{"gene":"AKT2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1999,"finding":"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.","method":"Subcellular fractionation, isoform-specific phosphorylation assays, microinjection of PKB substrate peptide/antibody in 3T3-L1 adipocytes","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, antibody microinjection, isoform-specific phosphorylation assays), functional readout of GLUT4 translocation","pmids":["10523666"],"is_preprint":false},{"year":2007,"finding":"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.","method":"In vitro kinase assay, siRNA knockdown of Akt2, dominant-negative Akt expression, co-immunoprecipitation, glucose transport assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation demonstrated, multiple orthogonal functional assays (siRNA, DN-Akt, transport assays), specific phosphosite identified","pmids":["17515613"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro kinase assay with purified Akt and recombinant ezrin, siRNA knockdown of Akt2, PI3K inhibition, pharmacological Akt inhibition, functional NHE3 translocation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro phosphorylation of defined substrate at specific residue, confirmed in intact cells by siRNA knockdown with functional readout","pmids":["15531580"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Kinase assay (Pak1 inhibition by Akt2 in vitro), co-immunoprecipitation, Akt2 knockout mouse fibroblasts, domain-swap experiments, migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay demonstrating Akt2-specific Pak1 inhibition, reciprocal Co-IP, KO cells with defined phenotype, domain-swap epistasis","pmids":["17012749"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Cell fractionation, transactivation assay, microinjection of isoform-specific antibodies, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, functional microinjection, transactivation assay), isoform-specific localization with functional consequence","pmids":["11087731"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Akt2 promoter cloning, EMSA (MyoD binding to E-boxes), promoter activity assay, microinjection of anti-Akt2 antibody, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter cloning with EMSA, functional reporter assays, antibody microinjection, multiple orthogonal methods in one study","pmids":["11948187"],"is_preprint":false},{"year":2008,"finding":"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.","method":"siRNA knockdown, co-immunoprecipitation (EGF-induced), SCID mouse metastasis model, Western blot for downstream phosphorylation","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP demonstrating isoform-specific interaction, siRNA knockdown with pathway readouts, single lab","pmids":["18353613"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA knockdown, Western blot for downstream phosphorylation, chemotaxis assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA knockdown with defined signaling readouts, consistent pathway placement, single lab","pmids":["19197940"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA knockdown of Akt2, Western blot for phosphorylation events, in vitro and in vivo invasion assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA with multiple downstream readouts showing pathway placement, single lab","pmids":["19330838"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Genetic sequencing, heterologous cell expression of mutant AKT2, subcellular localization assay, downstream signaling assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional characterization of constitutively active mutant with defined mechanism (membrane recruitment), validated in human patients and heterologous cells","pmids":["21979934"],"is_preprint":false},{"year":2015,"finding":"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.","method":"RNA sequencing of patient tumors, fusion protein detection by Western blot, kinase activity assay, CRISPR/Cas9-generated fusion, focus formation assay","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct biochemical demonstration of constitutive kinase activation, validated in patient tumors and in engineered cell lines, multiple orthogonal methods","pmids":["25733895"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Akt2 knockout mice, 2-[3H]deoxyglucose uptake assay, transverse aortic constriction, myocardial infarction model, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific metabolic and functional readouts, isoform specificity demonstrated by parallel Akt1 KO comparison","pmids":["16950770"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Akt2 knockout mice, in situ contraction, Western blot for Akt T308, GSK-3α Ser21, GSK-3β Ser9, glycogen synthase assays, glucose uptake assay","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific biochemical readouts, parallel isoform comparison, multiple substrates examined","pmids":["16803855"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro kinase assay, ribonucleoprotein complex immunoprecipitation, mRNA half-life measurement, C2C12 differentiation assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation of Pitx2 by Akt2, mechanistic dissection of mRNA stability complex with functional differentiation readout","pmids":["20019746"],"is_preprint":false},{"year":2008,"finding":"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.","method":"siRNA knockdown, co-immunoprecipitation of endogenous proteins, MyoD-induced fibroblast conversion assay, immunofluorescence","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of endogenous proteins showing isoform-specific interaction, siRNA with functional differentiation readout, single lab","pmids":["17565718"],"is_preprint":false},{"year":2004,"finding":"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.","method":"OptiPrep density gradient fractionation, immunocytochemistry, activity assays","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — membrane fractionation with biochemical activity readouts, mechanistic correlation with PTEN localization, single lab","pmids":["14699494"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA knockdown of PHLPPs, overexpression, Western blot for isoform-specific Akt phosphorylation, apoptosis assay, xenograft tumor model","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific phosphatase-substrate relationship demonstrated with both gain- and loss-of-function, in vitro and in vivo validation","pmids":["22044669"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation (FKBP51-AS160), FKBP51 knockout mice, pharmacological FKBP51 antagonist (SAFit2), glucose uptake assay, GLUT4 membrane fractionation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying novel complex, genetic and pharmacological intervention with functional readout, single lab","pmids":["29170369"],"is_preprint":false},{"year":2009,"finding":"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.","method":"FRET analysis, co-immunoprecipitation, dominant-negative constructs, MMP-2 assay, migration assay","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET and Co-IP demonstrating complex formation, functional readout of MMP-2 and migration, single lab","pmids":["19460343"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Intravital microscopy, bone marrow chimeras, Akt isoform KO mice, AKT2-specific inhibitor, flow cytometry, Ca2+ imaging","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with pharmacological inhibition and intravital imaging, multiple orthogonal functional readouts, isoform specificity established","pmids":["24642468"],"is_preprint":false},{"year":2014,"finding":"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.","method":"shRNA silencing of AKT2 vs AKT1, xenograft tumor model, Western blot for p21/BAX/IGF-1R, rescue experiments","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific KD with in vivo xenograft validation and pathway effector identification, single lab","pmids":["24838891"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Akt2-/- mice, gene silencing, miR-155 overexpression/silencing, DSS-colitis and LPS-shock models, cell depletion/reconstitution experiments","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with in vivo reconstitution experiments, gene silencing with pathway readouts, mechanistic link to miR-155/C/EBPβ established by overexpression/silencing","pmids":["22647600"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Isoform-specific siRNA knockdown, IGF-IR overexpression, cell migration assay, morphological/EMT marker analysis, ERK activation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — isoform-specific siRNA with multiple functional readouts and cross-regulation epistasis established, single lab with multiple orthogonal assays","pmids":["16365168"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Akt2 knockout mice, angiotensin II infusion model, ChIP assay (FOXO1 binding to promoters), Western blot, cultured human aortic VSMCs with AKT2 inhibition","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating FOXO1 promoter binding regulated by AKT2, in vivo KO model with functional aortic phenotype, single lab","pmids":["23250987"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro CK2 kinase assay with recombinant Akt2, in vivo phosphorylation analysis in multiple cell lines, palladin substrate assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with substrate specificity analysis, in vivo validation across multiple cell lines, mechanistically links linker phosphorylation to substrate specificity","pmids":["24769357"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — chemical genetics approach directly testing phosphosite without perturbing mTORC2, multiple orthogonal substrate and functional readouts in same study","pmids":["31548312"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Akt2-/- mice, bleomycin model, adoptive macrophage transfer, IL-33 stimulation, siRNA knockdown of FoxO3a, phosphorylation analysis, lung section analysis from IPF patients","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with adoptive transfer rescue, siRNA epistasis defining AKT2-FoxO3a-IL-13 axis, single lab","pmids":["28455433"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation of Sirt1-Akt2, high-fat diet mouse model, resveratrol/nicotinamide treatment, Western blot for mTOR/S6K1 signaling","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP demonstrating interaction, pharmacological and in vivo validation, single lab","pmids":["27317762"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Untargeted metabolomics, AKT2 knockdown/overexpression, in vitro kinase assay (AKT2 phosphorylation of CAD), mouse liver cancer models, site-directed mutagenesis of CAD phosphosites","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct phosphorylation of CAD by AKT2 demonstrated at specific residues, functional metabolomics validation, multiple model systems","pmids":["36122209"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Akt isoform-specific siRNA/overexpression, Western blot for palladin protein, transcriptional reporter assay, protein stability assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — isoform-specific regulation demonstrated at both transcript and protein stability levels, but limited mechanistic depth, single lab","pmids":["21050850"],"is_preprint":false},{"year":2017,"finding":"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.","method":"siRNA knockdown of Akt2, Western blot for phosphorylation, Transwell invasion assay, in vivo glioma invasion model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA with multiple downstream phosphorylation and functional readouts, in vivo validation, single lab","pmids":["19330838"],"is_preprint":false},{"year":2014,"finding":"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.","method":"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","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, Ca2+ imaging, RT-PCR, siRNA), genetic KO with pharmacological validation, single lab","pmids":["24496246"],"is_preprint":false},{"year":2018,"finding":"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.","method":"AKT2-specific inhibition/knockdown, FOXO1 nuclear localization assay, CLDN5 expression assay, barrier permeability assay, EAE mouse model","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic pathway placed (AKT2→FOXO1→CLDN5) with functional barrier readout, in vivo and in vitro evidence, single lab","pmids":["30574832"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Akt2-specific silencing in cardiomyocytes, TRB3 siRNA/overexpression, MT transgenic and KO mice, Western blot for isoform-specific Akt phosphorylation, streptozotocin diabetes model","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific phosphorylation readout, TRB3-AKT2 axis validated by gain/loss of function in vitro and in vivo, single lab","pmids":["29079702"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Conditional Akt1/Akt2 deletion (Myf5-Cre, Ucp1-Cre, Ucp1-CreER), Western blot for substrate phosphorylation, ChREBP activity assay, histological analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO models in multiple lineages, biochemical readouts of substrate phosphorylation and ChREBP activity, single lab","pmids":["30833219"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Inducible shRNA knockdown of Akt2, gene array analysis, Western blot for MTSS1/cortactin, actin polymerization assay, orthotopic implantation mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible isoform-specific KD with in vivo validation, defined signaling axis (Akt2→MTSS1→Src-cortactin), single lab","pmids":["28068324"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-IP (AKT2-SIRT5 interaction), AKT2 KI mice, iPSC-derived RPE with AMD risk variant, TFEB/TFE3 localization assay, lysosomal function assays, Western blot","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying novel binding partner, genetic mouse model and iPSC validation, multiple functional readouts, single lab","pmids":["39034314"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Akt2-/- hepatocytes, promoter analysis, CREB phosphorylation assay, FOXO1 ChIP, pyruvate tolerance test","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO hepatocytes with promoter/ChIP analysis identifying specific substrates and transcriptional mechanism, single lab","pmids":["32096546"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, luciferase, siRNA), isoform-specific Akt2 role established, single lab","pmids":["30927374"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Rat TMJOA model with in vivo force sensing, Akt2 inhibition, Western blot, immunofluorescence/IHC, RAW264.7 cell studies with RANTES stimulation","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo and in vitro evidence placing AKT2 downstream of RANTES-CCR signaling with osteoclast functional readout, single lab","pmids":["36173680"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Bleomycin mouse model, Akt2 and PDK1 inhibitors, Western blot for pAkt2 and PDK1, TGF-β1 stimulation, glycolysis/lactate assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pharmacological epistasis placing AKT2-PDK1, functional metabolic readout, single lab","pmids":["38226859"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Zebrafish akt2 morpholino knockdown, glut1 morpholino knockdown, bad morpholino rescue, glut1 mRNA overexpression rescue, quantitative RT-PCR, glucose uptake assay, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino epistasis in zebrafish with rescue experiments, mechanistic link from Akt2 to Glut1 expression established, single lab","pmids":["20356836"],"is_preprint":false}],"current_model":"AKT2 (PKBβ) is a plasma membrane-recruited serine/threonine kinase activated downstream of PI3K whose Ser474 hydrophobic-motif phosphorylation is required for maximal catalytic activity; it phosphorylates isoform-specific substrates including myosin 5a (Ser1650, mediating GLUT4 vesicle trafficking), ezrin (Thr567, triggering NHE3 translocation), Pitx2 (destabilizing Cyclin D1 mRNA to initiate muscle differentiation), CAD (S1406/S1859, driving pyrimidine synthesis), and CREB (maintaining basal gluconeogenic gene expression); it is selectively dephosphorylated by PHLPP1 and interacts with binding partners including SIRT5, PKCζ, Prohibitin2/REA, thymosin-β4/ILK, and FKBP51-AS160; isoform-specific functions include insulin-stimulated glucose uptake in muscle and fat, αMβ2 integrin membrane translocation in neutrophils, macrophage M1/M2 polarization via miR-155/C/EBPβ, suppression of Rac/PAK1 signaling and cell migration, and maintenance of FOXO1-regulated transcription in endothelium and liver."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1999,"claim":"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","pmids":["10523666"],"confidence":"High","gaps":["Did not identify the direct AKT2 substrates mediating GLUT4 translocation","Did not resolve why insulin but not PDGF recruits AKT2"]},{"year":2000,"claim":"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","pmids":["11087731"],"confidence":"High","gaps":["Did not identify nuclear AKT2 substrates","Mechanism of isoform-specific nuclear localization unknown"]},{"year":2002,"claim":"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","pmids":["11948187"],"confidence":"High","gaps":["Direct AKT2 substrate within the MyoD-MEF2 program not defined here"]},{"year":2004,"claim":"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","pmids":["15531580"],"confidence":"High","gaps":["Did not address isoform selectivity of ezrin phosphorylation"]},{"year":2006,"claim":"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","pmids":["16950770","16803855"],"confidence":"High","gaps":["Did not reconcile redundancy versus specificity between AKT1 and AKT2 across all metabolic outputs"]},{"year":2007,"claim":"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","pmids":["17515613"],"confidence":"High","gaps":["Relative contribution of myosin 5a versus AS160 to GLUT4 trafficking not quantified"]},{"year":2009,"claim":"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)","pmids":["17012749","18353613","19197940","19330838","20019746"],"confidence":"High","gaps":["The basis for opposite migratory outcomes across cell types is unresolved","Several downstream phosphorylation events shown only by knockdown, not direct kinase assay"]},{"year":2011,"claim":"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)","pmids":["21979934","22044669"],"confidence":"High","gaps":["Structural basis of PHLPP1 isoform selectivity not defined","Range of physiological E17K signaling outputs not fully mapped"]},{"year":2012,"claim":"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","pmids":["22647600","23250987"],"confidence":"High","gaps":["Direct AKT2 substrate linking it to miR-155 not identified","FOXO1 phosphosite controlling promoter eviction not defined"]},{"year":2014,"claim":"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","pmids":["24642468","24496246","16365168"],"confidence":"High","gaps":["Direct AKT2 substrate controlling integrin translocation not identified","Whether ETS1/IP3R2 regulation is direct or indirect unresolved"]},{"year":2015,"claim":"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","pmids":["25733895"],"confidence":"High","gaps":["Full oncogenic substrate repertoire of the fusion not defined"]},{"year":2019,"claim":"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","pmids":["31548312","30833219"],"confidence":"High","gaps":["Why S474A reduces but does not abolish substrate phosphorylation not mechanistically resolved"]},{"year":2022,"claim":"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","pmids":["36122209"],"confidence":"High","gaps":["Whether CAD phosphorylation is AKT2-isoform-specific not addressed"]},{"year":2024,"claim":"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","pmids":["39034314"],"confidence":"Medium","gaps":["SIRT5 interaction shown by Co-IP without reciprocal/structural validation","Whether AKT2 phosphorylates SIRT5 or PGC-1α directly is unknown"]},{"year":null,"claim":"How AKT2 achieves isoform-specific substrate selection and the structural determinants distinguishing it from AKT1 across its many context-dependent roles remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,13,28,25]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[25,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,23,37]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,10,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9,25]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,11,12,28,37]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,21,26]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,20]}],"complexes":[],"partners":["PAK1","PRKCZ","PHB2","PHLPP1","FKBP51","ILK","SIRT1","SIRT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31751","full_name":"RAC-beta serine/threonine-protein kinase","aliases":["Protein kinase Akt-2","Protein kinase B beta","PKB beta","RAC protein kinase beta","RAC-PK-beta"],"length_aa":481,"mass_kda":55.8,"function":"Serine/threonine kinase closely related to AKT1 and AKT3. All 3 enzymes, AKT1, AKT2 and AKT3, are collectively known as AKT kinase. AKT regulates many processes including metabolism, proliferation, cell survival, growth and angiogenesis, through the phosphorylation of a range of downstream substrates. Over 100 substrates have been reported so far, although for most of them, the precise AKT kinase catalyzing the reaction was not specified. AKT regulates glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT also regulates the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT also regulates cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor 1 (IGF1). AKT mediates the antiapoptotic effects of IGF1. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development (PubMed:21432781, PubMed:21620960). In response to lysophosphatidic acid stimulation, inhibits the ciliogenesis cascade. In this context, phosphorylates WDR44, hence stabilizing its interaction with Rab11 and preventing the formation of the ciliogenic Rab11-FIP3-RAB3IP complex. Also phosphorylates RAB3IP/Rabin8, thus may affect RAB3IP guanine nucleotide exchange factor (GEF) activity toward Rab8, which is important for cilia growth (PubMed:31204173). Phosphorylates PKP1, facilitating its interaction with YWHAG and translocation to the nucleus, ultimately resulting in a reduction in keratinocyte intercellular adhesion (By similarity). Phosphorylation of PKP1 increases PKP1 protein stability, translocation to the cytoplasm away from desmosome plaques and PKP1-driven cap-dependent translation (PubMed:23444369) Several AKT2-specific substrates have been identified, including ANKRD2, C2CD5, CLK2 and PITX2. May play a role in myoblast differentiation. In this context, may act through PITX2 phosphorylation. Unphosphorylated PITX2 associates with an ELAVL1/HuR-containing complex, which stabilizes CCND1 cyclin mRNA, ensuring cell proliferation. Phosphorylation by AKT2 impairs this association, leading to CCND1 mRNA destabilization and progression towards differentiation (By similarity). Also involved in the negative regulation of myogenesis in response to stress conditions. In this context, acts by phosphorylating ANKRD2 (By similarity). May also be a key regulator of glucose uptake. Regulates insulin-stimulated glucose transport by the increase of glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane. In this context, acts by phosphorylating C2CD5/CDP138 on 'Ser-197' in insulin-stimulated adipocytes (By similarity). Through the phosphorylation of CLK2 on 'Thr-343', involved in insulin-regulated suppression of hepatic gluconeogenesis (By similarity)","subcellular_location":"Cytoplasm; Nucleus; Cell membrane; Early endosome","url":"https://www.uniprot.org/uniprotkb/P31751/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKT2","classification":"Not Classified","n_dependent_lines":38,"n_total_lines":1208,"dependency_fraction":0.03145695364238411},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000105221","cell_line_id":"CID001124","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":2},{"compartment":"nucleoplasm","grade":2},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"AP1G1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001124","total_profiled":1310},"omim":[{"mim_id":"618044","title":"C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 5; C2CD5","url":"https://www.omim.org/entry/618044"},{"mim_id":"617535","title":"FAS APOPTOTIC INHIBITORY MOLECULE; FAIM","url":"https://www.omim.org/entry/617535"},{"mim_id":"615932","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 20; KCTD20","url":"https://www.omim.org/entry/615932"},{"mim_id":"611223","title":"AKT SERINE/THREONINE KINASE 3; AKT3","url":"https://www.omim.org/entry/611223"},{"mim_id":"611066","title":"PH DOMAIN AND LEUCINE-RICH REPEAT PROTEIN PHOSPHATASE-LIKE; PHLPPL","url":"https://www.omim.org/entry/611066"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AKT2"},"hgnc":{"alias_symbol":["PKBβ"],"prev_symbol":[]},"alphafold":{"accession":"P31751","domains":[{"cath_id":"2.30.29.30","chopping":"7-113","consensus_level":"high","plddt":81.2196,"start":7,"end":113},{"cath_id":"3.30.200.20","chopping":"150-233_434-450","consensus_level":"high","plddt":86.0508,"start":150,"end":450},{"cath_id":"1.10.510.10","chopping":"238-420","consensus_level":"high","plddt":93.5069,"start":238,"end":420}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31751","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31751-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31751-F1-predicted_aligned_error_v6.png","plddt_mean":82.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKT2","jax_strain_url":"https://www.jax.org/strain/search?query=AKT2"},"sequence":{"accession":"P31751","fasta_url":"https://rest.uniprot.org/uniprotkb/P31751.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31751/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31751"}},"corpus_meta":[{"pmid":"7657393","id":"PMC_7657393","title":"Molecular 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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.\",\n      \"method\": \"Subcellular fractionation, isoform-specific phosphorylation assays, microinjection of PKB substrate peptide/antibody in 3T3-L1 adipocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, antibody microinjection, isoform-specific phosphorylation assays), functional readout of GLUT4 translocation\",\n      \"pmids\": [\"10523666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, siRNA knockdown of Akt2, dominant-negative Akt expression, co-immunoprecipitation, glucose transport assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation demonstrated, multiple orthogonal functional assays (siRNA, DN-Akt, transport assays), specific phosphosite identified\",\n      \"pmids\": [\"17515613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay with purified Akt and recombinant ezrin, siRNA knockdown of Akt2, PI3K inhibition, pharmacological Akt inhibition, functional NHE3 translocation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro phosphorylation of defined substrate at specific residue, confirmed in intact cells by siRNA knockdown with functional readout\",\n      \"pmids\": [\"15531580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Kinase assay (Pak1 inhibition by Akt2 in vitro), co-immunoprecipitation, Akt2 knockout mouse fibroblasts, domain-swap experiments, migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay demonstrating Akt2-specific Pak1 inhibition, reciprocal Co-IP, KO cells with defined phenotype, domain-swap epistasis\",\n      \"pmids\": [\"17012749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Cell fractionation, transactivation assay, microinjection of isoform-specific antibodies, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, functional microinjection, transactivation assay), isoform-specific localization with functional consequence\",\n      \"pmids\": [\"11087731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Akt2 promoter cloning, EMSA (MyoD binding to E-boxes), promoter activity assay, microinjection of anti-Akt2 antibody, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter cloning with EMSA, functional reporter assays, antibody microinjection, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11948187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (EGF-induced), SCID mouse metastasis model, Western blot for downstream phosphorylation\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP demonstrating isoform-specific interaction, siRNA knockdown with pathway readouts, single lab\",\n      \"pmids\": [\"18353613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, Western blot for downstream phosphorylation, chemotaxis assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA knockdown with defined signaling readouts, consistent pathway placement, single lab\",\n      \"pmids\": [\"19197940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of Akt2, Western blot for phosphorylation events, in vitro and in vivo invasion assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA with multiple downstream readouts showing pathway placement, single lab\",\n      \"pmids\": [\"19330838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic sequencing, heterologous cell expression of mutant AKT2, subcellular localization assay, downstream signaling assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional characterization of constitutively active mutant with defined mechanism (membrane recruitment), validated in human patients and heterologous cells\",\n      \"pmids\": [\"21979934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"RNA sequencing of patient tumors, fusion protein detection by Western blot, kinase activity assay, CRISPR/Cas9-generated fusion, focus formation assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct biochemical demonstration of constitutive kinase activation, validated in patient tumors and in engineered cell lines, multiple orthogonal methods\",\n      \"pmids\": [\"25733895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Akt2 knockout mice, 2-[3H]deoxyglucose uptake assay, transverse aortic constriction, myocardial infarction model, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific metabolic and functional readouts, isoform specificity demonstrated by parallel Akt1 KO comparison\",\n      \"pmids\": [\"16950770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Akt2 knockout mice, in situ contraction, Western blot for Akt T308, GSK-3α Ser21, GSK-3β Ser9, glycogen synthase assays, glucose uptake assay\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific biochemical readouts, parallel isoform comparison, multiple substrates examined\",\n      \"pmids\": [\"16803855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, ribonucleoprotein complex immunoprecipitation, mRNA half-life measurement, C2C12 differentiation assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation of Pitx2 by Akt2, mechanistic dissection of mRNA stability complex with functional differentiation readout\",\n      \"pmids\": [\"20019746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation of endogenous proteins, MyoD-induced fibroblast conversion assay, immunofluorescence\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of endogenous proteins showing isoform-specific interaction, siRNA with functional differentiation readout, single lab\",\n      \"pmids\": [\"17565718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"OptiPrep density gradient fractionation, immunocytochemistry, activity assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — membrane fractionation with biochemical activity readouts, mechanistic correlation with PTEN localization, single lab\",\n      \"pmids\": [\"14699494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of PHLPPs, overexpression, Western blot for isoform-specific Akt phosphorylation, apoptosis assay, xenograft tumor model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific phosphatase-substrate relationship demonstrated with both gain- and loss-of-function, in vitro and in vivo validation\",\n      \"pmids\": [\"22044669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (FKBP51-AS160), FKBP51 knockout mice, pharmacological FKBP51 antagonist (SAFit2), glucose uptake assay, GLUT4 membrane fractionation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying novel complex, genetic and pharmacological intervention with functional readout, single lab\",\n      \"pmids\": [\"29170369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"FRET analysis, co-immunoprecipitation, dominant-negative constructs, MMP-2 assay, migration assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET and Co-IP demonstrating complex formation, functional readout of MMP-2 and migration, single lab\",\n      \"pmids\": [\"19460343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Intravital microscopy, bone marrow chimeras, Akt isoform KO mice, AKT2-specific inhibitor, flow cytometry, Ca2+ imaging\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with pharmacological inhibition and intravital imaging, multiple orthogonal functional readouts, isoform specificity established\",\n      \"pmids\": [\"24642468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA silencing of AKT2 vs AKT1, xenograft tumor model, Western blot for p21/BAX/IGF-1R, rescue experiments\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific KD with in vivo xenograft validation and pathway effector identification, single lab\",\n      \"pmids\": [\"24838891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Akt2-/- mice, gene silencing, miR-155 overexpression/silencing, DSS-colitis and LPS-shock models, cell depletion/reconstitution experiments\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with in vivo reconstitution experiments, gene silencing with pathway readouts, mechanistic link to miR-155/C/EBPβ established by overexpression/silencing\",\n      \"pmids\": [\"22647600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Isoform-specific siRNA knockdown, IGF-IR overexpression, cell migration assay, morphological/EMT marker analysis, ERK activation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isoform-specific siRNA with multiple functional readouts and cross-regulation epistasis established, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"16365168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Akt2 knockout mice, angiotensin II infusion model, ChIP assay (FOXO1 binding to promoters), Western blot, cultured human aortic VSMCs with AKT2 inhibition\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating FOXO1 promoter binding regulated by AKT2, in vivo KO model with functional aortic phenotype, single lab\",\n      \"pmids\": [\"23250987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro CK2 kinase assay with recombinant Akt2, in vivo phosphorylation analysis in multiple cell lines, palladin substrate assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with substrate specificity analysis, in vivo validation across multiple cell lines, mechanistically links linker phosphorylation to substrate specificity\",\n      \"pmids\": [\"24769357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chemical genetics approach directly testing phosphosite without perturbing mTORC2, multiple orthogonal substrate and functional readouts in same study\",\n      \"pmids\": [\"31548312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Akt2-/- mice, bleomycin model, adoptive macrophage transfer, IL-33 stimulation, siRNA knockdown of FoxO3a, phosphorylation analysis, lung section analysis from IPF patients\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with adoptive transfer rescue, siRNA epistasis defining AKT2-FoxO3a-IL-13 axis, single lab\",\n      \"pmids\": [\"28455433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of Sirt1-Akt2, high-fat diet mouse model, resveratrol/nicotinamide treatment, Western blot for mTOR/S6K1 signaling\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP demonstrating interaction, pharmacological and in vivo validation, single lab\",\n      \"pmids\": [\"27317762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Untargeted metabolomics, AKT2 knockdown/overexpression, in vitro kinase assay (AKT2 phosphorylation of CAD), mouse liver cancer models, site-directed mutagenesis of CAD phosphosites\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct phosphorylation of CAD by AKT2 demonstrated at specific residues, functional metabolomics validation, multiple model systems\",\n      \"pmids\": [\"36122209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Akt isoform-specific siRNA/overexpression, Western blot for palladin protein, transcriptional reporter assay, protein stability assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — isoform-specific regulation demonstrated at both transcript and protein stability levels, but limited mechanistic depth, single lab\",\n      \"pmids\": [\"21050850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of Akt2, Western blot for phosphorylation, Transwell invasion assay, in vivo glioma invasion model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA with multiple downstream phosphorylation and functional readouts, in vivo validation, single lab\",\n      \"pmids\": [\"19330838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, Ca2+ imaging, RT-PCR, siRNA), genetic KO with pharmacological validation, single lab\",\n      \"pmids\": [\"24496246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"AKT2-specific inhibition/knockdown, FOXO1 nuclear localization assay, CLDN5 expression assay, barrier permeability assay, EAE mouse model\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic pathway placed (AKT2→FOXO1→CLDN5) with functional barrier readout, in vivo and in vitro evidence, single lab\",\n      \"pmids\": [\"30574832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Akt2-specific silencing in cardiomyocytes, TRB3 siRNA/overexpression, MT transgenic and KO mice, Western blot for isoform-specific Akt phosphorylation, streptozotocin diabetes model\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific phosphorylation readout, TRB3-AKT2 axis validated by gain/loss of function in vitro and in vivo, single lab\",\n      \"pmids\": [\"29079702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Akt1/Akt2 deletion (Myf5-Cre, Ucp1-Cre, Ucp1-CreER), Western blot for substrate phosphorylation, ChREBP activity assay, histological analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO models in multiple lineages, biochemical readouts of substrate phosphorylation and ChREBP activity, single lab\",\n      \"pmids\": [\"30833219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Inducible shRNA knockdown of Akt2, gene array analysis, Western blot for MTSS1/cortactin, actin polymerization assay, orthotopic implantation mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible isoform-specific KD with in vivo validation, defined signaling axis (Akt2→MTSS1→Src-cortactin), single lab\",\n      \"pmids\": [\"28068324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP (AKT2-SIRT5 interaction), AKT2 KI mice, iPSC-derived RPE with AMD risk variant, TFEB/TFE3 localization assay, lysosomal function assays, Western blot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying novel binding partner, genetic mouse model and iPSC validation, multiple functional readouts, single lab\",\n      \"pmids\": [\"39034314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Akt2-/- hepatocytes, promoter analysis, CREB phosphorylation assay, FOXO1 ChIP, pyruvate tolerance test\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO hepatocytes with promoter/ChIP analysis identifying specific substrates and transcriptional mechanism, single lab\",\n      \"pmids\": [\"32096546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, luciferase, siRNA), isoform-specific Akt2 role established, single lab\",\n      \"pmids\": [\"30927374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Rat TMJOA model with in vivo force sensing, Akt2 inhibition, Western blot, immunofluorescence/IHC, RAW264.7 cell studies with RANTES stimulation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo and in vitro evidence placing AKT2 downstream of RANTES-CCR signaling with osteoclast functional readout, single lab\",\n      \"pmids\": [\"36173680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Bleomycin mouse model, Akt2 and PDK1 inhibitors, Western blot for pAkt2 and PDK1, TGF-β1 stimulation, glycolysis/lactate assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pharmacological epistasis placing AKT2-PDK1, functional metabolic readout, single lab\",\n      \"pmids\": [\"38226859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Zebrafish akt2 morpholino knockdown, glut1 morpholino knockdown, bad morpholino rescue, glut1 mRNA overexpression rescue, quantitative RT-PCR, glucose uptake assay, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino epistasis in zebrafish with rescue experiments, mechanistic link from Akt2 to Glut1 expression established, single lab\",\n      \"pmids\": [\"20356836\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AKT2 (PKBβ) is a plasma membrane-recruited serine/threonine kinase activated downstream of PI3K whose Ser474 hydrophobic-motif phosphorylation is required for maximal catalytic activity; it phosphorylates isoform-specific substrates including myosin 5a (Ser1650, mediating GLUT4 vesicle trafficking), ezrin (Thr567, triggering NHE3 translocation), Pitx2 (destabilizing Cyclin D1 mRNA to initiate muscle differentiation), CAD (S1406/S1859, driving pyrimidine synthesis), and CREB (maintaining basal gluconeogenic gene expression); it is selectively dephosphorylated by PHLPP1 and interacts with binding partners including SIRT5, PKCζ, Prohibitin2/REA, thymosin-β4/ILK, and FKBP51-AS160; isoform-specific functions include insulin-stimulated glucose uptake in muscle and fat, αMβ2 integrin membrane translocation in neutrophils, macrophage M1/M2 polarization via miR-155/C/EBPβ, suppression of Rac/PAK1 signaling and cell migration, and maintenance of FOXO1-regulated transcription in endothelium and liver.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #22]. 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 [#25]; AKT2 is selectively inactivated by the phosphatase PHLPP1, whereas linker-residue phosphorylation differences (lack of Ser131 modification) restrict its substrate range relative to AKT1 [#16, #24]. 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 [#0, #1, #11, #17]. 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 [#2, #13, #28]. 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 [#3, #6, #23, #32, #37]. In innate immunity, AKT2 directs neutrophil αMβ2 integrin translocation and macrophage M1/M2 polarization via a miR-155/C/EBPβ axis [#19, #21]. 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 [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that AKT2 is the insulin-selective AKT isoform in adipocytes, answering whether the two AKT isoforms have distinct upstream regulation and tissue roles.\",\n      \"evidence\": \"Subcellular fractionation and isoform-specific phosphorylation assays with substrate antibody microinjection in 3T3-L1 adipocytes\",\n      \"pmids\": [\"10523666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the direct AKT2 substrates mediating GLUT4 translocation\", \"Did not resolve why insulin but not PDGF recruits AKT2\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed AKT2 has an isoform-specific nuclear role in muscle differentiation, distinguishing it functionally from AKT1.\",\n      \"evidence\": \"Cell fractionation, isoform-specific antibody microinjection, and transactivation assays in myotubes\",\n      \"pmids\": [\"11087731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify nuclear AKT2 substrates\", \"Mechanism of isoform-specific nuclear localization unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined a positive feedback loop in which MyoD transcriptionally drives Akt2 and Akt2 reinforces MyoD-MEF2 activity, linking AKT2 to a transcriptional differentiation circuit.\",\n      \"evidence\": \"Promoter cloning, EMSA, reporter assays, and anti-Akt2 antibody microinjection\",\n      \"pmids\": [\"11948187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AKT2 substrate within the MyoD-MEF2 program not defined here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified ezrin Thr567 as a direct AKT2 substrate, providing the molecular link between AKT2 and NHE3 trafficking in epithelial transport.\",\n      \"evidence\": \"In vitro kinase assay with recombinant ezrin, siRNA, and NHE3 translocation readout\",\n      \"pmids\": [\"15531580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address isoform selectivity of ezrin phosphorylation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated AKT2-specific requirement for insulin-stimulated glucose metabolism and substrate phosphorylation (GSK-3α) in cardiac and skeletal muscle, with sensitization to ischemic apoptosis.\",\n      \"evidence\": \"Akt2-knockout mice with parallel Akt1 comparison, glucose uptake, contraction, and injury models\",\n      \"pmids\": [\"16950770\", \"16803855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile redundancy versus specificity between AKT1 and AKT2 across all metabolic outputs\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified myosin 5a Ser1650 as a direct AKT2 substrate, providing a molecular mechanism for anterograde GLUT4 vesicle delivery downstream of insulin.\",\n      \"evidence\": \"In vitro kinase assay, siRNA, dominant-negative Akt, and glucose transport assays\",\n      \"pmids\": [\"17515613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of myosin 5a versus AS160 to GLUT4 trafficking not quantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase/Co-IP and Akt2-KO fibroblasts (PAK1); EGF-induced Co-IP and siRNA with chemotaxis readouts (PKCζ)\",\n      \"pmids\": [\"17012749\", \"18353613\", \"19197940\", \"19330838\", \"20019746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The basis for opposite migratory outcomes across cell types is unresolved\", \"Several downstream phosphorylation events shown only by knockdown, not direct kinase assay\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Patient genetics with heterologous expression/localization assays (E17K); isoform-specific phosphatase gain/loss-of-function with xenografts (PHLPP1)\",\n      \"pmids\": [\"21979934\", \"22044669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PHLPP1 isoform selectivity not defined\", \"Range of physiological E17K signaling outputs not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Akt2-/- mice with reconstitution and miR-155 manipulation; Akt2-KO with FOXO1 ChIP and aortic injury model\",\n      \"pmids\": [\"22647600\", \"23250987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AKT2 substrate linking it to miR-155 not identified\", \"FOXO1 phosphosite controlling promoter eviction not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated isoform-specific AKT2 functions in innate immune adhesion and migration—neutrophil αMβ2 integrin translocation and dendritic cell Ca2+ signaling via ETS1/IP3R2.\",\n      \"evidence\": \"Akt isoform-KO mice with intravital imaging and AKT2 inhibitor (neutrophils); Akt2-/- DCs with electrophysiology and Ca2+ imaging\",\n      \"pmids\": [\"24642468\", \"24496246\", \"16365168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AKT2 substrate controlling integrin translocation not identified\", \"Whether ETS1/IP3R2 regulation is direct or indirect unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the recurrent BCAM-AKT2 fusion as a constitutively active, membrane-associated oncogenic kinase in ovarian cancer, generalizing AKT2 membrane-driven activation to cancer.\",\n      \"evidence\": \"RNA-seq of tumors, kinase activity assays, CRISPR-engineered fusion, and focus formation\",\n      \"pmids\": [\"25733895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full oncogenic substrate repertoire of the fusion not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined Ser474 hydrophobic-motif phosphorylation as required for maximal AKT2 activity using a chemical-genetic strategy that isolates the phosphosite from mTORC2 perturbation.\",\n      \"evidence\": \"MK2206-resistant S474A Akt2 with substrate phosphorylation and GLUT4/glucose uptake readouts in adipocytes\",\n      \"pmids\": [\"31548312\", \"30833219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why S474A reduces but does not abolish substrate phosphorylation not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected AKT2 to nucleotide metabolism by showing β-catenin-driven AKT2 directly phosphorylates CAD at S1406/S1859 to fuel pyrimidine synthesis in liver cancer.\",\n      \"evidence\": \"Metabolomics, in vitro kinase assay, CAD phosphosite mutagenesis, and mouse liver cancer models\",\n      \"pmids\": [\"36122209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CAD phosphorylation is AKT2-isoform-specific not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, AKT2 knock-in mice, and iPSC-derived RPE with TFEB localization and lysosomal assays\",\n      \"pmids\": [\"39034314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SIRT5 interaction shown by Co-IP without reciprocal/structural validation\", \"Whether AKT2 phosphorylates SIRT5 or PGC-1α directly is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AKT2 achieves isoform-specific substrate selection and the structural determinants distinguishing it from AKT1 across its many context-dependent roles remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 13, 28, 25]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [25, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 23, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 10, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9, 25]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 11, 12, 28, 37]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 21, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PAK1\", \"PRKCZ\", \"PHB2\", \"PHLPP1\", \"FKBP51\", \"ILK\", \"SIRT1\", \"SIRT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}