Evidence In vitro kinase assay with recombinant ezrin, siRNA, and NHE3 translocation readout

    PMID:15531580

    Open questions at the time
    • Did not address isoform selectivity of ezrin phosphorylation
  5. 2006 High

    Demonstrated AKT2-specific requirement for insulin-stimulated glucose metabolism and substrate phosphorylation (GSK-3α) in cardiac and skeletal muscle, with sensitization to ischemic apoptosis.

    Evidence Akt2-knockout mice with parallel Akt1 comparison, glucose uptake, contraction, and injury models

    PMID:16803855 PMID:16950770

    Open questions at the time
    • Did not reconcile redundancy versus specificity between AKT1 and AKT2 across all metabolic outputs
  6. 2007 High

    Identified myosin 5a Ser1650 as a direct AKT2 substrate, providing a molecular mechanism for anterograde GLUT4 vesicle delivery downstream of insulin.

    Evidence In vitro kinase assay, siRNA, dominant-negative Akt, and glucose transport assays

    PMID:17515613

    Open questions at the time
    • Relative contribution of myosin 5a versus AS160 to GLUT4 trafficking not quantified
  7. 2009 High

    Showed AKT2 both promotes and restrains migration depending on context—suppressing Rac/PAK1 while acting through PKCζ-LIMK/cofilin in other cell types—revealing context-dependent cytoskeletal control.

    Evidence In vitro kinase/Co-IP and Akt2-KO fibroblasts (PAK1); EGF-induced Co-IP and siRNA with chemotaxis readouts (PKCζ)

    PMID:17012749 PMID:18353613 PMID:19197940 PMID:19330838 PMID:20019746

    Open questions at the time
    • The basis for opposite migratory outcomes across cell types is unresolved
    • Several downstream phosphorylation events shown only by knockdown, not direct kinase assay
  8. 2011 High

    Established disease-relevant constitutive activation: the E17K mutation drives membrane-localized, insulin-independent AKT2 signaling causing hypoglycemia, and PHLPP1 was identified as the AKT2-selective inactivating phosphatase.

    Evidence Patient genetics with heterologous expression/localization assays (E17K); isoform-specific phosphatase gain/loss-of-function with xenografts (PHLPP1)

    PMID:21979934 PMID:22044669

    Open questions at the time
    • Structural basis of PHLPP1 isoform selectivity not defined
    • Range of physiological E17K signaling outputs not fully mapped
  9. 2012 High

    Placed AKT2 within immune and vascular transcriptional programs via miR-155/C/EBPβ macrophage polarization and FOXO1-dependent MMP-9/TIMP-1 regulation in vascular smooth muscle.

    Evidence Akt2-/- mice with reconstitution and miR-155 manipulation; Akt2-KO with FOXO1 ChIP and aortic injury model

    PMID:22647600 PMID:23250987

    Open questions at the time
    • Direct AKT2 substrate linking it to miR-155 not identified
    • FOXO1 phosphosite controlling promoter eviction not defined
  10. 2014 High

    Demonstrated isoform-specific AKT2 functions in innate immune adhesion and migration—neutrophil αMβ2 integrin translocation and dendritic cell Ca2+ signaling via ETS1/IP3R2.

    Evidence Akt isoform-KO mice with intravital imaging and AKT2 inhibitor (neutrophils); Akt2-/- DCs with electrophysiology and Ca2+ imaging

    PMID:16365168 PMID:24496246 PMID:24642468

    Open questions at the time
    • Direct AKT2 substrate controlling integrin translocation not identified
    • Whether ETS1/IP3R2 regulation is direct or indirect unresolved
  11. 2015 High

    Identified the recurrent BCAM-AKT2 fusion as a constitutively active, membrane-associated oncogenic kinase in ovarian cancer, generalizing AKT2 membrane-driven activation to cancer.

    Evidence RNA-seq of tumors, kinase activity assays, CRISPR-engineered fusion, and focus formation

    PMID:25733895

    Open questions at the time
    • Full oncogenic substrate repertoire of the fusion not defined
  12. 2019 High

    Defined Ser474 hydrophobic-motif phosphorylation as required for maximal AKT2 activity using a chemical-genetic strategy that isolates the phosphosite from mTORC2 perturbation.

    Evidence MK2206-resistant S474A Akt2 with substrate phosphorylation and GLUT4/glucose uptake readouts in adipocytes

    PMID:30833219 PMID:31548312

    Open questions at the time
    • Why S474A reduces but does not abolish substrate phosphorylation not mechanistically resolved
  13. 2022 High

    Connected AKT2 to nucleotide metabolism by showing β-catenin-driven AKT2 directly phosphorylates CAD at S1406/S1859 to fuel pyrimidine synthesis in liver cancer.

    Evidence Metabolomics, in vitro kinase assay, CAD phosphosite mutagenesis, and mouse liver cancer models

    PMID:36122209

    Open questions at the time
    • Whether CAD phosphorylation is AKT2-isoform-specific not addressed
  14. 2024 Medium

    Expanded the AKT2 interactome and autophagy/lysosomal axis by identifying SIRT5 as a binding partner and AKT2 control of PGC-1α/TFEB-dependent lysosomal function.

    Evidence Co-IP, AKT2 knock-in mice, and iPSC-derived RPE with TFEB localization and lysosomal assays

    PMID:39034314

    Open questions at the time
    • SIRT5 interaction shown by Co-IP without reciprocal/structural validation
    • Whether AKT2 phosphorylates SIRT5 or PGC-1α directly is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AKT2 achieves isoform-specific substrate selection and the structural determinants distinguishing it from AKT1 across its many context-dependent roles remain unresolved.
  • No structural model explaining isoform-specific partner/substrate selection
  • The signals routing AKT2 toward promigratory versus antimigratory programs are undefined
  • Many downstream effects are placed by knockdown rather than direct kinase assays

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0140110 transcription regulator activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
FKBP51ILKPAK1PHB2PHLPP1PRKCZSIRT1SIRT5

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PKBβ/AKT2 is preferentially expressed in adipocytes over PKBα, and insulin (but not PDGF) stimulates translocation of PKBβ to the plasma membrane and high-density microsome fractions, supporting a specific role for AKT2 in insulin-stimulated GLUT4 translocation. Subcellular fractionation, isoform-specific phosphorylation assays, microinjection of PKB substrate peptide/antibody in 3T3-L1 adipocytes Molecular and cellular biology High 10523666
2007 Myosin 5a is a direct substrate of AKT2; insulin stimulation leads to AKT2-mediated phosphorylation of myosin 5a at serine 1650, enhancing its interaction with the actin cytoskeleton and facilitating anterograde GLUT4 vesicle movement to the cell surface. In vitro kinase assay, siRNA knockdown of Akt2, dominant-negative Akt expression, co-immunoprecipitation, glucose transport assay Molecular and cellular biology High 17515613
2004 AKT2 phosphorylates ezrin at threonine 567 in vitro and in intact cells, and this phosphorylation is required for NHE3 translocation and activation following Na+-glucose cotransport initiation. In vitro kinase assay with purified Akt and recombinant ezrin, siRNA knockdown of Akt2, PI3K inhibition, pharmacological Akt inhibition, functional NHE3 translocation assay The Journal of biological chemistry High 15531580
2009 AKT2 interacts with and inhibits PAK1 kinase activity in vitro; Akt2-knockout mouse embryo fibroblasts show elevated Pak1 and Rac activities, enhanced dorsal ruffling, and faster migration through ECM, demonstrating that AKT2 suppresses Rac/Pak1 signaling and cell migration. Kinase assay (Pak1 inhibition by Akt2 in vitro), co-immunoprecipitation, Akt2 knockout mouse fibroblasts, domain-swap experiments, migration assays The Journal of biological chemistry High 17012749
2000 PKBβ/AKT2, but not PKBα/AKT1, localizes to the nucleus in differentiated myotubes and is specifically required for muscle-specific gene expression; microinjection of anti-PKBβ antibodies inhibits muscle differentiation whereas anti-PKBα antibodies do not. Cell fractionation, transactivation assay, microinjection of isoform-specific antibodies, immunofluorescence The Journal of biological chemistry High 11087731
2002 Akt2 is transcriptionally regulated by MyoD via E-box elements in the Akt2 promoter; in turn, Akt2 activates MyoD-MEF2 transcriptional activity and induces myogenin expression, establishing a positive feedback loop between Akt2 and MyoD-MEF2 during muscle differentiation. Akt2 promoter cloning, EMSA (MyoD binding to E-boxes), promoter activity assay, microinjection of anti-Akt2 antibody, Western blot The Journal of biological chemistry High 11948187
2008 AKT2 directly interacts with PKCζ (but not Akt1) upon EGF stimulation in breast cancer cells, and AKT2 acts upstream of PKCζ to regulate LIMK/cofilin phosphorylation, integrin β1 phosphorylation, actin polymerization, and chemotaxis. siRNA knockdown, co-immunoprecipitation (EGF-induced), SCID mouse metastasis model, Western blot for downstream phosphorylation Cellular signalling Medium 18353613
2009 AKT2 is required for macrophage chemotaxis: siRNA-mediated Akt2 depletion impairs CSF-1- and MCP-1-induced macrophage migration by reducing PKCζ and LIMK/cofilin phosphorylation, leading to defects in actin polymerization. siRNA knockdown, Western blot for downstream phosphorylation, chemotaxis assays European journal of immunology Medium 19197940
2009 AKT2 depletion in glioma cells impairs cofilin phosphorylation (actin polymerization), Girdin phosphorylation (actin cytoskeleton integrity), ACAP1 phosphorylation, integrin β1 phosphorylation, and reduces MMP-9 expression, collectively inhibiting cell migration and invasion. siRNA knockdown of Akt2, Western blot for phosphorylation events, in vitro and in vivo invasion assays International journal of cancer Medium 19330838
2011 The p.Glu17Lys (E17K) activating mutation in AKT2 causes constitutive recruitment of AKT2 to the plasma membrane and insulin-independent activation of downstream signaling, resulting in severe hypoglycemia in children. Genetic sequencing, heterologous cell expression of mutant AKT2, subcellular localization assay, downstream signaling assay Science High 21979934
2015 A recurrent BCAM-AKT2 chromosomal fusion in high-grade serous ovarian cancer produces a membrane-associated, constitutively phosphorylated and activated AKT2 fusion kinase that escapes normal regulation by external stimuli and drives oncogenic focus formation. RNA sequencing of patient tumors, fusion protein detection by Western blot, kinase activity assay, CRISPR/Cas9-generated fusion, focus formation assay PNAS High 25733895
2006 AKT2, but not AKT1, is required for insulin-stimulated glucose uptake and metabolism in cardiomyocytes; Akt2-knockout mice display normal cardiac growth but are sensitized to cardiomyocyte apoptosis after ischemic injury. Akt2 knockout mice, 2-[3H]deoxyglucose uptake assay, transverse aortic constriction, myocardial infarction model, apoptosis assay The Journal of biological chemistry High 16950770
2006 AKT2 is required for insulin-stimulated GSK-3α Ser21 phosphorylation during muscle contraction in tibialis anterior, but is not required for exercise-stimulated glucose uptake or glycogen synthesis in soleus, demonstrating isoform-specific regulation of GSK-3α. Akt2 knockout mice, in situ contraction, Western blot for Akt T308, GSK-3α Ser21, GSK-3β Ser9, glycogen synthase assays, glucose uptake assay American journal of physiology. Endocrinology and metabolism High 16803855
2009 Akt2 phosphorylates Pitx2, and this phosphorylation disrupts the Pitx2/HuR/Cyclin D1 mRNA-stabilizing complex, leading to Ccnd1 mRNA destabilization and the switch from myoblast proliferation to differentiation. In vitro kinase assay, ribonucleoprotein complex immunoprecipitation, mRNA half-life measurement, C2C12 differentiation assay Cell death and differentiation High 20019746
2008 Akt2, but not Akt1, binds Prohibitin2/REA (PHB2/REA) as shown by co-immunoprecipitation of endogenous proteins; Akt2-PHB2 interaction does not include Prohibitin1. Akt2 and PHB2 levels are inversely correlated, and Akt2 is required for myogenic differentiation and cell cycle exit in muscle cells. siRNA knockdown, co-immunoprecipitation of endogenous proteins, MyoD-induced fibroblast conversion assay, immunofluorescence Journal of cellular physiology Medium 17565718
2004 Akt2 and PI3K are present in lipid rafts of intestinal absorptive cells; Akt2 is active in the detergent-soluble (non-lipid raft) pool of ileal brush border membrane upon EGF stimulation, correlating with PI3K-dependent NHE3 trafficking. PTEN in lipid rafts suppresses Akt2 activity there. OptiPrep density gradient fractionation, immunocytochemistry, activity assays Gastroenterology Medium 14699494
2011 PHLPP1 selectively dephosphorylates Akt2 (while PHLPP2 selectively dephosphorylates Akt1) in pancreatic cancer cells; PHLPP1 overexpression inactivates Akt2 and promotes apoptosis, whereas PHLPP1 knockdown increases Akt2 phosphorylation. siRNA knockdown of PHLPPs, overexpression, Western blot for isoform-specific Akt phosphorylation, apoptosis assay, xenograft tumor model Gastroenterology High 22044669
2017 FKBP51 associates with AS160, a direct AKT2 substrate involved in glucose uptake; FKBP51 antagonism increases AS160 phosphorylation and GLUT4 membrane expression, enhancing glucose uptake in skeletal myotubes, placing FKBP51 as a negative regulator of AKT2-AS160 signaling. Co-immunoprecipitation (FKBP51-AS160), FKBP51 knockout mice, pharmacological FKBP51 antagonist (SAFit2), glucose uptake assay, GLUT4 membrane fractionation Nature communications Medium 29170369
2009 In endothelial cells, thymosin-β4 binds integrin-linked kinase (ILK) in lamellipodia upon profilin-dependent G-actin dissociation, and Tbeta4-ILK complexes recruit and activate AKT2, resulting in MMP-2 production and cell motility. FRET analysis, co-immunoprecipitation, dominant-negative constructs, MMP-2 assay, migration assay Developmental cell Medium 19460343
2014 Neutrophil AKT2 is specifically required for membrane translocation of αMβ2 integrin, β2-talin1 interaction, and intracellular Ca2+ mobilization during neutrophil-platelet interactions and neutrophil adhesion on activated endothelium. Intravital microscopy, bone marrow chimeras, Akt isoform KO mice, AKT2-specific inhibitor, flow cytometry, Ca2+ imaging The Journal of clinical investigation High 24642468
2014 AKT2 silencing in PTEN-deficient prostate cancer cells upregulates p21 and BAX and downregulates IGF-1R, promoting tumor regression; p21 is identified as a functional effector of AKT2 in mediating prostate tumor maintenance. shRNA silencing of AKT2 vs AKT1, xenograft tumor model, Western blot for p21/BAX/IGF-1R, rescue experiments Cancer discovery Medium 24838891
2012 AKT2 ablation in macrophages results in an M2 (alternatively activated) phenotype; miR-155 expression is repressed in Akt2-/- macrophages leading to upregulation of C/EBPβ (an M2 marker regulating Arg1), defining a miR-155/C/EBPβ axis downstream of AKT2 in macrophage polarization. Akt2-/- mice, gene silencing, miR-155 overexpression/silencing, DSS-colitis and LPS-shock models, cell depletion/reconstitution experiments PNAS High 22647600
2005 AKT2 down-regulation suppresses the EMT-like morphological conversion induced by AKT1 loss in IGF-IR-overexpressing breast epithelial cells and inhibits EGF-stimulated cell migration, demonstrating that AKT2 promotes EMT and migration downstream of growth factor receptors. Isoform-specific siRNA knockdown, IGF-IR overexpression, cell migration assay, morphological/EMT marker analysis, ERK activation assay The Journal of cell biology High 16365168
2012 AKT2 in vascular smooth muscle cells prevents binding of transcription factor FOXO1 to the MMP-9 and TIMP-1 promoters, thereby inhibiting MMP-9 expression and stimulating TIMP-1 expression to protect the aortic wall. Akt2 knockout mice, angiotensin II infusion model, ChIP assay (FOXO1 binding to promoters), Western blot, cultured human aortic VSMCs with AKT2 inhibition Circulation research Medium 23250987
2014 Protein kinase CK2 does not phosphorylate Akt2 at Ser131 (the homolog of Akt1 Ser129) in vivo despite Akt2 being a CK2 substrate in vitro; lack of Ser131 phosphorylation contributes to Akt2's low efficiency in targeting the Akt1-specific substrate palladin. In vitro CK2 kinase assay with recombinant Akt2, in vivo phosphorylation analysis in multiple cell lines, palladin substrate assay Biochimica et biophysica acta Medium 24769357
2019 Ser474 phosphorylation of AKT2 is required for maximal AKT2 kinase activity in adipocytes; S474A mutation reduces phosphorylation of four bona fide substrates (TSC2, PRAS40, FOXO1/3a, AS160) by ~50% and attenuates mTORC1 activation, FOXO nuclear exclusion, GLUT4 translocation, and glucose uptake. Chemical genetics approach (S474A + W80A MK2206-resistant Akt2), insulin-stimulated phosphorylation assays, FOXO nuclear exclusion assay, GLUT4 translocation assay, glucose uptake assay in 3T3-L1 adipocytes The Journal of biological chemistry High 31548312
2017 AKT2 deficiency in macrophages decreases IL-13 and TGF-β1 production via attenuated phosphorylation of FoxO3a; siRNA knockdown of FoxO3a increases IL-13 expression, placing AKT2-FoxO3a signaling upstream of IL-13 in macrophage-driven pulmonary fibrosis. Akt2-/- mice, bleomycin model, adoptive macrophage transfer, IL-33 stimulation, siRNA knockdown of FoxO3a, phosphorylation analysis, lung section analysis from IPF patients Journal of immunology Medium 28455433
2017 SIRT1 interacts with AKT2 (co-immunoprecipitation), and this interaction is enhanced by resveratrol; Sirt1 suppresses AKT2 phosphorylation and reduces raptor levels to inactivate mTORC1, attenuating adipose inflammation via the mTOR/S6K1 pathway. Co-immunoprecipitation of Sirt1-Akt2, high-fat diet mouse model, resveratrol/nicotinamide treatment, Western blot for mTOR/S6K1 signaling Journal of lipid research Medium 27317762
2022 Oncogenic β-catenin transcriptionally upregulates AKT2, which then phosphorylates the de novo pyrimidine synthesis enzyme CAD at S1406 and S1859 to potentiate nucleotide synthesis and support liver cancer cell proliferation. Untargeted metabolomics, AKT2 knockdown/overexpression, in vitro kinase assay (AKT2 phosphorylation of CAD), mouse liver cancer models, site-directed mutagenesis of CAD phosphosites PNAS High 36122209
2010 Akt2 regulates palladin expression by maintaining protein stability and upregulating transcription; Akt2 (but not Akt1) enhances palladin levels, further distinguishing isoform-specific roles in cytoskeletal regulation. Akt isoform-specific siRNA/overexpression, Western blot for palladin protein, transcriptional reporter assay, protein stability assay FEBS letters Medium 21050850
2017 Akt2 inhibition in glioma cells blocks cofilin, Girdin, ACAP1, and integrin β1 phosphorylation, and reduces MMP-9 expression, impairing cytoskeleton formation, adhesion, and invasion; Akt2 knockdown also reduced in vivo tumor invasion. siRNA knockdown of Akt2, Western blot for phosphorylation, Transwell invasion assay, in vivo glioma invasion model International journal of cancer Medium 19330838
2014 Akt2 deficiency in dendritic cells reduces ETS1-dependent IP3 receptor 2 (IP3R2) transcription, impairing Ca2+ release from intracellular stores, SOCE, CRAC channel activity, and CCL21-induced migration. Akt2-/- bone marrow-derived DCs, Fura-2 Ca2+ imaging, whole-cell patch clamp, RT-PCR for IP3R2 and ETS1, siRNA knockdown of ETS1, IP3R inhibitor Cellular physiology and biochemistry Medium 24496246
2018 AKT2 maintains claudin-5 (CLDN5)-dependent BBB integrity in brain microvascular endothelial cells via the IR/AKT2/FOXO1 signaling axis; IL-1β inactivates AKT2, leading to FOXO1 nuclear accumulation and loss of CLDN5 expression. AKT2-specific inhibition/knockdown, FOXO1 nuclear localization assay, CLDN5 expression assay, barrier permeability assay, EAE mouse model Journal of cerebral blood flow and metabolism Medium 30574832
2017 Diabetes-induced TRB3 upregulation inhibits AKT2 (but not AKT1) phosphorylation in hearts; metallothionein prevents TRB3 expression and preserves AKT2-mediated glucose metabolic signaling, and TRB3 overexpression abolishes this cardiac protection. Akt2-specific silencing in cardiomyocytes, TRB3 siRNA/overexpression, MT transgenic and KO mice, Western blot for isoform-specific Akt phosphorylation, streptozotocin diabetes model Diabetes Medium 29079702
2019 AKT2 is required for adipocyte lipid filling and efficient downstream AKT substrate phosphorylation in brown adipose tissue; combined deletion of Akt1 and Akt2 (but not either alone) ablates BAT, and AKT signaling promotes adipogenesis partly by stimulating ChREBP activity. Conditional Akt1/Akt2 deletion (Myf5-Cre, Ucp1-Cre, Ucp1-CreER), Western blot for substrate phosphorylation, ChREBP activity assay, histological analysis Molecular metabolism Medium 30833219
2017 Akt2 loss-of-function in CRC cells upregulates metastasis suppressor MTSS1 at mRNA and protein level; MTSS1 activates the MTSS1-Src-cortactin inhibitory axis, reducing functional cortactin (pY421) and inhibiting migration and actin polymerization. Inducible shRNA knockdown of Akt2, gene array analysis, Western blot for MTSS1/cortactin, actin polymerization assay, orthotopic implantation mouse model Oncogene Medium 28068324
2024 AKT2 inhibits PGC-1α to downregulate SIRT5, which is identified as an AKT2 binding partner; the AKT2/SIRT5 crosstalk facilitates TFEB-dependent lysosomal function in RPE cells, and AKT2 overexpression disrupts lysosomal/autophagy signaling causing a dry AMD-like phenotype. Co-IP (AKT2-SIRT5 interaction), AKT2 KI mice, iPSC-derived RPE with AMD risk variant, TFEB/TFE3 localization assay, lysosomal function assays, Western blot Nature communications Medium 39034314
2020 Hepatic AKT2 is required for basal PEPCK and G6Pase expression by phosphorylating CREB; AKT2 also maintains FOXO1 in a transcriptionally inactive state at the PEPCK promoter in the absence of insulin, acting as a priming mechanism for gluconeogenic gene regulation. Akt2-/- hepatocytes, promoter analysis, CREB phosphorylation assay, FOXO1 ChIP, pyruvate tolerance test The Biochemical journal Medium 32096546
2019 Amlodipine activates Akt2 (but not Akt1) in VSMCs, which activates transcription factor Sp1 to bind the miR-21 promoter at the -2034/-2027 site, inducing miR-21 expression and smooth muscle cell differentiation; Akt2 or Sp1 knockdown abolishes this effect. Western blot (Akt2/Akt1 specificity), immunofluorescence for Sp1 nuclear translocation, ChIP-qPCR and EMSA for Sp1-miR-21 promoter binding, siRNA knockdown of Akt2 and Sp1, luciferase reporter assay British journal of pharmacology Medium 30927374
2022 Increased joint loading activates the RANTES-CCR-AKT2 axis; RANTES binds CCRs and activates AKT2 to regulate osteoclast formation and subchondral bone loss in temporomandibular joint osteoarthritis. Rat TMJOA model with in vivo force sensing, Akt2 inhibition, Western blot, immunofluorescence/IHC, RAW264.7 cell studies with RANTES stimulation JCI insight Medium 36173680
2024 Phosphorylated AKT2 activates PDK1, which promotes glycolysis and lactate accumulation; AKT2 and PDK1 inhibitors suppress the fibrotic process in bleomycin-induced pulmonary fibrosis, placing AKT2 upstream of PDK1-driven glycolysis in fibrogenesis. Bleomycin mouse model, Akt2 and PDK1 inhibitors, Western blot for pAkt2 and PDK1, TGF-β1 stimulation, glycolysis/lactate assays FASEB journal Medium 38226859
2010 Akt2 regulates Glut1 expression at the transcript level; akt2 morphant zebrafish embryos exhibit decreased glut1 mRNA, impaired glucose uptake, increased neuronal apoptosis (rescued by Bad knockdown or Glut1 overexpression), demonstrating that Akt2 modulates glucose availability to control apoptosis. Zebrafish akt2 morpholino knockdown, glut1 morpholino knockdown, bad morpholino rescue, glut1 mRNA overexpression rescue, quantitative RT-PCR, glucose uptake assay, apoptosis assay The Journal of biological chemistry Medium 20356836

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. International journal of cancer 722 7657393
2012 Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proceedings of the National Academy of Sciences of the United States of America 496 22647600
2005 Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. The Journal of cell biology 492 16365168
1999 A role for protein kinase Bbeta/Akt2 in insulin-stimulated GLUT4 translocation in adipocytes. Molecular and cellular biology 277 10523666
2010 AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species. Blood 231 20354168
2000 The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Molecular and cellular biology 213 10594016
2006 Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer biology & therapy 153 16721043
2006 Akt2 regulates cardiac metabolism and cardiomyocyte survival. The Journal of biological chemistry 137 16950770
2011 An activating mutation of AKT2 and human hypoglycemia. Science (New York, N.Y.) 131 21979934
2010 MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2. Molecular cancer 127 20409325
2006 Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. The Journal of biological chemistry 126 17012749
2008 Regulation of cancer cell survival, migration, and invasion by Twist: AKT2 comes to interplay. Cancer research 111 18281467
2007 Akt1 and Akt2 are required for alphabeta thymocyte survival and differentiation. Proceedings of the National Academy of Sciences of the United States of America 111 17609365
2009 Akt2 and Akt3 play a pivotal role in malignant gliomas. Neuro-oncology 100 20167810
2000 Protein kinase B beta/Akt2 plays a specific role in muscle differentiation. The Journal of biological chemistry 99 11087731
2007 Myosin 5a is an insulin-stimulated Akt2 (protein kinase Bbeta) substrate modulating GLUT4 vesicle translocation. Molecular and cellular biology 98 17515613
2017 Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function. Nature communications 97 29170369
2012 AKT2 confers protection against aortic aneurysms and dissections. Circulation research 86 23250987
2014 Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology 85 25416384
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
2014 PTEN-deficient tumors depend on AKT2 for maintenance and survival. Cancer discovery 82 24838891
2011 The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation. Gastroenterology 80 22044669
2004 Akt2 phosphorylates ezrin to trigger NHE3 translocation and activation. The Journal of biological chemistry 79 15531580
2009 Akt1 and Akt2 promote peripheral B-cell maturation and survival. Blood 78 20042722
1995 Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene 78 7566964
2009 Reduction of Akt2 inhibits migration and invasion of glioma cells. International journal of cancer 75 19330838
2017 AKT2 Regulates Pulmonary Inflammation and Fibrosis via Modulating Macrophage Activation. Journal of immunology (Baltimore, Md. : 1950) 74 28455433
2011 Akt1 and Akt2: differentiating the aktion. Histology and histopathology 72 21432781
2011 Roles of AKT1 and AKT2 in non-small cell lung cancer cell survival, growth, and migration. Cancer science 68 21722267
2021 LncRNA HOTTIP inhibits cell pyroptosis by targeting miR-148a-3p/AKT2 axis in ovarian cancer. Cell biology international 66 33710684
2016 Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells. International journal of oncology 65 27878243
2004 Akt2, phosphatidylinositol 3-kinase, and PTEN are in lipid rafts of intestinal cells: role in absorption and differentiation. Gastroenterology 64 14699494
2014 Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice. Journal of lipid research 60 25240046
2009 Spatial coordination of actin polymerization and ILK-Akt2 activity during endothelial cell migration. Developmental cell 57 19460343
2020 Akt2 Affects Periodontal Inflammation via Altering the M1/M2 Ratio. Journal of dental research 56 32228353
2014 Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation. The Journal of clinical investigation 56 24642468
2009 Distinct actions of Akt1 and Akt2 in skeletal muscle differentiation. Journal of cellular physiology 55 19142853
2019 Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease. Cells 53 31671832
2020 The Role of Akt2 in the Protective Effect of Fenofibrate against Diabetic Nephropathy. International journal of biological sciences 52 32025205
2018 RNA-binding protein LIN28B inhibits apoptosis through regulation of the AKT2/FOXO3A/BIM axis in ovarian cancer cells. Signal transduction and targeted therapy 52 30174831
2021 Ablation of Akt2 and AMPKα2 rescues high fat diet-induced obesity and hepatic steatosis through Parkin-mediated mitophagy. Acta pharmaceutica Sinica. B 51 34900533
2018 AKT2 contributes to increase ovarian cancer cell migration and invasion through the AKT2-PKM2-STAT3/NF-κB axis. Cellular signalling 50 29374601
2012 Differential function of Akt1 and Akt2 in human adipocytes. Molecular and cellular endocrinology 49 22480544
2006 Role of Akt2 in contraction-stimulated cell signaling and glucose uptake in skeletal muscle. American journal of physiology. Endocrinology and metabolism 49 16803855
2002 Positive feedback regulation between Akt2 and MyoD during muscle differentiation. Cloning of Akt2 promoter. The Journal of biological chemistry 49 11948187
2018 Double knockout of Akt2 and AMPK predisposes cardiac aging without affecting lifespan: Role of autophagy and mitophagy. Biochimica et biophysica acta. Molecular basis of disease 48 31109453
2012 Decreased spermatogenesis, fertility, and altered Slc2A expression in Akt1-/- and Akt2-/- testes and sperm. Reproductive sciences (Thousand Oaks, Calif.) 46 22228739
2009 Akt2 is required for macrophage chemotaxis. European journal of immunology 45 19197940
2022 Increased joint loading induces subchondral bone loss of the temporomandibular joint via the RANTES-CCRs-Akt2 axis. JCI insight 43 36173680
2018 Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction. Naunyn-Schmiedeberg's archives of pharmacology 43 30460386
2015 Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma. Proceedings of the National Academy of Sciences of the United States of America 43 25733895
1998 Induction of Akt-2 correlates with differentiation in Sol8 muscle cells. Biochemical and biophysical research communications 43 9790996
2017 AKT2 suppresses pro-survival autophagy triggered by DNA double-strand breaks in colorectal cancer cells. Cell death & disease 42 28837154
2009 Overexpression and activation of Akt2 protein in oral squamous cell carcinoma. Oral oncology 42 19628421
2013 Distinct and specific roles of AKT1 and AKT2 in androgen-sensitive and androgen-independent prostate cancer cells. Cellular signalling 41 23567263
2020 AKT2 drives cancer progression and is negatively modulated by miR-124 in human lung adenocarcinoma. Respiratory research 40 32873299
2016 Sirt1 decreased adipose inflammation by interacting with Akt2 and inhibiting mTOR/S6K1 pathway in mice. Journal of lipid research 39 27317762
2010 AKT2 expression is associated with glioma malignant progression and required for cell survival and invasion. Oncology reports 39 20514445
2019 Brown fat organogenesis and maintenance requires AKT1 and AKT2. Molecular metabolism 38 30833219
2017 Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis. Oncogene 38 28068324
2016 Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis. Oncotarget 38 27175587
2020 Regulation of basal expression of hepatic PEPCK and G6Pase by AKT2. The Biochemical journal 37 32096546
2019 Serine 474 phosphorylation is essential for maximal Akt2 kinase activity in adipocytes. The Journal of biological chemistry 37 31548312
2008 Reduction of Akt2 expression inhibits chemotaxis signal transduction in human breast cancer cells. Cellular signalling 37 18353613
2008 Akt2 is implicated in skeletal muscle differentiation and specifically binds Prohibitin2/REA. Journal of cellular physiology 36 17565718
2004 Antisense and dominant-negative AKT2 cDNA inhibits glioma cell invasion. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 36 15557754
2022 Oncogenic β-catenin stimulation of AKT2-CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer. Proceedings of the National Academy of Sciences of the United States of America 35 36122209
2013 Sirt1 inhibits akt2-mediated porcine adipogenesis potentially by direct protein-protein interaction. PloS one 35 23951196
2010 Akt2 regulates expression of the actin-bundling protein palladin. FEBS letters 35 21050850
2009 Akt2-mediated phosphorylation of Pitx2 controls Ccnd1 mRNA decay during muscle cell differentiation. Cell death and differentiation 35 20019746
2013 Akt2 regulates metastatic potential in neuroblastoma. PloS one 34 23468863
2020 ROR2 suppresses metastasis of prostate cancer via regulation of miR-199a-5p-PIAS3-AKT2 signaling axis. Cell death & disease 33 32415173
2017 Metallothionein Preserves Akt2 Activity and Cardiac Function via Inhibiting TRB3 in Diabetic Hearts. Diabetes 33 29079702
2016 Polymorphisms in the AKT1 and AKT2 genes and oesophageal squamous cell carcinoma risk in an Eastern Chinese population. Journal of cellular and molecular medicine 33 26828791
2018 PHLPP1 mediates melanoma metastasis suppression through repressing AKT2 activation. Oncogene 32 29391600
2015 Implications of Akt2/Twist crosstalk on breast cancer metastatic outcome. Drug discovery today 32 26136161
2014 Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 25392271
2013 Activating AKT2 mutation: hypoinsulinemic hypoketotic hypoglycemia. The Journal of clinical endocrinology and metabolism 32 24285683
2014 Differential phosphorylation of Akt1 and Akt2 by protein kinase CK2 may account for isoform specific functions. Biochimica et biophysica acta 31 24769357
2018 AKT2 maintains brain endothelial claudin-5 expression and selective activation of IR/AKT2/FOXO1-signaling reverses barrier dysfunction. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 30 30574832
2017 Expression of AKT1 along with AKT2 in granulosa-lutein cells of hyperandrogenic PCOS patients. Archives of gynecology and obstetrics 29 28271235
2019 Depletion of Akt1 and Akt2 Impairs the Repair of Radiation-Induced DNA Double Strand Breaks via Homologous Recombination. International journal of molecular sciences 27 31847370
2017 Triangle of AKT2, miRNA, and Tumorigenesis in Different Cancers. Applied biochemistry and biotechnology 26 29199386
2016 Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways. Oncotarget 26 26918455
2010 Akt2 deficiency promotes cardiac induction of Rab4a and myocardial β-adrenergic hypersensitivity. Journal of molecular and cellular cardiology 26 20728450
2024 The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD. Nature communications 24 39034314
2020 Cell-Autonomous versus Systemic Akt Isoform Deletions Uncovered New Roles for Akt1 and Akt2 in Breast Cancer. Molecular cell 24 32931746
2017 Prohibitin-2 negatively regulates AKT2 expression to promote prostate cancer cell migration. International journal of molecular medicine 24 29207197
2010 Akt2 modulates glucose availability and downstream apoptotic pathways during development. The Journal of biological chemistry 24 20356836
2024 Lactate accumulation induced by Akt2-PDK1 signaling promotes pulmonary fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 38226859
2023 PM2.5 induces cardiac malformations via PI3K/akt2/mTORC1 signaling pathway in zebrafish larvae. Environmental pollution (Barking, Essex : 1987) 23 36804889
2017 Zebrafish akt2 is essential for survival, growth, bone development, and glucose homeostasis. Mechanisms of development 23 28132765
2014 AKT1 and AKT2 induce distinct phosphorylation patterns in HL-1 cardiac myocytes. Journal of proteome research 23 25162660
2020 PKBβ/AKT2 deficiency impacts brain mTOR signaling, prefrontal cortical physiology, hippocampal plasticity and select murine behaviors. Molecular psychiatry 22 33328589
2019 Amlodipine induces vasodilation via Akt2/Sp1-activated miR-21 in smooth muscle cells. British journal of pharmacology 22 30927374
2014 Akt2- and ETS1-dependent IP3 receptor 2 expression in dendritic cell migration. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 22 24496246
2014 Zinc rescue of Akt2 gene deletion-linked murine cardiac dysfunction and pathological changes is metallothionein-dependent. Journal of molecular and cellular cardiology 22 24819347
2018 AKT2 is the predominant AKT isoform expressed in human skeletal muscle. Physiological reports 21 29595878
2018 Mitochondrial Dysfunctions Regulated Radioresistance through Mitochondria-to-Nucleus Retrograde Signaling Pathway of NF-κB/PI3K/AKT2/mTOR. Radiation research 21 29863983
2018 Clusterin enhances AKT2-mediated motility of normal and cancer prostate cells through a PTEN and PHLPP1 circuit. Journal of cellular physiology 21 30565691

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