Affinage

AKT1S1

Proline-rich AKT1 substrate 1 · UniProt Q96B36

Length
256 aa
Mass
27.4 kDa
Annotated
2026-06-09
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AKT1S1 (PRAS40) is a raptor-binding inhibitory subunit of mTORC1 that couples growth-factor and nutrient signaling to control of protein synthesis, cell growth, and survival (PMID:17386266, PMID:17510057). PRAS40 binds raptor through a TOS motif (FVMDE) and acts as a substrate-competitive inhibitor, blocking access of mTORC1 substrates such as 4E-BP1; high-resolution structures show it occupies both substrate-recruitment sites of mTORC1, the raptor TOS-binding site and the FRB domain (PMID:17510057, PMID:29236692). Inhibition is relieved upon phosphorylation: insulin/growth-factor-activated Akt phosphorylates PRAS40 at Thr246, after which mTORC1 itself phosphorylates additional sites (Ser183/Ser221) in a hierarchical manner, driving PRAS40 dissociation from raptor and association with the cytosolic anchor 14-3-3, thereby activating mTORC1 toward S6K1 and 4E-BP1 (PMID:17386266, PMID:17277771, PMID:17604271, PMID:20138985). Beyond Akt, multiple kinases — PIM1, PKM2, MELK, and PGK1 — directly phosphorylate PRAS40 at Thr246 or adjacent sites to release it from raptor and activate mTORC1 independently of canonical hormone/Akt input, frequently in cancer contexts (PMID:19276681, PMID:26876154, PMID:31813279, PMID:35058442). PRAS40 also exerts mTORC1-independent functions: nuclear phospho-PRAS40 binds RPL11 to suppress the RPL11–HDM2–p53 nucleolar stress response (PMID:24704832), it couples protein synthesis to immunoproteasome β-subunit assembly (PMID:26876939), and Akt-Thr246 phosphorylation of PRAS40 is necessary and sufficient to drive exosome-mediated secretion (PMID:28674187). Genetic ablation studies establish PRAS40 as a brake on basal mTORC1 activity that modulates insulin sensitivity, glucose homeostasis, tissue hypertrophy, vascular inflammation, and survival in ischemic injury (PMID:25931147, PMID:20629086, PMID:31728028, PMID:24583056).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 High

    Established PRAS40 as a physiological inhibitor of mTORC1 whose inhibition is relieved by Akt phosphorylation, defining the core regulatory node linking insulin signaling to mTORC1 activity.

    Evidence Raptor co-IP, in vitro mTORC1 kinase reconstitution with Rheb1-GTP, and cell-based S6K1 assays with Akt phosphorylation

    PMID:17277771 PMID:17386266

    Open questions at the time
    • Did not resolve the structural basis of substrate-competitive inhibition
    • Relative contributions of individual phosphosites not fully separated
  2. 2007 High

    Defined the molecular mechanism of inhibition: PRAS40 uses a TOS motif to bind raptor and competitively block substrate recruitment, while 14-3-3 binding upon phosphorylation provides the off-switch.

    Evidence TOS-motif mutagenesis, competitive binding assays with 4E-BP1/raptor, in vitro kinase assays, and 14-3-3 co-IP regulated by TSC1/2 and Rheb

    PMID:17510057 PMID:17604271 PMID:18030348

    Open questions at the time
    • Stoichiometry of PRAS40 within mTORC1 not defined
    • mTORC1-independent apoptotic role mechanistically unexplained
  3. 2010 High

    Resolved the order of phosphorylation events, showing Akt Thr246 phosphorylation is the priming step required for subsequent mTORC1-mediated Ser183 phosphorylation and 14-3-3 binding.

    Evidence T246A site-directed mutagenesis with rapamycin/wortmannin/palmitate treatment across cell lines, rat tissues, and human skeletal muscle insulin clamp

    PMID:20138985

    Open questions at the time
    • Functional consequence of each phosphosite for downstream substrates not individually mapped
  4. 2017 High

    Provided the definitive structural mechanism, showing PRAS40 blocks both the raptor TOS site and the FRB substrate site of mTORC1.

    Evidence 3.0 Å cryo-EM of mTORC1 and crystal structures of raptor-TOS and mTOR FRB-substrate complexes with biochemical validation

    PMID:29236692

    Open questions at the time
    • Conformational changes upon phosphorylation-driven dissociation not captured
    • Structure of phospho-PRAS40–14-3-3 complex not determined
  5. 2009 High

    Demonstrated that PRAS40 phosphorylation and mTORC1 activation are not exclusive to Akt, opening the concept of multiple input kinases converging on Thr246.

    Evidence In vitro kinase assay with PIM1, wortmannin (Akt-independence), and PIM1 inhibitor controls

    PMID:19276681

    Open questions at the time
    • Physiological contexts where PIM1 dominates over Akt not delineated
  6. 2016 High

    Expanded the kinase repertoire and revealed metabolism-driven, hormone-independent mTORC1 activation via PKM2 phosphorylation of PRAS40, and uncovered an immunoproteasome-biogenesis function.

    Evidence Phosphoproteomics, in vitro kinase assays, S202/203 mutagenesis, and immunoproteasome assembly assays across RAS/PTEN/TSC1 mutant cells

    PMID:26876154 PMID:26876939

    Open questions at the time
    • Integration of PKM2-driven signaling with canonical Akt input unclear
    • Mechanism coupling PRAS40 to β-subunit assembly not structurally defined
  7. 2014 High

    Identified mTORC1-independent nuclear functions of PRAS40, linking it to the RPL11–HDM2–p53 stress response.

    Evidence Nuclear fractionation, RPL11 co-IP, T246A rescue, and p53/senescence assays

    PMID:24704832

    Open questions at the time
    • Nuclear import/retention mechanism of phospho-PRAS40 unknown
    • Direct versus indirect effect on HDM2 not resolved
  8. 2017 High

    Established that Akt-Thr246 phosphorylation of PRAS40 drives exosome secretion as a discrete output downstream of TGF-α signaling.

    Evidence siRNA knockdown, dominant-negative and T246 mutants, gene rescue, and exosome secretion assays in multiple cell types

    PMID:28674187

    Open questions at the time
    • Molecular machinery linking phospho-PRAS40 to exosome biogenesis not identified
    • Selectivity for TGF-α over EGF mechanistically unexplained
  9. 2019 Medium

    Genetic and tissue-specific loss-of-function studies confirmed PRAS40 as an in vivo brake on basal mTORC1 controlling insulin sensitivity, vascular inflammation, and tissue remodeling, with additional Akt-independent inputs (PDK1/leucine).

    Evidence PRAS40 knockout and endothelium-specific knockout mice, PDK1 L155E knock-in, glucose tolerance and atherogenic remodeling models, and hypertrophy assays

    PMID:20051528 PMID:20629086 PMID:24583056 PMID:25931147 PMID:31728028

    Open questions at the time
    • Tissue-specific weighting of mTORC1-dependent versus -independent effects unresolved
    • Whether IRS1 stabilization is direct not established
  10. 2022 Medium

    Extended the kinase network to MELK and PGK1, linking PRAS40 phosphorylation to autophagy suppression and cancer progression.

    Evidence PGK1-PRAS40 and MELK co-IP, in vitro kinase assays, raptor-disruption assays, and in vivo proliferation/autophagy tracing

    PMID:31813279 PMID:35058442

    Open questions at the time
    • Site specificity of MELK phosphorylation not mapped
    • Switch between PGK1 binding PRAS40 versus Beclin1 mechanistically incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse upstream kinases and the multiple PRAS40 phosphosites are integrated to dictate the choice between mTORC1 regulation, nuclear p53 control, immunoproteasome assembly, and exosome secretion remains unresolved.
  • No unified model distinguishing which output a given phospho-state selects
  • Spatial control (nuclear versus cytoplasmic) of phospho-PRAS40 not mechanistically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 2
Partners
AKT1MTORPGK1PIM1PKM2RPL11RPTORYWHAE
Complex memberships
mTORC1

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 PRAS40 binds to raptor (a component of mTORC1) in insulin-deprived cells, and this interaction inhibits mTORC1 kinase activity. In vitro, PRAS40 prevents the increase in mTORC1 kinase activity induced by Rheb1-GTP. Insulin stimulates Akt/PKB-mediated phosphorylation of PRAS40, which disrupts its inhibition of mTORC1 both in cells and in vitro. Raptor co-immunoprecipitation, in vitro mTORC1 kinase assay, cell-based S6K1 phosphorylation assays, overexpression and knockdown experiments Molecular cell High 17386266
2007 PRAS40 binds the mTOR kinase domain and its interaction with mTOR is induced under conditions that inhibit mTOR signaling (nutrient/serum deprivation, mitochondrial metabolic inhibition). PRAS40 phosphorylation by Akt and association with the cytosolic anchor 14-3-3 are required for insulin to stimulate mTOR. PRAS40 silencing inactivates IRS-1 and Akt and uncouples mTOR response to Akt signals. Co-immunoprecipitation, siRNA knockdown, phosphorylation assays, binding studies with 14-3-3 Nature cell biology High 17277771
2007 PRAS40 contains a TOS (TOR signaling) motif (FVMDE) required for interaction with raptor. PRAS40 inhibits mTORC1 kinase activity in vivo and in vitro by functioning as a direct competitive inhibitor of substrate (4E-BP1) binding to raptor. Insulin stimulation markedly decreases PRAS40 bound to mTORC1. Mutagenesis of TOS motif, in vitro mTORC1 kinase assay, shRNA knockdown, competitive binding assays with 4E-BP1 and raptor The Journal of biological chemistry High 17510057
2007 PRAS40 is a substrate for phosphorylation by mTORC1 itself (in addition to Akt). PRAS40 interacts with raptor via its TOS motif, and requires amino acids and insulin for 14-3-3 binding. Binding of PRAS40 to 14-3-3 is inhibited by TSC1/2 and stimulated by Rheb in a rapamycin-sensitive manner. PRAS40 knockdown impairs amino acid- and insulin-stimulated phosphorylation of 4E-BP1 and S6, placing PRAS40 downstream of mTORC1 but upstream of S6K1 and 4E-BP1. siRNA knockdown, rapamycin treatment, amino acid deprivation, co-immunoprecipitation with 14-3-3, phosphorylation assays The Journal of biological chemistry High 17604271
2007 PRAS40 binds mTORC1 via raptor, is an mTOR phosphorylation substrate, and inhibits mTORC1 autophosphorylation and mTORC1 kinase activity toward 4E-BP1. PRAS40 knockdown in HeLa cells protects against TNFα/cycloheximide-induced apoptosis, and this protection is not mimicked by rapamycin, indicating PRAS40 mediates apoptosis independently of its mTORC1 inhibitory function. 2D LC-MS/MS proteomic identification, co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, apoptosis assays PloS one High 18030348
2017 Cryo-EM structure of mTORC1 and crystal structure of a truncated mTOR–PRAS40 complex reveal that PRAS40 inhibits both substrate-recruitment sites on mTORC1 (the RAPTOR-TOS motif binding site and the FRB domain site), explaining its substrate-competitive mechanism of mTORC1 inhibition. 3.0 Å cryo-EM structure of mTORC1, crystal structures of RAPTOR-TOS motif complexes and mTOR FRB-substrate complex, biochemical validation Nature High 29236692
2009 PIM1 protein kinase directly phosphorylates PRAS40 at Thr246 in vitro (an Akt phosphorylation site), independently of Akt activation. PIM1 overexpression reduces PRAS40 association with mTOR and increases mTOR-directed phosphorylation of 4EBP1 and p70S6K. In vitro kinase assay, co-immunoprecipitation, wortmannin treatment (Akt-independence), PIM1 inhibitor treatment, overexpression Cancer biology & therapy High 19276681
2016 Pyruvate kinase M2 (PKM2) phosphorylates PRAS40 at Ser202/203, releasing PRAS40 from raptor and facilitating its binding to 14-3-3, resulting in hormone- and nutrient-signal-independent activation of mTORC1 in cancer cells. Quantitative phosphoproteomics, in vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (S202/203), TEPP-46 pharmacological treatment, overexpression/knockdown Scientific reports High 26876154
2010 Efficient phosphorylation of PRAS40 at Ser183 by mTORC1 requires prior phosphorylation of PRAS40 at Thr246 by PKB/Akt. Substitution of Thr246 with Ala alone is sufficient to abolish 14-3-3 binding under intact mTORC1 signaling conditions, indicating a hierarchical phosphorylation mechanism. Site-directed mutagenesis (T246A), rapamycin/wortmannin/palmitate treatment, insulin clamp in human skeletal muscle, Western blot in multiple cell lines and rat tissues Cellular signalling High 20138985
2014 Akt- and mTORC1-mediated phosphorylation of PRAS40 at T246 and S221 respectively promotes nuclear-specific association of PRAS40 with ribosomal protein L11 (RPL11). PRAS40 negatively regulates the RPL11-HDM2-p53 nucleolar stress response pathway; PRAS40 silencing induces p53 upregulation dependent on RPL11, and a T246A mutant incapable of RPL11 binding cannot rescue this effect. Co-immunoprecipitation, PRAS40 silencing, T246A mutagenesis, p53 and senescence assays, nuclear fractionation Oncogene High 24704832
2016 mTORC1 sequesters precursors of immunoproteasome β subunits via PRAS40. When mTORC1 is activated, it phosphorylates PRAS40 to simultaneously enhance protein synthesis and facilitate assembly of immunoproteasome β subunits, coupling elevated protein synthesis with immunoproteasome biogenesis to clear aberrant proteins. Co-immunoprecipitation, phosphorylation assays, immunoproteasome assembly assays, genetic mTORC1/PRAS40 manipulation, RAS/PTEN/TSC1 mutation cell lines Molecular cell High 26876939
2017 PRAS40 is a unique downstream effector of TGF-α (but not EGF) signaling via Thr308-phosphorylated Akt. Akt-mediated phosphorylation of PRAS40 at Thr246 is both necessary and sufficient to trigger exosome-mediated secretion. PRAS40 knockdown or dominant-negative mutant blocks TGF-α-, hypoxia-, and H2O2-induced exosome secretion without affecting the ER/Golgi pathway. PRAS40 siRNA knockdown, dominant-negative mutant overexpression, T246 site-directed mutagenesis, gene rescue, exosome secretion assays in multiple cell types Molecular and cellular biology High 28674187
2007 Phosphorylated PRAS40 binds the cytosolic docking protein 14-3-3, and this interaction is regulated by the PI3K/Akt pathway. In spinal cord injury models, increased pPRAS40 via PRAS40 transfection promotes motor neuron survival; co-immunoprecipitation shows that pPRAS40–14-3-3 binding increases after injury and is dependent on the PI3K/Akt pathway. Liposome-mediated PRAS40 transfection, co-immunoprecipitation, PI3K/Akt inhibitor (LY294002, Akt inhibitor IV), immunohistochemistry, Western blot in SOD1 transgenic rats Journal of cerebral blood flow and metabolism Medium 17457363
2007 PRAS40 is an Akt3 substrate in melanoma. Phospho-PRAS40 levels parallel Akt3 activity during melanoma tumor progression. Targeting PRAS40 (via siRNA) or upstream Akt3 similarly reduces anchorage-independent growth and tumor development, and decreasing pPRAS40 increases tumor cell apoptosis and chemosensitivity. siRNA knockdown of PRAS40 and Akt3, anchorage-independent growth assays, mouse tumor xenograft experiments, apoptosis assays, Western blot Cancer research Medium 17440074
2011 In radioresistant NSCLC cells, nuclear PIM1 phosphorylates PRAS40, and phospho-PRAS40 forms a trimeric complex with 14-3-3 and Akt-activated phospho-FOXO3a, driving cytoplasmic retention of FOXO3a, downregulation of proapoptotic genes, and radioresistance. Protein phosphatases PP2A and PP5 negatively regulate this pathway. Co-immunoprecipitation (trimeric complex), nuclear fractionation, irradiation assays, PIM1 overexpression, PP2A/PP5 knockdown, apoptotic gene expression Radiation research Medium 21910584
2010 In response to leucine (but not insulin), PDK1 is required for PRAS40 phosphorylation and subsequent mTOR/p70S6K activation in the heart. A PDK1 L155E mutation that preserves insulin/Akt-dependent mTOR signaling abolishes leucine-induced PRAS40 phosphorylation, indicating a distinct PDK1-dependent, Akt-independent mechanism for leucine to activate mTORC1 via PRAS40. PDK1 knockout mice, PDK1 L155E knock-in mutation, in vitro kinase assay, phosphorylation assays in cardiac tissue American journal of physiology. Endocrinology and metabolism Medium 20051528
2010 High glucose increases PRAS40 phosphorylation at Thr246 via PI3K/Akt, dissociating PRAS40 from the raptor-PRAS40 complex, thereby activating mTORC1 and promoting mesangial cell hypertrophy. A phosphorylation-deficient PRAS40 mutant (in contrast to PRAS40 knockdown) inhibits 4EBP-1 and S6K phosphorylation and reduces hypertrophy, identifying PRAS40 phosphorylation as the mechanistic node. PI3K/Akt inhibitors, co-immunoprecipitation of raptor-PRAS40, phosphorylation-deficient PRAS40 mutant, PRAS40 siRNA, protein synthesis and hypertrophy assays Journal of cellular physiology Medium 20629086
2012 EWS (Ewing sarcoma protein) negatively regulates PRAS40 expression by binding the 3' UTR of PRAS40 mRNA. Loss of EWS leads to elevated PRAS40, which promotes Ewing sarcoma cell proliferation and metastatic growth; PRAS40 knockdown reverses the proliferative effect of EWS knockdown. RNA binding assay (EWS-3'UTR interaction), siRNA knockdown of PRAS40 and EWS, cell proliferation assays, metastatic growth assays, Western blot Cancer research Medium 22241085
2019 PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. PRAS40 knockdown in endothelial cells promotes TNFα-induced mTORC1 signaling and inflammatory marker upregulation, while PRAS40 overexpression blocks these. In vivo, endothelium-specific PRAS40 deficiency enhances neointimal hyperplasia and atherosclerotic lesion formation. PRAS40 siRNA knockdown, overexpression, endothelium-specific PRAS40 knockout mice, phosphorylation assays, monocyte recruitment assays, in vivo atherogenic remodeling model Scientific reports Medium 31728028
2022 Phosphoglycerate kinase 1 (PGK1) binds PRAS40 and phosphorylates it at Thr246 under normoxia, suppressing autophagy-mediated cell death and promoting liver cancer cell proliferation. Under hypoxia, PGK1 binding switches from PRAS40 to Beclin1, increasing Beclin1 phosphorylation and autophagy induction. Co-immunoprecipitation (PGK1-PRAS40 interaction), in vitro kinase assay, site-directed blocking of interaction, in vitro and in vivo proliferation assays, autophagy tracing Cell death & disease Medium 35058442
2019 MELK kinase phosphorylates PRAS40, disrupting the interaction between PRAS40 and raptor and thereby over-activating mTORC1 signaling to promote clear cell renal cell carcinoma progression. Co-immunoprecipitation (PRAS40-raptor), MELK overexpression and knockdown, phosphorylation assays, cell proliferation and invasion assays Cell transplantation Medium 31813279
2014 PRAS40 gene transfer in rats reduces cerebral infarction size by promoting phosphorylation of Akt, FOXO1, PRAS40, and mTOR. PRAS40 knockout increases infarction size and reduces p-S6K and p-S6 in the mTOR pathway after stroke; co-immunoprecipitation shows less Akt-mTOR interaction in PRAS40 KO, identifying PRAS40 as a physical bridge linking Akt and mTOR signaling in the context of ischemia. Lentiviral PRAS40 overexpression, PRAS40 knockout mice, cerebral ischemia model, co-immunoprecipitation (Akt-mTOR), Western blot Neurobiology of disease Medium 24583056
2015 Genetic ablation of PRAS40 in mice results in increased hepatic Akt (T308) and mTORC1 (p-p70S6K) signaling, altered hepatic GLUT4 levels, and improved glucose homeostasis, demonstrating that PRAS40 limits basal mTORC1 activity and insulin sensitivity in vivo. PRAS40 knockout mice, streptozotocin-induced diabetes model, glucose tolerance tests, Western blot, shPRAS40 Hep3B cells Biochemical pharmacology Medium 25931147
2014 Over-expression of wild-type PRAS40 (but not AAA-PRAS40 mutant with mutated phosphorylation and mTORC1-binding sites) impairs insulin-mediated mTORC1 pathway activation but increases Akt phosphorylation and insulin sensitivity in skeletal muscle cells, identifying a role for PRAS40 in regulating insulin sensitivity through IRS1 stabilization and proteasome inhibition, independent of its mTORC1-binding function. WT-PRAS40 and AAA-PRAS40 overexpression in human skeletal muscle cells and mouse skeletal muscle, phosphorylation assays, proteasome activity assay, IRS1 protein levels Archives of physiology and biochemistry Medium 24576065
2005 PRAS40 is phosphorylated via the PI3K/Akt pathway (inhibited by wortmannin and LY294002 but not rapamycin); 14-3-3 is identified as a PRAS40 binding protein. PRAS40 constitutive phosphorylation activity is higher in pre-malignant and malignant cancer cell lines compared to normal cells. Kinase inhibitor treatment (wortmannin, LY294002, rapamycin, UO126), Western blot, co-immunoprecipitation with 14-3-3 Acta pharmacologica Sinica Low 16174443
2019 AKT3 (but not AKT1 or AKT2) is the specific Akt isoform mediating M2-tumor-associated macrophage-induced phosphorylation of PRAS40 (Thr246) in intrahepatic cholangiocarcinoma cells, leading to EMT activation. AKT3 silencing specifically inhibits p-AKT and p-PRAS40 under M2-TAM co-culture conditions. AKT isoform-specific siRNA knockdown (AKT1, AKT2, AKT3), co-culture assays, phosphorylation assays (p-AKT Ser473, p-PRAS40 Thr246), EMT invasion assays Journal of cellular biochemistry Low 31692069

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Molecular cell 1010 17386266
2007 Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nature cell biology 949 17277771
2002 Frontal lobe and cognitive development. Journal of neurocytology 541 12815254
2005 Genetic and functional subdivision of the Drosophila antennal lobe. Current biology : CB 481 16139209
2017 Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 443 29236692
1984 Temporal lobe volumetric cell densities in temporal lobe epilepsy. Epilepsia 411 6510381
2007 PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. The Journal of biological chemistry 384 17510057
2009 Mitochondria, oxidative stress, and temporal lobe epilepsy. Epilepsy research 261 19850449
2007 PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PloS one 221 18030348
2007 PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. The Journal of biological chemistry 211 17604271
2006 Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain : a journal of neurology 210 17020904
2007 Complement activation in experimental and human temporal lobe epilepsy. Neurobiology of disease 183 17412602
2022 METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis. Molecular cancer 168 35164771
2012 Role of PRAS40 in Akt and mTOR signaling in health and disease. American journal of physiology. Endocrinology and metabolism 152 22354785
1994 Neuroanatomy of fragile X syndrome: the temporal lobe. Neurology 148 8035938
1992 "No longer Gage": frontal lobe dysfunction and emotional changes. Journal of consulting and clinical psychology 145 1619089
1999 GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy. Neurochemistry international 135 10397372
2011 Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway. Cellular signalling 123 21906675
2009 PIM1 protein kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells. Cancer biology & therapy 117 19276681
2016 Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1. Scientific reports 112 26876154
2013 P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PloS one 111 23565201
2007 PRAS40 deregulates apoptosis in malignant melanoma. Cancer research 105 17440074
2020 A disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy. Nature communications 93 32066723
2015 Crucial role of astrocytes in temporal lobe epilepsy. Neuroscience 91 25592426
2009 Mitochondrial involvement in temporal lobe epilepsy. Experimental neurology 91 19268667
1999 Expression of the glutamate transporters in human temporal lobe epilepsy. Neuroscience 90 10336123
2017 Short parietal lobe connections of the human and monkey brain. Cortex; a journal devoted to the study of the nervous system and behavior 84 29157936
2002 Pheromonal and host-odor processing in the insect antennal lobe: how different? Current opinion in neurobiology 79 12139986
2010 Phosphorylation of PRAS40 on Thr246 by PKB/AKT facilitates efficient phosphorylation of Ser183 by mTORC1. Cellular signalling 77 20138985
2006 The role of synaptic reorganization in mesial temporal lobe epilepsy. Epilepsy & behavior : E&B 72 16500154
2007 Cholinergic dysfunction in temporal lobe epilepsy. Epilepsia 70 17910592
2014 PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways. Neurobiology of disease 69 24583056
2022 Inhibition of connexin hemichannels alleviates neuroinflammation and hyperexcitability in temporal lobe epilepsy. Proceedings of the National Academy of Sciences of the United States of America 68 36322757
2012 PRAS40 is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection. PloS one 65 23029019
2012 Wnt1 inducible signaling pathway protein 1 (WISP1) targets PRAS40 to govern β-amyloid apoptotic injury of microglia. Current neurovascular research 57 22873724
2016 mTORC1 Coordinates Protein Synthesis and Immunoproteasome Formation via PRAS40 to Prevent Accumulation of Protein Stress. Molecular cell 56 26876939
2011 PIM1-activated PRAS40 regulates radioresistance in non-small cell lung cancer cells through interplay with FOXO3a, 14-3-3 and protein phosphatases. Radiation research 54 21910584
2017 PRAS40 signaling in tumor. Oncotarget 52 28978182
2006 Lobe and Serrate are required for cell survival during early eye development in Drosophila. Development (Cambridge, England) 52 17090721
2000 From nocturnal paroxysmal dystonia to nocturnal frontal lobe epilepsy. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 52 10996549
1997 The medial temporal lobe in schizophrenia. The Journal of neuropsychiatry and clinical neurosciences 52 9276847
2019 M2-polarized tumor-associated macrophages promote epithelial-mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma. Journal of cellular biochemistry 51 31692069
2014 Automated quantitative multiplex immunofluorescence in situ imaging identifies phospho-S6 and phospho-PRAS40 as predictive protein biomarkers for prostate cancer lethality. Proteome science 50 25075204
2010 Alcohol and PRAS40 knockdown decrease mTOR activity and protein synthesis via AMPK signaling and changes in mTORC1 interaction. Journal of cellular biochemistry 49 20127721
2019 Lobe specificity of iron binding to transferrin modulates murine erythropoiesis and iron homeostasis. Blood 47 31434707
2006 Nocturnal frontal lobe epilepsy. Epilepsia 47 17105470
2014 Nuclear PRAS40 couples the Akt/mTORC1 signaling axis to the RPL11-HDM2-p53 nucleolar stress response pathway. Oncogene 46 24704832
2010 Activation of the cardiac mTOR/p70(S6K) pathway by leucine requires PDK1 and correlates with PRAS40 phosphorylation. American journal of physiology. Endocrinology and metabolism 44 20051528
2010 PRAS40 acts as a nodal regulator of high glucose-induced TORC1 activation in glomerular mesangial cell hypertrophy. Journal of cellular physiology 44 20629086
2012 GABAA receptor modulation by neurosteroids in models of temporal lobe epilepsies. Epilepsia 43 23216582
2010 Leukocyte nucleus segmentation and nucleus lobe counting. BMC bioinformatics 42 21073711
2005 Expression of proline-rich Akt-substrate PRAS40 in cell survival pathway and carcinogenesis. Acta pharmacologica Sinica 42 16174443
2009 Lateral temporal lobe epilepsies: clinical and genetic features. Epilepsia 40 19469848
2008 Optic lobe development. Advances in experimental medicine and biology 39 18683642
2022 Characterisation of NLRP3 pathway-related neuroinflammation in temporal lobe epilepsy. PloS one 38 35972937
2013 MRI parcellation of ex vivo medial temporal lobe. NeuroImage 38 23702414
2011 High glucose upregulation of early-onset Parkinson's disease protein DJ-1 integrates the PRAS40/TORC1 axis to mesangial cell hypertrophy. Cellular signalling 38 21426932
2018 Doublecortin-expressing cell types in temporal lobe epilepsy. Acta neuropathologica communications 36 30005693
2010 PRAS40 regulates protein synthesis and cell cycle in C2C12 myoblasts. Molecular medicine (Cambridge, Mass.) 36 20464060
2005 Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene. Annals of neurology 36 16222669
2023 The neurovasculature as a target in temporal lobe epilepsy. Brain pathology (Zurich, Switzerland) 35 36599709
1996 Hippocampal pathology and pathophysiology in temporal lobe epilepsy. Neurologia (Barcelona, Spain) 35 9019099
2013 Altered Kir and gap junction channels in temporal lobe epilepsy. Neurochemistry international 34 23357483
1995 Hippocampal MRI volumetrics and temporal lobe substrates in medial temporal lobe epilepsy. Magnetic resonance imaging 34 8750318
2022 PGK1 represses autophagy-mediated cell death to promote the proliferation of liver cancer cells by phosphorylating PRAS40. Cell death & disease 33 35058442
2017 PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated Secretion. Molecular and cellular biology 33 28674187
2016 Organization and control of epileptic circuits in temporal lobe epilepsy. Progress in brain research 33 27323941
2015 Proline-rich AKT substrate of 40-kDa (PRAS40) in the pathophysiology of cancer. Biochemical and biophysical research communications 33 26003731
2011 Progress in cell grafting therapy for temporal lobe epilepsy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 33 21892793
2014 Adenosine kinase, glutamine synthetase and EAAT2 as gene therapy targets for temporal lobe epilepsy. Gene therapy 32 25231174
2001 Abnormal neurochemical asymmetry in the temporal lobe of schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry 32 11383982
2009 PRAS40: target or modulator of mTORC1 signalling and insulin action? Archives of physiology and biochemistry 30 19480563
1996 Memory, memory impairment, and the medial temporal lobe. Cold Spring Harbor symposia on quantitative biology 30 9246447
2021 Targeting PRAS40: a novel therapeutic strategy for human diseases. Journal of drug targeting 28 33504218
2012 Frontal lobe ataxia. Handbook of clinical neurology 28 21827922
2012 PRAS40 is a functionally critical target for EWS repression in Ewing sarcoma. Cancer research 28 22241085
1992 Neurotransmitters and their receptors in human temporal lobe epilepsy. Epilepsy research. Supplement 28 1361331
2022 Human RIPK3 C-lobe phosphorylation is essential for necroptotic signaling. Cell death & disease 27 35739084
2021 Differential glutamate receptor expression and function in the hippocampus, anterior temporal lobe and neocortex in a pilocarpine model of temporal lobe epilepsy. Experimental neurology 27 34752784
2018 Down-regulation of Rictor enhances cell sensitivity to PI3K inhibitor LY294002 by blocking mTORC2-medicated phosphorylation of Akt/PRAS40 in esophageal squamous cell carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 30119206
2016 MYO6 knockdown inhibits the growth and induces the apoptosis of prostate cancer cells by decreasing the phosphorylation of ERK1/2 and PRAS40. Oncology reports 27 27431378
2014 Decreased astroglial monocarboxylate transporter 4 expression in temporal lobe epilepsy. Molecular neurobiology 26 24464262
2024 Mitochondrial Dysfunction of Astrocytes Mediates Lipid Accumulation in Temporal Lobe Epilepsy. Aging and disease 25 37450928
2022 Frontal lobe seizures: overview and update. Journal of neurology 25 35006387
2015 Galanin pathogenic mutations in temporal lobe epilepsy. Human molecular genetics 25 25691535
2015 Genetic ablation of PRAS40 improves glucose homeostasis via linking the AKT and mTOR pathways. Biochemical pharmacology 25 25931147
2007 Increased expression of a proline-rich Akt substrate (PRAS40) in human copper/zinc-superoxide dismutase transgenic rats protects motor neurons from death after spinal cord injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 25 17457363
2019 Molecular alterations in the medial temporal lobe in schizophrenia. Schizophrenia research 24 31227207
2012 bantam is required for optic lobe development and glial cell proliferation. PloS one 24 22412948
2023 MicroRNAs as potential biomarkers in temporal lobe epilepsy and mesial temporal lobe epilepsy. Neural regeneration research 22 36204827
2020 Long Noncoding RNA LINC01134 Promotes Hepatocellular Carcinoma Metastasis via Activating AKT1S1 and NF-κB Signaling. Frontiers in cell and developmental biology 21 32656205
2019 PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells. Scientific reports 21 31728028
2013 Differences between RNA and DNA due to RNA editing in temporal lobe epilepsy. Neurobiology of disease 21 23607937
2012 Nocturnal frontal lobe epilepsy and the acetylcholine receptor. The neurologist 21 23114665
2019 MELK is Upregulated in Advanced Clear Cell Renal Cell Carcinoma and Promotes Disease Progression by Phosphorylating PRAS40. Cell transplantation 20 31813279
2016 Targeting PRAS40 for multiple diseases. Drug discovery today 20 27086010
2015 Neuroprotective agents and modulation of temporal lobe epilepsy. Frontiers in bioscience (Elite edition) 20 25553365
2014 Over-expression of PRAS40 enhances insulin sensitivity in skeletal muscle. Archives of physiology and biochemistry 20 24576065
2014 p19Ink4d is a tumor suppressor and controls pituitary anterior lobe cell proliferation. Molecular and cellular biology 20 24687853
2019 Bloom Syndrome Protein Activates AKT and PRAS40 in Prostate Cancer Cells. Oxidative medicine and cellular longevity 19 31210839

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