Affinage

AKT1

RAC-alpha serine/threonine-protein kinase · UniProt P31749

Length
480 aa
Mass
55.7 kDa
Annotated
2026-06-09
100 papers in source corpus 42 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKT1/PKB is a plasma-membrane-recruited serine/threonine kinase that serves as the central effector of PI3K signaling, converting growth-factor and insulin inputs into pro-survival, growth, metabolic, and migratory outputs (PMID:10872470, PMID:9716402). Its activation follows an ordered, multi-step mechanism: PI3K-generated 3'-phosphoinositides bind the AKT PH domain to drive plasma-membrane translocation and co-localization with PDK1, which phosphorylates the activation-loop Thr308 (PMID:10872470, PMID:10226029), while the rictor-mTOR complex (mTORC2), whose assembly requires mSin1, is the hydrophobic-motif Ser473 kinase that facilitates full activation (PMID:15718470, PMID:16919458). In the resting state AKT is held in a closed, autoinhibited conformation via an intramolecular PH-domain–kinase-domain interaction that blocks activation-loop phosphorylation (PMID:19166270); membrane recruitment within lipid raft nanodomains and additional inputs relieve this constraint (PMID:18641634). Beyond mTORC2, Ser473 phosphorylation is contributed by DNA-PK and ATM in a stimulus-dependent manner (PMID:15262962, PMID:15546863), Ack1 supplies an activating Tyr176 phosphorylation downstream of RTKs (PMID:20333297), and CK2 phosphorylation at Ser129 further enhances catalytic output (PMID:15818404, PMID:21506126). Active AKT recognizes the consensus motif RxRxxS/T (PMID:10945990) and phosphorylates a broad substrate network that executes its biological programs: it inactivates FOXO/DAF-16 transcription factors to suppress pro-apoptotic genes such as Bim (PMID:9716402, PMID:17957242), drives cytoplasmic retention or stabilization of the CDK inhibitors p27Kip1 and p21Cip1 (PMID:12244302, PMID:12244301, PMID:11756412), activates CREB- and NF-κB-dependent transcription (PMID:9829964, PMID:10359702), and phosphorylates cytoskeletal and migratory effectors including Girdin and Skp2 (PMID:16139227, PMID:19270694). AKT also acts through kinase-independent protein binding, sequestering Smad3 to block TGF-β-induced apoptosis (PMID:15048128) and binding JIP1 to restrain JNK activation in neurons (PMID:12194869), and it controls cell and organ size cell-autonomously downstream of the insulin/PI3K axis (PMID:10587646). AKT signaling is terminated by PTEN-mediated dephosphorylation of PIP3 and by caspase cleavage during apoptosis (PMID:9778245, PMID:10623893).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    Establishing how AKT activity is negatively gated, PTEN was shown to be the phosphatase that removes the PIP3 signal driving AKT, defining the off-switch of the pathway.

    Evidence In vitro lipid phosphatase assay, PIP3 measurement, and PTEN re-expression rescue in PTEN-deficient MEFs

    PMID:9778245

    Open questions at the time
    • Does not address how PIP3 is generated
    • Does not resolve which AKT-activating kinases act downstream
  2. 1999 High

    Genetic epistasis in C. elegans and Drosophila placed AKT downstream of insulin/PI3K and defined its core physiological outputs — antagonizing FOXO/DAF-16 transcription and controlling cell-autonomous growth.

    Evidence daf-16 suppression of akt-1/akt-2 mutants in C. elegans; clonal mosaic cell-size analysis in Drosophila imaginal discs

    PMID:10587646 PMID:9716402

    Open questions at the time
    • Does not define the biochemical activation steps
    • Substrate phosphorylation sites in mammals not addressed
  3. 1999 High

    Resolving the membrane-recruitment step, the AKT PH domain was shown to bind PI3K-generated 3'-phosphoinositides and localize AKT to the membrane where PDK1 phosphorylates Thr308, defining the multi-step AGC-kinase activation paradigm.

    Evidence Phosphoinositide binding assays, GFP-PH live-cell imaging, PI3K inhibitor and binding-mutant controls

    PMID:10226029 PMID:10872470

    Open questions at the time
    • Identity of the Ser473 hydrophobic-motif kinase unresolved at this stage
    • Mechanism of resting-state autoinhibition not defined
  4. 2000 High

    Defining substrate selectivity, the optimal RxRxxS/T consensus motif was determined, enabling prediction and validation of AKT substrates.

    Evidence Oriented peptide library screening with cDNA expression-library validation and kinetic analysis

    PMID:10945990

    Open questions at the time
    • Does not identify which physiological substrates are phosphorylated in vivo
    • Context-dependent substrate selection not addressed
  5. 2001 High

    Connecting AKT to cell-cycle control, AKT was shown to phosphorylate the CDK inhibitors p21Cip1 and p27Kip1 to alter their localization and stability, promoting proliferation and survival.

    Evidence In vitro kinase assays, T145/S146 and T157A mutagenesis, nuclear import reconstitution, and PCNA-binding assays

    PMID:11756412 PMID:12244301 PMID:12244302

    Open questions at the time
    • In vivo contribution to tumor proliferation not quantified
    • Crosstalk with other p21/p27 kinases not resolved
  6. 2004 High

    Expanding AKT beyond kinase activity, AKT was shown to physically sequester Smad3 in a kinase-independent manner, defining a non-catalytic mechanism for suppressing TGF-β-induced apoptosis.

    Evidence Protein-fragment complementation, co-IP, AKT siRNA rescue, and Smad3 reporter assays

    PMID:15048128

    Open questions at the time
    • Structural basis of the AKT-Smad3 interface unknown
    • Stoichiometry and regulation of the complex not defined
  7. 2004 Medium

    Addressing the long-standing Ser473 kinase question, DNA-PK and ATM were each implicated as stimulus-dependent contributors to AKT Ser473 phosphorylation.

    Evidence DNA-PK purification with in vitro phosphorylation and PRKDC complementation; ATM inhibitors/siRNA and AT-patient/KO cells

    PMID:15262962 PMID:15546863

    Open questions at the time
    • Relative contribution versus mTORC2 across stimuli not quantified
    • Whether these act on membrane-recruited AKT or nuclear AKT unclear
  8. 2005 High

    Identifying the principal hydrophobic-motif kinase, mTORC2 (rictor-mTOR) was shown to directly phosphorylate AKT Ser473 in vitro and facilitate Thr308 phosphorylation, completing the canonical activation model.

    Evidence Reconstituted in vitro kinase assay with purified rictor-mTOR plus rictor/mTOR knockdown in Drosophila and human cells

    PMID:15718470

    Open questions at the time
    • Does not reconcile multiplicity of reported Ser473 kinases
    • Spatial coordination of mTORC2 with membrane AKT not addressed
  9. 2005 High

    Adding a tuning input, CK2 was shown to phosphorylate already-active AKT at Ser129 to further enhance catalytic activity and downstream β-catenin signaling.

    Evidence In vitro CK2 kinase assay, two structurally distinct inhibitors plus siRNA; later S129A mutant analysis of β-catenin/survivin

    PMID:15818404 PMID:21506126

    Open questions at the time
    • Physiological stimuli engaging CK2-AKT crosstalk not defined
    • Quantitative contribution to overall AKT output unclear
  10. 2006 High

    Defining the mTORC2 assembly requirement, mSin1 was identified as an essential subunit needed for mTORC2 to phosphorylate AKT Ser473, and prolonged rapamycin was shown to disrupt mTORC2 and reduce AKT signaling.

    Evidence Co-IP, mSin1 siRNA, in vitro mTORC2 kinase assay, mass spec isoform mapping; mTORC2 assembly assays with rapamycin-resistant AKT rescue

    PMID:16603397 PMID:16919458

    Open questions at the time
    • Functional distinction among mSin1 isoform complexes not fully resolved
    • How rapamycin selectively disrupts assembly mechanistically unclear
  11. 2009 High

    Revealing the basis of resting-state inhibition, AKT was shown to adopt a closed PH-domain–kinase-domain conformation that blocks Thr308 phosphorylation and is exploited by isoform-selective allosteric inhibitors.

    Evidence Molecular modeling, FRET/two-photon FLIM, biochemical kinase assays, and domain mutagenesis

    PMID:19166270

    Open questions at the time
    • High-resolution structure of the autoinhibited state not provided
    • How PIP3 binding kinetically relieves the closed state not detailed
  12. 2009 High

    Linking AKT to ubiquitin-ligase control and migration, AKT was shown to phosphorylate Skp2 (and earlier Girdin), driving SCF activity, 14-3-3-dependent cytoplasmic relocalization, and cell motility.

    Evidence In vitro kinase assays, phospho-defective mutants, ubiquitylation and migration assays, human tumor specimen analysis

    PMID:16139227 PMID:19270694

    Open questions at the time
    • In vivo metastatic relevance of these substrates not established
    • Isoform specificity of cytoskeletal substrate phosphorylation not resolved
  13. 2010 High

    Adding tyrosine-kinase input, Ack1 was shown to phosphorylate AKT at Tyr176 to promote membrane localization and prime activation-loop/hydrophobic-motif phosphorylation downstream of RTKs.

    Evidence In vitro phosphorylation, Y176F mutagenesis, fractionation, and an Ack1-driven prostate cancer mouse model

    PMID:20333297

    Open questions at the time
    • Generality across RTK contexts not established
    • Structural effect of Tyr176 phosphorylation on conformation unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple reported Ser473 kinases (mTORC2, DNA-PK, ATM, Pak1) are deployed across distinct stimuli, subcellular compartments, and cell types — and how isoform-specific (AKT1 vs AKT2) substrate choice is achieved — remains unresolved.
  • No unified model reconciling competing Ser473 kinases
  • Mechanistic basis of AKT1/AKT2 functional divergence incompletely defined
  • Compartment-specific substrate engagement not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0008289 lipid binding 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1640170 Cell Cycle 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
ACK1JIP1MAPKSIN1MTORPDPK1PTENRICTORSMAD3
Complex memberships
mTORC2

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 The rictor-mTOR complex (mTORC2) directly phosphorylates AKT1 on Ser473 in vitro and facilitates subsequent Thr308 phosphorylation by PDK1, establishing mTORC2 as the long-sought Ser473 kinase for AKT activation. In vitro kinase assay with purified rictor-mTOR complex, siRNA knockdown of rictor/mTOR in Drosophila and human cells, epistasis analysis Science High 15718470
2006 Prolonged rapamycin treatment inhibits mTORC2 assembly, reducing Ser473 phosphorylation of AKT/PKB below levels needed to maintain AKT signaling; this mechanism underlies some proapoptotic and antitumor effects of rapamycin. mTORC2 assembly assays, Western blotting of phospho-AKT in multiple cell lines after prolonged rapamycin, rescue with rapamycin-resistant AKT mutant Molecular cell High 16603397
2006 mSin1 is an essential component of mTORC2 required for mTORC2 assembly and its capacity to phosphorylate AKT/PKB on Ser473; alternative splicing generates at least three distinct mTORC2 complexes, only two of which are regulated by insulin. Co-immunoprecipitation, siRNA knockdown of mSin1, in vitro mTORC2 kinase assay, mass spectrometry identification of mSin1 isoforms Current biology High 16919458
1998 PTEN negatively regulates AKT/PKB activity and phosphorylation by dephosphorylating phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in vitro and in vivo; PTEN-deficient cells show constitutively elevated AKT activity and resistance to apoptosis, which is reversed by re-expression of wild-type PTEN. In vitro lipid phosphatase assay, genetic rescue (PTEN re-expression in mutant cells), measurement of PI(3,4,5)P3 levels, PKB kinase assays in PTEN-deficient MEFs Cell High 9778245
1999 PI3K-generated D3-phosphoinositides bind the AKT PH domain, inducing plasma membrane translocation and co-localization with PDK1, which then phosphorylates the AKT activation loop (Thr308); this multi-step activation mechanism is shared with other AGC kinases. Phosphoinositide binding assays, subcellular fractionation, kinase assays, domain mutagenesis Annual review of biochemistry High 10872470
2004 DNA-dependent protein kinase (DNA-PK) was purified as a major Ser473 kinase from HEK293 cells: it co-localizes and associates with AKT at the plasma membrane, phosphorylates AKT on Ser473 in vitro (~10-fold activation), and siRNA knockdown of DNA-PK inhibits insulin- and pervanadate-induced Ser473 phosphorylation; DNA-PK-deficient cells fail to phosphorylate Ser473 in response to insulin, restored by PRKDC complementation. Biochemical purification, in vitro kinase assay, siRNA knockdown, genetic complementation in DNA-PK-deficient cells, co-localization by microscopy The Journal of biological chemistry High 15262962
1998 AKT/PKB directly phosphorylates CREB at Ser133 in serum-stimulated cells, promoting CBP recruitment and CREB-dependent target gene expression; this effect requires AKT kinase activity and is PI3K-dependent. Overexpression of AKT in serum-stimulated cells, phospho-Ser133 CREB detection, CBP co-immunoprecipitation, reporter gene assays, PI3K inhibitor (LY294002) The Journal of biological chemistry Medium 9829964
1999 AKT/PKB activation of NF-κB occurs at the level of IκB degradation and requires AKT kinase activity and its PH domain; AKT does not act alone but cooperates with other pathway signals to induce NF-κB-dependent cytokine promoters. Overexpression of kinase-dead and PH-domain mutant AKT in Jurkat cells, NF-κB reporter assays, IκB degradation assays Current biology Medium 10359702
2002 AKT/PKB phosphorylates p27Kip1 at Thr157 within its nuclear localization signal, impairing nuclear import of p27 and causing cytoplasmic retention; cells expressing the T157A mutant p27 are refractory to AKT-mediated nuclear exclusion and retain G1-arrest activity. In vitro kinase assay with recombinant AKT and p27, site-directed mutagenesis (T157A), subcellular fractionation/immunofluorescence, CDK2 activity assays, in vitro nuclear import assays Nature medicine High 12244301 12244302
2001 AKT/PKB directly phosphorylates p21Cip1/WAF1 at Thr145 and Ser146; Thr145 phosphorylation inhibits PCNA binding, while Ser146 phosphorylation stabilizes p21 protein, enhancing cell survival and CDK4/cyclin D1 complex assembly. In vitro kinase assay, site-directed mutagenesis, protein stability assays, co-immunoprecipitation for PCNA binding, kinase activity assays in glioblastoma cell lines The Journal of biological chemistry High 11756412
2004 PKB/AKT physically interacts with Smad3 through a kinase-activity-independent mechanism; insulin induces complex formation while TGF-β inhibits it. AKT inhibits Smad3 by preventing its phosphorylation, Smad4 binding, and nuclear translocation, thereby suppressing TGF-β-induced apoptosis. Protein fragment complementation assay (PCA) in live cells, co-immunoprecipitation, siRNA knockdown of AKT, reporter assays for Smad3-dependent transcription, phosphorylation assays Nature cell biology High 15048128
2005 AKT/PKB phosphorylates Girdin/APE at Ser1416; phosphorylated Girdin accumulates at the leading edge of migrating cells and is required for stress fiber/lamellipodia formation and cell migration. Cells expressing S1416A-Girdin show impaired migration and lamellipodia formation. Identification of Girdin as AKT substrate by mass spectrometry, in vitro kinase assay, site-directed mutagenesis (S1416A), immunofluorescence of phospho-Girdin localization, cell migration assays Developmental cell High 16139227
2005 Protein kinase CK2 phosphorylates AKT/PKB at Ser129 in vitro and in vivo; this phosphorylation of already-activated AKT further increases its catalytic activity, and CK2 inhibition (by two structurally distinct inhibitors or siRNA) reduces AKT activity and promotes apoptosis. In vitro kinase assay with CK2 and AKT, 32P incorporation, CK2 siRNA, two structurally distinct CK2 inhibitors, immunoprecipitate kinase assay Cell death and differentiation High 15818404
2010 The non-receptor tyrosine kinase Ack1 directly phosphorylates AKT at the evolutionarily conserved Tyr176 in the kinase domain; Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes subsequent Thr308/Ser473 phosphorylation and AKT activation downstream of RTKs. Direct in vitro phosphorylation assay, site-directed mutagenesis (Y176F), subcellular fractionation, phospho-specific antibodies, mouse prostate cancer model with activated Ack1 PloS one High 20333297
2000 AKT/PKB optimal phosphorylation consensus motif was defined as Arg-Xaa-Arg-Xaa-Xaa-(Ser/Thr) with Arg at −3, −5, and −7 being most critical for high Vmax/Km; this was validated against a cDNA library screen of HeLa cell substrates. Oriented peptide library screening, cDNA expression library screening (λGEX phage), kinetic analysis The Journal of biological chemistry High 10945990
2009 AKT/PKB exists in an inactive closed conformation through an intramolecular interaction between its PH domain and kinase domain that prevents PDK1 phosphorylation of the activation loop; allosteric inhibitor AKT inhibitor VIII stabilizes this closed conformation and shows isoform selectivity based on differences at the PH-kinase domain interface. Molecular modeling, FRET/two-photon FLIM, classical biochemical kinase assays, domain mutagenesis PLoS biology High 19166270
2009 AKT/PKB directly phosphorylates Skp2, triggering SCF complex formation and E3 ligase activity; AKT-mediated phosphorylation also induces 14-3-3β-dependent cytoplasmic relocalization of Skp2, where cytosolic Skp2 promotes cell migration. Co-immunoprecipitation, direct in vitro kinase assay, phosphorylation-defective mutant (Skp2-S72A), ubiquitylation assays, subcellular fractionation, cell migration assays, analysis of human cancer specimens Nature cell biology High 19270694
1999 In C. elegans, Akt/PKB homologs AKT-1 and AKT-2 transduce insulin receptor-like signals from AGE-1 PI3K downstream; loss-of-function of DAF-16 (Forkhead transcription factor) suppresses the akt-1/akt-2 requirement, establishing that AKT/PKB functions primarily to antagonize DAF-16 transcription factor activity. Genetic epistasis (daf-16 suppression of akt-1/akt-2 mutant phenotype), gain-of-function akt-1 screen, overexpression dosage experiments, expression pattern analysis in C. elegans Genes & development High 9716402
2004 ATM kinase is required for full AKT/PKB activation at Ser473 in response to insulin or gamma-radiation; this effect is mediated through the PI3K-like kinase domain of ATM and affects downstream AKT targets (Forkhead transcription factors) in ATM-deficient cells. Transient transfection, ATM inhibitors, ATM siRNA, cell lines from AT patients and ATM knockout mice, Ser473-specific phosphorylation analysis The Journal of biological chemistry Medium 15546863
2001 AKT1 directly associates with JIP1 (JNK-interacting protein 1/scaffold) in primary neurons; this interaction inhibits JIP1-mediated potentiation of JNK activity by decreasing JIP1 binding to specific JNK pathway kinases. Excitotoxic stimuli disrupt the Akt1-JIP1 interaction, releasing JNK activation, and Akt1-deficient neurons show enhanced kainate susceptibility. Co-immunoprecipitation, direct binding assay, kinase assays, Akt1-deficient mouse neurons, overexpression of Akt1 mutants Neuron High 12194869
2007 Akt2/PKBβ phosphorylates and inhibits PGC-1α, a global regulator of hepatic metabolism during fasting; phosphorylation prevents PGC-1α recruitment to cognate promoters, impairing gluconeogenesis and fatty acid oxidation programs. In vitro phosphorylation assay, chromatin immunoprecipitation, reporter assays, hepatocyte-specific Akt2 knockout, metabolic phenotyping Nature Medium 17554339
1999 In Drosophila, Akt/PKB regulates cell and organ size in a cell-autonomous manner downstream of the insulin receptor/Chico/Dp110 (PI3K) pathway; ectopic Akt expression increases cell size without affecting apoptosis, cell fate, or proliferation rates. Drosophila genetic mosaic analysis, imaginal disc clonal analysis, gain- and loss-of-function transgenes, cell size measurement Nature cell biology High 10587646
1999 AKT/PKB PH domain binds PI3K-generated 3'-phosphoinositides and localizes to membrane ruffles upon mitogen treatment; in epithelial cells, AKT PH domain localizes to sites of cell-cell and cell-matrix contact (distinct from focal contacts) in a PI3K-activity-dependent and phosphoinositide-binding-dependent manner, providing a constitutive survival signal. GFP-Akt and GFP-PH domain fusion live-cell imaging, immunofluorescence microscopy, PI3K inhibitor treatment, PH domain phosphoinositide-binding mutants Current biology High 10226029
2003 Akt/PKB phosphorylates tau at Thr212 and Ser214 independently in vitro; only one site per molecule is phosphorylated at a time (no AT100 double-phosphorylated tau produced by Akt alone). Prior Ser214 phosphorylation by Akt blocked subsequent PKA activity at that site, while GSK3β selectively blocked Ser214 phosphorylation. In vitro kinase assay with recombinant Akt and tau isoforms, phospho-site-specific antibodies, immunoprecipitation, mixed kinase assays Biochimica et biophysica acta Medium 14636947
2001 AKT/PKB promotes cancer cell invasion by increasing cell motility and MMP-9 production via NF-κB transcriptional activation; AKT/PKB localizes to the leading edge membrane of migrating cells in a PI3K- and PH-domain-dependent manner. Confocal live-cell imaging, invasion assays, MMP-9 production assays, NF-κB reporter assays, kinase-dead and PH-domain mutant AKT constructs, PI3K inhibitors FASEB journal Medium 11532975
2004 AKT/PKB phosphorylates heme oxygenase-1 (HO-1) at Ser188 in vitro and in vivo; the phosphomimetic S188D mutant shows ~1.6-fold higher enzymatic activity and slightly altered binding to cytochrome P450 reductase and biliverdin reductase as measured by FRET. In vitro kinase assay with recombinant HO-1, site-directed mutagenesis (S188A, S188D), 32P metabolic labeling in HEK293T cells, FRET assays for protein-protein interactions, HO-1 enzymatic activity assay FEBS letters Medium 15581622
2006 Akt1 phosphorylates FoxO3a to prevent its nuclear localization, thereby suppressing transactivation of the proapoptotic target gene Bim in osteoblasts; Akt1-deficient mice show low bone mass through increased osteoblast apoptosis via the Akt1/FoxO3a/Bim axis and decreased Runx2 transcriptional activity. Akt1 knockout mouse model, ex vivo osteoblast culture, apoptosis assays, FoxO3a nuclear localization by immunofluorescence, Bim expression analysis, Runx2 transcriptional activity assays PloS one Medium 17957242
2006 Akt1 has opposing roles to Akt2 in regulating cell migration and cytoskeletal organization: Akt1-deficient MEFs migrate more slowly and respond poorly to PDGF, while Akt2-deficient cells migrate faster. Akt2 inhibits Pak1 kinase activity in direct kinase assays; N-terminal PH domain and linker region distinguish the two isoforms' functions. Akt1/Akt2 knockout MEFs, cell migration assays, dorsal ruffling assays, domain-swap constructs between Akt1/Akt2, direct Pak1 kinase assays, Rac activity measurements The Journal of biological chemistry Medium 17012749
2003 Akt/PKB directly binds the actin cytoskeleton via its N-terminal PH domain; PDGF stimulation increases the amount of Akt associated with the actin skeleton, and this association requires Ser473/Thr308 phosphorylation (abolished by S473A/T308A double mutant). Small GTPases Rac1 and Cdc42 facilitate actin binding. In situ cytoskeletal matrix preparations, co-immunoprecipitation, in vitro binding and overlay assays with recombinant proteins, subcellular fractionation, expression of Akt domain mutants Cellular and molecular life sciences Medium 14685694
2006 Akt/PKB phosphorylates TopBP1 in vitro and in vivo; phosphorylation induces TopBP1 oligomerization through its 7th and 8th BRCT domains. Akt-dependent oligomerization is required for TopBP1 to interact with and repress E2F1 proapoptotic activity. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, TopBP1 oligomerization assays, E2F1 reporter assays, PI3K inhibitor treatment The EMBO journal Medium 17006541
2000 Caspases cleave AKT/PKB at three sites during apoptosis (TVAD108↓G, EEMD119↓F between PH and kinase domains, and SETD434↓T in the C-terminal regulatory domain), generating 40- and 44-kDa fragments; loss of the C-terminal domain reduces kinase activity and overexpression of the truncated fragment sensitizes cells to apoptosis. In vitro cleavage with purified caspases, caspase inhibitor rescue in cells, kinase activity assays of cleavage fragments, overexpression of truncated Akt constructs Journal of cellular physiology Medium 10623893
2008 Lipid raft nanodomains facilitate AKT/PKB recruitment and activation at the plasma membrane upon PI3K-generated PIP3 accumulation; specific inhibition of sphingolipid and cholesterol biosynthesis abolishes raft nanodomains and impairs AKT Ser473/Thr308 phosphorylation. Fluorescence correlation spectroscopy (FCS) in live cells, specific inhibition of sphingolipid and cholesterol biosynthesis, PIP3 measurement, phospho-AKT Western blotting Nature chemical biology Medium 18641634
2008 p53 stabilization in response to ionizing radiation requires AKT/PKB: DNA-PK is activated by ionizing radiation, phosphorylates and activates AKT/PKB, which in turn inactivates GSK-3; inactive GSK-3 fails to phosphorylate Mdm2 at sites required for p53 degradation, leading to p53 accumulation. Lymphoblasts from AT patients, ATR siRNA, AKT/PKB knockdown, DNA-PK knockdown, phospho-specific Western blotting of AKT, GSK-3, Mdm2, p53 accumulation assays Proceedings of the National Academy of Sciences Medium 18505846
2010 Inhibition of AKT/PKB in late G2 cells restores DNA double-strand break processing (RPA, ATR, Rad51, CtIP recruitment to damage foci) and Chk1 checkpoint activation after irradiation; normally, AKT activity in late G2 suppresses DSB processing and prevents checkpoint activation. Chemical genetic Cdk1 inhibition to arrest cells in late G2, AKT inhibitor treatment, immunofluorescence for DSB repair factors (RPA, ATR, Rad51, CtIP, γ-H2AX), Chk1 phosphorylation Western blot The Journal of cell biology Medium 20679434
2011 OX40 (CD134) assembles a signaling complex containing TRAF2, PI3K, and AKT/PKB upon ligation by OX40L; this complex forms in lipid microdomains independent of TCR engagement, but strong PI3K-AKT phosphorylation and functional activation only occur when antigen is also recognized, indicating OX40 augments TCR-induced AKT signaling quantitatively. Co-immunoprecipitation of OX40 complexes, detergent-resistant membrane fraction isolation, phospho-AKT Western blotting, TRAF2-deficient cells Journal of immunology Medium 21289304
2007 Pak1 (P21-activated kinase-1) directly phosphorylates AKT at Ser473 but not Thr308 in vitro; silencing or inactivating Pak1 reduces AKT Ser473 and Thr308 phosphorylation in cardiomyocytes, and Pak1 overexpression is cardioprotective in an AKT-dependent manner. In vitro kinase assay with purified Pak1 and AKT, Pak1 siRNA, dominant-negative Pak1, cardiomyocyte overexpression/knockdown, AKT inhibitor rescue Journal of molecular and cellular cardiology Medium 18054038
2019 AKT/PKB promotes nuclear import of HDAC4 upon muscle denervation, enabling epigenetic changes and synaptic gene upregulation required for neuromuscular endplate remodeling; mTORC1 activation must be tightly balanced to allow dynamic autophagy regulation in denervated muscle. Muscle-specific transgenic mice with constitutive mTORC1 activation or AKT inhibition, HDAC4 nuclear localization assays, autophagy flux assays, NMJ morphology analysis Nature communications Medium 31320633
2007 In mouse oocytes, Thr308-phosphorylated AKT localizes to pericentriolar materials while Ser473-phosphorylated AKT co-distributes with spindle microtubules; both are required for metaphase II spindle assembly. Ser473-phosphorylated AKT is specifically required for second polar body emission, while Thr308-phosphorylated AKT regulates microtubule organization during meiosis. Antibody injection into oocytes, immunofluorescence with phospho-specific antibodies, spindle morphology analysis, polar body emission assay Developmental biology Medium 18177853
2011 Inositol polyphosphate multikinase (IPMK) acts as a physiological PI3-kinase that generates PIP3 and activates AKT/PKB; IPMK deletion reduces growth factor-elicited AKT signaling uniquely through loss of its PI3K activity, and p110 PI3-kinases must act first to phosphorylate/activate IPMK in a sequential PIP3-generating cascade. IPMK knockout cells, in vitro PI3K activity assay, wortmannin inhibition, growth factor stimulation, AKT phosphorylation assays, cell proliferation assays Proceedings of the National Academy of Sciences Medium 21220345
2011 CK2-mediated phosphorylation of AKT at Ser129 is necessary for AKT-dependent upregulation of β-catenin transcriptional activity and nuclear localization; CK2α overexpression increased β-catenin activity and survivin expression, and these effects were abolished by expression of an AKT-S129A mutant. Overexpression of wild-type, constitutively active, and dominant-negative CK2 and AKT, AKT-S129A mutant, β-catenin transcriptional reporter, nuclear fractionation, survivin expression assay Journal of cellular physiology Medium 21506126
2000 In platelets activated through integrin αIIbβ3, PtdIns(3,4)P2 that activates AKT/PKB is generated primarily via a novel pathway: PI3K generates PtdIns3P, which is then phosphorylated by PtdIns3P 4-kinase — not by 5'-phosphatase hydrolysis of PtdIns(3,4,5)P3, which is not detected in this context. Wortmannin and calpain inhibitor both block this pathway and AKT activation. Lipid analysis (PtdIns3P, PtdIns(3,4)P2, PtdIns(3,4,5)P3 measurement), wortmannin/calpeptin inhibition, PKB kinase assay in human platelets, integrin activation by anti-LIBS Fab The Journal of biological chemistry Medium 9417038

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science (New York, N.Y.) 5546 15718470
2007 AKT/PKB signaling: navigating downstream. Cell 5001 17604717
2017 AKT/PKB Signaling: Navigating the Network. Cell 2942 28431241
2006 Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular cell 2226 16603397
1998 Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 2134 9778245
2005 The activation of Akt/PKB signaling pathway and cell survival. Journal of cellular and molecular medicine 1521 15784165
2004 Rho and Rac take center stage. Cell 1495 14744429
2001 PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? Journal of cell science 936 11686294
2012 PI3K-PKB/Akt pathway. Cold Spring Harbor perspectives in biology 867 22952397
1999 AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annual review of biochemistry 846 10872470
1998 CREB is a regulatory target for the protein kinase Akt/PKB. The Journal of biological chemistry 829 9829964
2002 PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nature medicine 784 12244302
1999 The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Experimental cell research 774 10579924
1999 Induction of NF-kappaB by the Akt/PKB kinase. Current biology : CB 730 10359702
2003 Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell cycle (Georgetown, Tex.) 707 12851486
2002 PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nature medicine 664 12244301
1997 PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends in biochemical sciences 624 9301337
2004 Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochimica et biophysica acta 579 15023346
1998 Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes & development 571 9716402
2006 mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Current biology : CB 553 16919458
2001 PKB/AKT: functional insights from genetic models. Nature reviews. Molecular cell biology 504 11584303
2002 PKB binding proteins. Getting in on the Akt. Cell 470 12419241
2005 The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 433 16288295
2001 Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 432 11532975
2004 Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. The Journal of biological chemistry 421 15262962
2007 Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature 401 17554339
2001 AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. The Journal of biological chemistry 400 11756412
1998 Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Current biology : CB 384 9799739
2005 Akt/PKB regulates actin organization and cell motility via Girdin/APE. Developmental cell 378 16139227
2005 PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 361 16007182
2003 Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. Journal of leukocyte biology 355 12773501
2001 The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene 333 11753656
2000 Peptide and protein library screening defines optimal substrate motifs for AKT/PKB. The Journal of biological chemistry 333 10945990
2004 PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nature cell biology 319 15048128
1999 Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nature cell biology 318 10587646
2009 Rac1 GTPase: a "Rac" of all trades. Cellular and molecular life sciences : CMLS 297 19151919
2006 Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes & development 292 17182864
2005 Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell death and differentiation 292 15818404
1999 Akt/PKB localisation and 3' phosphoinositide generation at sites of epithelial cell-matrix and cell-cell interaction. Current biology : CB 265 10226029
2017 AKT Inhibition in Solid Tumors With AKT1 Mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 257 28489509
2006 Akt1 in endothelial cell and angiogenesis. Cell cycle (Georgetown, Tex.) 247 16552185
2008 Raft nanodomains contribute to Akt/PKB plasma membrane recruitment and activation. Nature chemical biology 240 18641634
2014 Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes. Diabetes, metabolic syndrome and obesity : targets and therapy 236 24611020
2013 PKB/Akt-dependent regulation of cell motility. Journal of the National Cancer Institute 233 23355761
2010 The PKB/AKT pathway in cancer. Current pharmaceutical design 232 20214616
2008 Function of Akt/PKB signaling to cell motility, invasion and the tumor stroma in cancer. Cellular signalling 231 19110052
2007 Akt1 in osteoblasts and osteoclasts controls bone remodeling. PloS one 226 17957242
2004 Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM. The Journal of biological chemistry 223 15546863
2009 Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition. PLoS biology 217 19166270
2009 Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nature cell biology 215 19270694
2001 Protein kinase B (PKB/Akt)--a key regulator of glucose transport? FEBS letters 211 11257494
2010 Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. Current topics in microbiology and immunology 208 20517722
2007 PKB and the mitochondria: AKTing on apoptosis. Cellular signalling 193 17716864
2009 PIKKing on PKB: regulation of PKB activity by phosphorylation. Current opinion in cell biology 189 19303758
2002 Akt1 regulates a JNK scaffold during excitotoxic apoptosis. Neuron 179 12194869
2005 AKT/PKB signaling mechanisms in cancer and chemoresistance. Frontiers in bioscience : a journal and virtual library 166 15569636
2006 Cisplatin induces PKB/Akt activation and p38(MAPK) phosphorylation of the EGF receptor. Oncogene 161 16785992
2015 Akt/PKB: one kinase, many modifications. The Biochemical journal 151 25997832
2005 Regulation of Akt/PKB Ser473 phosphorylation. Molecular cell 148 15837416
2010 Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PloS one 137 20333297
2006 Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovascular research 130 16901477
2008 p53 stabilization in response to DNA damage requires Akt/PKB and DNA-PK. Proceedings of the National Academy of Sciences of the United States of America 129 18505846
2006 Akt/PKB signaling in cancer: a function in cell motility and invasion. Cell cycle (Georgetown, Tex.) 128 16582622
2006 Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. The Journal of biological chemistry 126 17012749
1999 Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB. The Journal of neuroscience : the official journal of the Society for Neuroscience 126 10377346
2005 The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation. Current topics in medicinal chemistry 122 15853641
1998 A novel integrin-activated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets. The Journal of biological chemistry 113 9417038
2015 Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092. PloS one 109 26469692
2003 Increase of AKT/PKB expression correlates with gleason pattern in human prostate cancer. International journal of cancer 107 14520710
2002 Activation of the PKB/AKT pathway by ICAM-2. Immunity 106 11825565
2011 Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB. Proceedings of the National Academy of Sciences of the United States of America 104 21220345
2005 A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. The Journal of biological chemistry 104 15753085
2003 Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. Biochimica et biophysica acta 100 14636947
2019 mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4. Nature communications 97 31320633
2004 Protein kinase Akt/PKB phosphorylates heme oxygenase-1 in vitro and in vivo. FEBS letters 97 15581622
2000 Cleavage and inactivation of antiapoptotic Akt/PKB by caspases during apoptosis. Journal of cellular physiology 96 10623893
2008 Decrease in Akt/PKB signalling in human skeletal muscle by resistance exercise. European journal of applied physiology 95 18535836
2017 PKB/Akt-dependent regulation of inflammation in cancer. Seminars in cancer biology 89 28476657
2006 Regulation of TopBP1 oligomerization by Akt/PKB for cell survival. The EMBO journal 88 17006541
2005 PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. Carcinogenesis 85 15845651
2006 Expression and localisation of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients. British journal of cancer 84 16721361
2011 OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling. Journal of immunology (Baltimore, Md. : 1950) 82 21289304
2003 Involvement of the Akt/PKB signaling pathway with disease processes. Molecular and cellular biochemistry 80 14619975
2000 A novel Akt/PKB-related kinase is essential for morphogenesis in Dictyostelium. Current biology : CB 79 10873800
1999 Differential roles of Akt, Rac, and Ral in R-Ras-mediated cellular transformation, adhesion, and survival. Molecular and cellular biology 76 10454580
2015 Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy. Journal of the National Cancer Institute 75 26071042
2007 Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. Journal of molecular and cellular cardiology 73 18054038
2011 Akt1 and Akt2: differentiating the aktion. Histology and histopathology 72 21432781
2010 PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiation. Oncogene 71 20956948
2003 Targeting of the Akt/PKB kinase to the actin skeleton. Cellular and molecular life sciences : CMLS 70 14685694
2008 Neuronal AKAP150 coordinates PKA and Epac-mediated PKB/Akt phosphorylation. Cellular signalling 68 18565730
2010 Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2. The Journal of cell biology 65 20679434
2004 Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells. Oncogene 65 15064712
2020 circRNA-AKT1 Sequesters miR-942-5p to Upregulate AKT1 and Promote Cervical Cancer Progression. Molecular therapy. Nucleic acids 63 32193155
2011 Phosphorylation of AKT/PKB by CK2 is necessary for the AKT-dependent up-regulation of β-catenin transcriptional activity. Journal of cellular physiology 63 21506126
2000 Akt1/PKB upregulation leads to vascular smooth muscle cell hypertrophy and polyploidization. The Journal of clinical investigation 63 11032861
2004 Lipoxins inhibit Akt/PKB activation and cell cycle progression in human mesangial cells. The American journal of pathology 62 14982847
2011 Promiscuous affairs of PKB/AKT isoforms in metabolism. Archives of physiology and biochemistry 59 21214427
2020 Targeting AKT/PKB to improve treatment outcomes for solid tumors. Mutation research 58 32120136
2007 Protein kinase B (PKB/Akt) is required for the completion of meiosis in mouse oocytes. Developmental biology 58 18177853

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