Affinage

TBC1D4

TBC1 domain family member 4 · UniProt O60343

Length
1298 aa
Mass
146.6 kDa
Annotated
2026-04-28
100 papers in source corpus 49 papers cited in narrative 49 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBC1D4 (AS160) is a Rab-GTPase-activating protein that serves as a central phosphorylation-dependent switch integrating insulin, AMPK, and other kinase signals to control vesicle trafficking of GLUT4 and additional cargo proteins. In its basal, unphosphorylated state, TBC1D4 localizes to GLUT4 storage vesicles (GSVs) via its second PTB domain binding to IRAP, where its GAP activity maintains Rab10, Rab8A, and Rab14 in GDP-bound states to block GSV docking and fusion at the plasma membrane; Akt2-mediated phosphorylation (principally at Thr642 and Ser588) triggers 14-3-3 protein binding, displaces TBC1D4 from GSVs without altering intrinsic GAP catalytic activity, and thereby derepresses Rab-dependent GLUT4 exocytosis, while AMPK phosphorylation at Ser711 is specifically required for the post-exercise enhancement of insulin-stimulated glucose uptake (PMID:15971998, PMID:16154996, PMID:16880201, PMID:33872597, PMID:37074686, PMID:21195350). Beyond GLUT4, TBC1D4 employs the same phosphorylation-dependent RabGAP mechanism to regulate trafficking of CD36 (via Rab8a in cardiomyocytes), ENaC (via SGK1/14-3-3 in kidney), AQP2 in collecting duct cells, and Na⁺/K⁺-ATPase, and its GAP activity is also required to maintain GLUT4 protein levels by preventing lysosomal degradation (PMID:22315395, PMID:20410134, PMID:21511697, PMID:20943949, PMID:27554475). Loss-of-function mutations in human TBC1D4 cause tissue-specific muscle insulin resistance and postprandial hyperglycemia, as demonstrated by a high-frequency nonsense variant (p.Arg684Ter) in Greenlandic Inuit and a dominant-negative truncation (R363X) in other populations (PMID:25043022, PMID:19470471).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 High

    Establishing that AS160 acts specifically on the exocytic limb of GLUT4 trafficking resolved where in the pathway a phospho-regulated brake operates, showing that AS160 blocks a pre-fusion step of vesicle delivery to the plasma membrane.

    Evidence Dominant-negative AS160 overexpression with quantitative exocytosis/endocytosis assays in adipocytes

    PMID:15254270

    Open questions at the time
    • Exact identity of the Rab target(s) was not yet known
    • Whether the block was at tethering, docking, or priming was unresolved
  2. 2005 High

    Identification of the Rab substrates (Rab2A, 8A, 10, 14) and demonstration that GAP catalytic activity (requiring the conserved arginine) is essential for basal GLUT4 retention established TBC1D4 as a bona fide RabGAP gating GLUT4 vesicle release.

    Evidence In vitro GAP assays with recombinant domain, R→K mutagenesis, shRNA knockdown with WT vs. GAP-dead rescue in adipocytes

    PMID:15971998 PMID:16213228

    Open questions at the time
    • Relative importance of individual Rab substrates in different tissues not resolved
    • How AS160 is recruited to GLUT4 vesicles was unknown
  3. 2006 High

    Multiple convergent studies established how AS160 is recruited to GSVs and how phosphorylation inactivates it: AS160 binds IRAP on GSVs via its second PTB domain; Akt2 phosphorylation (especially Thr642) recruits 14-3-3 proteins, and this 14-3-3 binding is both necessary and sufficient for GLUT4 translocation; phosphorylation-deficient AS160 blocks both insulin- and contraction-stimulated glucose uptake through its GAP activity.

    Evidence Co-IP/domain mapping of AS160–IRAP interaction, 14-3-3 identification by LC-MS/MS with constitutive 14-3-3-binding rescue of 4P mutant, in vivo muscle electroporation with double-mutant epistasis (4P + GAP-dead), Akt2-KO and AMPK-transgenic mice

    PMID:16762977 PMID:16804075 PMID:16804077 PMID:16880201 PMID:16935857

    Open questions at the time
    • Whether phosphorylation alters intrinsic GAP activity or only membrane association was unclear
    • Specific Rab downstream of AS160 in muscle vs. adipocytes not defined
  4. 2007 High

    Epistasis experiments identified Rab10 as the key downstream target of AS160 in adipocytes and Rab8A/Rab14 in muscle cells, resolving tissue-specific Rab utilization; mapping of phosphorylation by multiple kinases (Akt, RSK1, SGK1, AMPK) revealed a complex multi-kinase input code converging on AS160.

    Evidence Rab10 double-knockdown with AS160 KD, constitutively active Rab8A/14 rescue of 4P-AS160 in L6 myotubes, systematic in vitro kinase assays with mutagenesis and MS phosphosite mapping

    PMID:17208202 PMID:17403373 PMID:17617058

    Open questions at the time
    • Whether Rab10 is the sole relevant substrate in adipocytes (partial rescue) remained open
    • Calmodulin-binding domain function was not yet understood
  5. 2007 High

    Discovery of a calmodulin-binding domain in AS160 that is selectively required for contraction- but not insulin-stimulated glucose uptake established a signal-specific regulatory input distinct from phosphorylation.

    Evidence CBD-mutant AS160 electroporation in mouse muscle, calmodulin pulldown, in vivo glucose uptake with contraction vs. insulin, GAP-dead double-mutant rescue

    PMID:17717281

    Open questions at the time
    • Mechanism by which calmodulin modulates GAP activity not defined
    • Whether calmodulin regulation operates in non-muscle tissues unknown
  6. 2008 High

    Real-time single-vesicle imaging and pathway ordering experiments established that AS160 regulates GLUT4 vesicle docking/tethering at the plasma membrane rather than post-docking fusion, placing AS160-controlled Rab activation upstream of SNARE-mediated fusion and downstream of actin-dependent vesicle recruitment.

    Evidence Dual-color fusion assay quantifying docking and fusion rates with dominant-negative AS160; Rab8A knockdown combined with non-phosphorylatable AS160, Latrunculin B, and dominant-negative Rac

    PMID:18063571 PMID:18650435

    Open questions at the time
    • Identity of the tethering/docking machinery directly activated by GTP-Rab8A/10 was unknown
    • Fusion step regulation by other Akt substrates not identified
  7. 2009 High

    Human genetic evidence confirmed the physiological importance of TBC1D4: a dominant-negative truncation (R363X) causing insulin resistance via dimerization with wild-type protein, and identification of AMPK-specific Ser711 as a novel phosphosite, though S711A alone did not impair acute glucose uptake.

    Evidence Patient mutation R363X with co-IP showing dimerization and reduced GLUT4 translocation; MS phosphosite identification, AMPK kinase-dead transgenic mice, S711A mutant in vivo glucose uptake

    PMID:19470471 PMID:19923418

    Open questions at the time
    • Function of Ser711 phosphorylation beyond acute glucose uptake was unclear
    • Scope of dominant-negative effect of truncation mutations not fully characterized
  8. 2010 High

    Extension of the AS160 paradigm to non-GLUT4 cargo established it as a general trafficking regulator: AS160 controls Na⁺/K⁺-ATPase surface expression downstream of AMPK in epithelia, and SGK1-mediated phosphorylation at Thr568/Ser751 with 14-3-3 binding controls ENaC forward trafficking in response to aldosterone.

    Evidence Co-IP/domain mapping of AS160–Na⁺/K⁺-ATPase interaction with KD epistasis; site-specific AS160 mutagenesis with amiloride-sensitive current measurement for ENaC

    PMID:20410134 PMID:20943949

    Open questions at the time
    • Whether the same Rab substrates mediate ENaC and Na⁺/K⁺-ATPase trafficking not identified
    • Tissue-specific splice variant contributions not addressed
  9. 2011 High

    Thr649Ala knock-in mice demonstrated that this single phosphosite is essential for insulin-stimulated glucose uptake specifically in muscle but not adipocytes, revealing tissue-specific reliance on the pThr642/14-3-3 mechanism; kinetic studies showed AS160 controls the size of a docking-competent vesicle pool rather than the intrinsic exocytosis rate.

    Evidence Thr649Ala KI mouse with euglycemic clamp and isolated tissue glucose uptake; crystal structures of the RabGAP domain at 3.5 Å; shRNA knockdown kinetic modeling of exocytosis/endocytosis rate constants

    PMID:21195350 PMID:21454505 PMID:21613213

    Open questions at the time
    • Adipocyte-specific compensatory mechanism for Thr649 loss not identified
    • Whether oligomeric state of full-length AS160 affects tissue-specific function unknown
  10. 2012 High

    Studies using membrane-targeting constructs, PTB domain lipid-binding analysis, and AS160/TBC1D1 double-KO mice established that membrane association (not just phosphorylation) is critical for AS160 function, that the two RabGAPs are non-redundant and together essential for GLUT4 trafficking, and that AS160 KO causes multi-tissue metabolic derangement.

    Evidence Membrane-targeting vs. cytosol-tethering constructs with phosphosite mutagenesis; phospholipid-binding assay for PTB2 domain; TBC1D1/TBC1D4 double-KO mice with insulin/AICAR-stimulated glucose uptake

    PMID:18801932 PMID:23011063 PMID:23045393 PMID:25249576

    Open questions at the time
    • How TBC1D1 and TBC1D4 divide labor on different Rab pools remained unclear
    • Mechanism of GLUT4 protein destabilization in KO mice not yet understood
  11. 2014 High

    A common TBC1D4 nonsense variant (p.Arg684Ter) in Greenlandic Inuit provided population-scale human genetic proof that TBC1D4 loss causes muscle-specific insulin resistance with reduced muscle GLUT4 protein; separately, AS160 was shown to regulate lipid droplet fusion via GAP activity on Rab8a in complex with Fsp27.

    Evidence Population genotyping of >2,500 Inuit with OGTT and muscle biopsies; co-IP of ternary AS160–Fsp27–Rab8a complex with Rab8a KD and GDP-locked mutant in hepatocytes

    PMID:25043022 PMID:25158853

    Open questions at the time
    • Mechanism by which loss of AS160 reduces GLUT4 protein level not resolved
    • Whether Fsp27-mediated lipid droplet fusion pathway is relevant in non-hepatic tissues unknown
  12. 2016 High

    Three key mechanistic points were resolved: GAP-dead knock-in (R917K) phenocopied AS160-KO and revealed that GAP activity prevents GLUT4 lysosomal degradation; PP1-α was identified as the specific phosphatase for Ser588/Thr642; and Rab28 was identified as an additional substrate whose GTP-loading is insulin-regulated.

    Evidence R917K GAP-dead KI mouse with lysosomal inhibitor rescue; PP1-α co-IP with isoform-specific KD and cell-free dephosphorylation; in vitro GAP assay for Rab28 with insulin stimulation in muscle

    PMID:27246912 PMID:27554475 PMID:27929607

    Open questions at the time
    • How GAP-inactive AS160 leads to GLUT4 rerouting to lysosomes mechanistically unresolved
    • Physiological role of Rab28 in GLUT4 trafficking needs in vivo validation
  13. 2021 High

    Reconstitution with full-length recombinant TBC1D4 resolved a longstanding question: phosphorylation by Akt or AMPK does not alter intrinsic GAP catalytic activity but disrupts TBC1D4–IRAP interaction, definitively establishing that the mechanism of phosphorylation-dependent derepression is vesicle dissociation rather than enzymatic inhibition.

    Evidence Baculovirus-expressed full-length TBC1D4, quantitative Michaelis-Menten GAP kinetics, MS-based phosphosite mapping, IRAP co-IP before and after phosphorylation

    PMID:33872597

    Open questions at the time
    • Whether phosphorylation-induced conformational changes also affect 14-3-3 steric occlusion of the GAP domain not tested
    • Full structural model of oligomeric TBC1D4 lacking
  14. 2023 High

    Ser711 knock-in mice and AS160-KO rat rescue experiments established that AMPK-mediated Ser711 phosphorylation is specifically required for the post-exercise insulin-sensitizing effect, and that AS160 protein expression (not just GLUT4 expression) is necessary for exercise-enhanced insulin sensitivity.

    Evidence S711A KI mice with hyperinsulinemic clamp after exercise; AS160-KO rats with AAV-mediated rescue of AS160 vs. GLUT4 alone vs. triple phosphosite mutant

    PMID:34753801 PMID:37074686

    Open questions at the time
    • Signal connecting exercise/AMPK/pSer711 to enhanced Thr642 phosphorylation not identified
    • Whether additional exercise-responsive AS160 sites contribute remains possible
  15. 2023 High

    TBC1D4 KO in heart abolished insulin-stimulated cardiac glucose uptake and caused baseline ER stress and increased extracellular matrix deposition, revealing cardiac-specific consequences beyond glucose transport.

    Evidence Tbc1d4 KO mice with [18F]-FDG PET, ex vivo LV glucose uptake, transcriptomics, ischemia/reperfusion model

    PMID:36707786

    Open questions at the time
    • Whether cardiac ER stress is a direct consequence of impaired Rab regulation or secondary to chronic metabolic deficiency is unclear
    • Cardiac-specific Rab substrates of TBC1D4 not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for oligomeric full-length TBC1D4 function and Rab selectivity; the mechanism by which loss of GAP activity reroutes GLUT4 to lysosomes; the molecular basis for the exercise-induced insulin-sensitizing signal transduced through Ser711; and identity of the effectors downstream of Rab10/8A that execute vesicle tethering/docking.
  • No high-resolution structure of full-length oligomeric TBC1D4
  • Mechanism linking GAP inactivation to lysosomal GLUT4 degradation unknown
  • Downstream effectors of GTP-loaded Rab10/Rab8A at the plasma membrane not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 9 GO:0098772 molecular function regulator activity 6 GO:0008289 lipid binding 1
Localization
GO:0031410 cytoplasmic vesicle 4 GO:0005829 cytosol 2 GO:0005811 lipid droplet 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-382551 Transport of small molecules 8 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-9609507 Protein localization 4 R-HSA-1430728 Metabolism 1
Partners
FKBP5IRAPPPP1CARAB10RAB14RAB8AYWHABYWHAE
Complex memberships
TBC1D4–14-3-3 phospho-dependent complexTBC1D4–Fsp27–Rab8a ternary complexTBC1D4–IRAP complex on GLUT4 storage vesicles

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 TBC1D4/AS160 harbors a functional Rab GTPase-activating protein (GAP) domain that is active against Rabs 2A, 8A, 10, and 14; GAP activity requires the catalytic arginine residue, as an R→K substitution abolishes activity. Rabs 2A, 8A, and 14 were found on GLUT4 vesicles. In vitro GAP activity assay with recombinant GAP domain, active-site mutagenesis (R→K), immunoblotting of GLUT4 vesicle fractions, mass spectrometry The Biochemical journal High 15971998
2005 AS160 associates with GLUT4 storage vesicles (GSVs) in the basal state via an interaction with the cytosolic tail of insulin-regulated aminopeptidase (IRAP), and dissociates from GSVs in response to insulin. siRNA knockdown of AS160 increased plasma membrane GLUT4 in an insulin-independent manner, establishing an inhibitory role in basal GLUT4 retention. Proteomic analysis of affinity-purified GLUT4 vesicles, co-IP of endogenous proteins, in vitro binding assay, shRNA knockdown with GLUT4 surface measurement The Journal of biological chemistry High 16154996
2004 AS160 RabGAP is required specifically for insulin stimulation of GLUT4 exocytosis but not for insulin-induced inhibition of GLUT4 endocytosis. A dominant-inhibitory AS160 mutant blocks exocytosis at a step before vesicle fusion with the plasma membrane. Dominant-negative AS160 overexpression, quantitative GLUT4 exocytosis/endocytosis assays in adipocytes Molecular biology of the cell High 15254270
2005 AS160 GAP activity is required for basal GLUT4 retention: AS160 knockdown increases basal GLUT4 exocytosis 3-fold, and re-expression of wild-type but not GAP-dead AS160 restores normal GLUT4 retention. shRNA knockdown, rescue with wild-type vs. GAP-dead mutant, GLUT4 surface quantification and exocytosis rate measurement in adipocytes Cell metabolism High 16213228
2006 Insulin-stimulated AS160 phosphorylation occurs via Akt2 (wortmannin-sensitive, abolished in Akt2 KO mice), while contraction-stimulated AS160 phosphorylation is only partially Akt2-dependent and also requires AMPKα2 activity, revealing AS160 as a convergence point for insulin and contraction signaling in skeletal muscle. In vivo/in vitro/in situ exercise and AICAR stimulation, wortmannin inhibition, Akt2 KO mice, AMPKα2-inactive transgenic mice, phospho-AS160 immunoblotting Diabetes High 16804077
2006 Overexpression of phosphorylation-deficient AS160 (4P mutant, preventing phosphorylation on four Akt sites) inhibits both insulin- and contraction-stimulated glucose uptake in mouse skeletal muscle in vivo; this inhibition is completely prevented by concomitant disruption of AS160 Rab-GAP activity, establishing that AS160 acts through its GAP function downstream of phosphorylation. In vivo electroporation of WT and mutant AS160 constructs in mouse tibialis anterior, [3H]2-deoxyglucose uptake in vivo with IV glucose or in situ contraction The Journal of biological chemistry High 16935857
2006 AMPKα2β2γ1 and α2β2γ1 trimeric complexes phosphorylate AS160 in a cell-free assay; AICAR-stimulated AS160 phosphorylation in skeletal muscle is abolished in AMPKα2 KO and γ3 KO mice, identifying AMPK as a direct upstream kinase for AS160. Cell-free kinase assay with recombinant AMPK heterotrimeric complexes, AICAR stimulation of isolated muscle from AMPK KO and KD mice Diabetes High 16804075
2007 Rab10 is a downstream target of AS160 in the insulin-GLUT4 pathway in adipocytes: constitutively GTP-bound Rab10 increases surface GLUT4 in basal cells; Rab10 knockdown reduces insulin-stimulated GLUT4 exocytosis; and the basal GLUT4 increase from AS160 knockdown is partially blocked by simultaneous Rab10 knockdown. Overexpression of GTP-hydrolysis-deficient Rab10, siRNA knockdown of Rab10 alone and in combination with AS160 knockdown, GLUT4 exocytosis quantification Cell metabolism High 17403373
2006 14-3-3 proteins interact with AS160 in an insulin- and Akt-dependent manner, primarily via phospho-Thr642. Introducing a constitutive 14-3-3 binding site into the phosphorylation-deficient AS160(4P) mutant restores GLUT4 translocation, demonstrating that 14-3-3 binding to AS160 is mechanistically required for insulin-stimulated GLUT4 trafficking. LC-MS/MS identification of 14-3-3 as AS160 interactor, co-IP, Thr642 mutagenesis, constitutive 14-3-3 binding site rescue experiment, GLUT4 translocation assay The Journal of biological chemistry High 16880201
2006 AS160 binds directly to the cytosolic N-terminal region of IRAP (insulin-regulated aminopeptidase), a GSV marker protein. This interaction is mediated by the second PTB domain of AS160 and is not regulated by AS160 phosphorylation, suggesting AS160 is tethered to GLUT4 vesicles via IRAP to locally suppress Rab activity. Co-IP of overexpressed and endogenous proteins, confocal colocalization, domain mapping with PTB-domain constructs Molecular endocrinology High 16762977
2007 Multiple AGC kinases (Akt/PKB, RSK1, SGK1) and AMPK phosphorylate AS160 at distinct sites: Akt, RSK1, and SGK1 all phosphorylate Ser318, Ser588, and Thr642; RSK1 additionally phosphorylates Ser341 and Ser751; SGK1 phosphorylates Thr568 and Ser751; AMPK preferentially phosphorylates Ser588. 14-3-3 binding to AS160 requires primarily pThr642 and secondarily pSer341. 14-3-3 affinity chromatography purification of AS160, phospho-site mapping by MS, in vitro phosphorylation by recombinant kinases, mutagenesis of individual sites, 14-3-3 binding assays The Biochemical journal High 17617058
2006 Rab8A and Rab14 (but not Rab10) function as physiologically relevant targets of AS160 in L6 muscle cells: coexpression of constitutively active or wild-type Rab8A/Rab14 rescues GLUT4 translocation inhibited by the non-phosphorylatable 4P-AS160 mutant. Epistasis by coexpression of 4P-AS160 with constitutively active or wild-type Rab GTPases in L6 myotubes, GLUT4myc surface quantification Biochemical and biophysical research communications Medium 17208202
2007 AS160 contains a calmodulin-binding domain (CBD) that is specifically required for contraction- but not insulin-stimulated glucose uptake in mouse skeletal muscle. CBD-mutant AS160 fails to bind biotinylated calmodulin in vitro. The inhibitory effect of the CBD mutation on contraction-stimulated uptake is rescued by concomitant disruption of Rab-GAP activity, placing calmodulin upstream of AS160 GAP function in the contraction pathway. In vivo electroporation of CBD-mutant AS160 in mouse muscle, biotinylated calmodulin pulldown, in vivo glucose uptake measurements with insulin stimulation and in situ contraction Diabetes High 17717281
2008 In the insulin-GLUT4 pathway, AS160 functions at the level of GLUT4 vesicle docking: real-time dual-color fusion assay shows that a dominant-negative AS160 mutant proportionally inhibits both docking and fusion rates of GSVs, but does not selectively inhibit post-docking fusion events. Novel dual-color fluorescent probe for real-time monitoring of GSV fusion events in 3T3-L1 adipocytes, quantification of docking and fusion rates with dominant-negative AS160 expression The Journal of biological chemistry Medium 18063571
2008 GLUT4 vesicle recruitment to the cell periphery requires actin dynamics (Rac/actin arm), whereas AS160 phosphorylation is essential for the downstream docking/fusion step. Selective Rab8A knockdown magnifies the defect caused by non-phosphorylatable AS160, placing Rab8A downstream of AS160 in vesicle membrane docking/fusion. Dominant-negative Rac, Latrunculin B, non-phosphorylatable AS160 (4P) expression, Rab8A siRNA knockdown, VAMP2 cleavage by tetanus toxin, confocal quantification of cortical and surface GLUT4myc The Journal of biological chemistry High 18650435
2009 A novel AS160 splice variant (AS160_v2) lacking exons 11 and 12 is expressed in a tissue-specific pattern. Unlike full-length AS160, overexpression of AS160_v2 in rat myoblasts increases rather than inhibits GLUT4 translocation and glucose uptake in response to insulin/IGF-1, and directly associates with GLUT4 in the basal state. RT-PCR cloning, doxycycline-inducible expression in rat myoblast line, GLUT4myc surface assay, glucose uptake measurement, immunofluorescence Cellular signalling Medium 18771725
2009 A novel AS160/TBC1D4 phosphorylation site, Ser711, is phosphorylated by AMPK (but not by Akt1, Akt2, or PKCζ) in vitro and in vivo in response to AICAR and exercise in skeletal muscle. Phosphorylation requires AMPKα2 activity. Mutation of S711 to alanine does not alter AICAR-, contraction-, or insulin-stimulated glucose uptake. Mass spectrometry identification of novel sites, phosphospecific antibody, in vitro kinase assay with recombinant AMPK/Akt, AMPKα2 kinase-dead transgenic mice, S711A mutant glucose uptake assay American journal of physiology. Cell physiology High 19923418
2009 A heterozygous premature stop mutation (R363X) in human TBC1D4 reduces expression of the full-length protein, causes dominant-negative dimerization with wild-type TBC1D4, and reduces insulin-stimulated GLUT4 translocation in adipocytes, demonstrating that TBC1D4 loss-of-function causes insulin resistance in humans. Patient genetic screening, immunoblot of patient lymphocytes, expression of truncated protein in 3T3-L1 adipocytes, co-IP showing dimerization, GLUT4 translocation assay Proceedings of the National Academy of Sciences of the United States of America High 19470471
2010 AS160 directly associates with the Na+,K+-ATPase α-subunit NP domain and mediates AMPK-dependent regulation of sodium pump surface expression: AMPK inhibition (Compound C) induces Na+,K+-ATPase endocytosis, and AS160 knockdown prevents this effect, placing AS160 in the AMPK→Na+,K+-ATPase trafficking pathway. Co-IP/pulldown identifying AS160–Na+,K+-ATPase interaction, domain mapping to NP domain, shRNA knockdown of AS160, AMPK inhibitor treatment, cell surface Na+,K+-ATPase quantification Molecular biology of the cell High 20943949
2010 Aldosterone/SGK1-dependent phosphorylation of AS160 at Thr568 and Ser751 (SGK1 sites) triggers 14-3-3β/ε binding to AS160, which is required for ENaC forward trafficking to the apical membrane; mutations at these SGK1 sites block selective 14-3-3 binding and suppress aldosterone-stimulated ENaC surface expression. AS160 overexpression and knockdown in CCD epithelia, aldosterone treatment, site-specific AS160 phosphorylation mutagenesis, 14-3-3 co-IP, amiloride-sensitive current measurement, cell surface biotinylation Molecular biology of the cell High 20410134
2011 Crystal structures of the TBC1D4 (AS160) and TBC1D1 RabGAP domains solved at 3.5 Å and 2.2 Å resolution, respectively, reveal 16 α-helices with no β-sheet elements. Ala-scanning mutagenesis of predicted Rab-binding residues and GLUT4 translocation assays identified residues beyond those in the yeast Gyp1p/Rab33B interface as critical for catalytic activity. X-ray crystallography, Ala-scanning mutagenesis of RabGAP domain, in vitro GAP activity assay, GLUT4 translocation assay The Journal of biological chemistry High 21454505
2011 Insulin-induced phosphorylation of AS160-Thr649 (mouse equivalent of human Thr642) and its resulting 14-3-3 binding are required for insulin-stimulated GLUT4 trafficking and glucose uptake specifically in muscle but not adipocytes in vivo: Thr649Ala knock-in mice show abolished 14-3-3 binding to AS160 and impaired insulin-stimulated glucose transport in muscle. Thr649Ala knockin mouse model, euglycemic clamp, isolated muscle and adipocyte glucose uptake, cell surface GLUT4 content measurement, 14-3-3 binding assay Cell metabolism High 21195350
2011 AS160 knockdown causes GLUT4 to accumulate in a primed pre-fusion pool (cycling pool) in basal adipocytes without increasing the intrinsic rate of exocytosis; insulin then increases the exocytosis rate constant through an AS160-independent Akt substrate, suggesting AS160 controls the tethering/docking step by stimulating GTP hydrolysis on a Rab protein. AS160 shRNA knockdown, kinetic measurements of exocytosis (kex), endocytosis (ken), and retention release constants, PI3K/Akt inhibition in knockdown cells, mathematical modeling The Journal of biological chemistry High 21613213
2011 Vasopressin (dDAVP)-induced AS160 phosphorylation via the PI3K/Akt pathway is required for AQP2 retention in intracellular compartments; AS160 knockdown increases AQP2 plasma membrane density even without dDAVP stimulation, establishing AS160 as a regulator of AQP2 trafficking in collecting duct cells. siRNA knockdown of AS160 and Akt1 in M-1/mpkCCDc14 cells, immunocytochemistry, cell surface biotinylation of AQP2, PI3K inhibitor treatment American journal of physiology. Renal physiology Medium 21511697
2012 AS160 mediates insulin- and AMPK-stimulated CD36 surface translocation in cardiomyocytes via Rab8a: AS160 knockdown constitutively redistributes CD36 to the surface; phosphorylation-deficient AS160 suppresses stimulus-induced CD36 membrane recruitment; and Rab8a knockdown/overexpression specifically modulates insulin/AICAR-induced CD36 trafficking. AS160 knockdown and overexpression, phosphorylation-deficient AS160-4P mutant, Rab8a siRNA and overexpression, AICAR treatment, cardiomyocyte surface CD36 quantification Journal of lipid research High 22315395
2012 TBC1D4 association with GLUT4 vesicle membranes (under basal conditions) is required for its inhibitory action on GLUT4 translocation; phosphorylation of TBC1D4 at T642 per se (without membrane dissociation) is sufficient to permit GLUT4 translocation. TBC1D4 membrane targeting and cytosol-tethering constructs, phosphorylation site mutagenesis, insulin and non-insulin agonist treatments, GLUT4 translocation assay, fractionation Molecular endocrinology High 18801932
2012 The second PTB domain of TBC1D4/AS160 functions as a phospholipid-binding domain that facilitates plasma membrane targeting of AS160. A distinct, nonoverlapping region in this domain binds GSV cargo. Constitutive AS160 targeting to the plasma membrane increases surface GLUT4 by enhancing AS160 phosphorylation/14-3-3 binding and inhibiting GAP activity. This function is conserved in related TBC proteins and a Drosophila ortholog. Domain mutagenesis, phospholipid-binding assays, plasma membrane targeting constructs, GLUT4 surface quantification, 14-3-3 binding assays, cross-species comparison Molecular and cellular biology High 23045393
2012 AS160 deletion in mice impairs insulin-stimulated glucose uptake and GLUT4 expression in adipocytes and soleus muscle, increases basal glucose uptake in adipocytes (via increased plasma membrane GLUT4), and causes hepatic insulin resistance with elevated gluconeogenesis, demonstrating multi-tissue roles for AS160 in glucose homeostasis. AS160 knockout mouse, euglycemic clamp, isolated adipocyte and muscle glucose uptake, plasma membrane GLUT4 isolation, photoaffinity labeling of cell surface GLUT4, pyruvate tolerance test American journal of physiology. Endocrinology and metabolism High 23011063
2012 Thr649Ala knock-in mutation does not impair contraction- or AICAR-stimulated glucose uptake in mouse muscle, and contraction/AICAR do not increase AS160-Thr649 phosphorylation or 14-3-3 binding; the increased PAS antibody band at ~160 kDa seen with contraction represents TBC1D1, not AS160. Site-specific phospho-antibodies on AS160 immunoprecipitates, Thr649Ala KI mice, TBC1D1 deletion mouse, in situ muscle contraction, AICAR treatment, glucose uptake assay American journal of physiology. Endocrinology and metabolism High 22318952
2014 AS160 acts as the GAP for Rab8a in a ternary complex with Fsp27, and GDP-bound Rab8a promotes lipid droplet fusion; AS160 inactivation of Rab8a GTPase positively regulates lipid droplet fusion and hepatic lipid accumulation. MSS4 (a GEF for Rab8a) antagonizes this fusion activity. Co-IP identifying ternary AS160–Fsp27–Rab8a complex, Rab8a knockdown in ob/ob mouse liver, GDP-locked Rab8a mutant overexpression, lipid droplet fusion assay, hepatic lipid measurement Developmental cell High 25158853
2014 A loss-of-function nonsense mutation (p.Arg684Ter) in TBC1D4 at 17% allele frequency in Greenlandic Inuit causes tissue-specific muscle insulin resistance: homozygous carriers have severely decreased insulin-stimulated muscle glucose uptake, lower GLUT4 protein in muscle, and markedly elevated post-load glucose/insulin despite near-normal fasting levels. Genetic association with oral glucose tolerance test, muscle biopsy mRNA/protein quantification, euglycemic clamp (implied), population-scale genotyping Nature High 25043022
2014 Simultaneous deletion of TBC1D1 and TBC1D4 in mice almost completely abolishes insulin- and AICAR-stimulated glucose uptake in skeletal muscle and adipose cells, reduces GLUT4 protein in both tissues, and impairs GLUT4 intracellular retention, demonstrating that TBC1D1 and TBC1D4 together are essential and non-redundant regulators of GLUT4-mediated glucose uptake. TBC1D1/TBC1D4 double-KO mice, insulin/AICAR stimulated glucose uptake in isolated muscle and adipocytes, plasma membrane GLUT4 surface labeling, GLUT4 protein quantification Diabetes High 25249576
2016 The RabGAP activity of AS160 is required to maintain GLUT4 protein levels: RabGAP-inactive AS160(R917K) knock-in mice phenocopy AS160-KO mice, and inactivation of AS160 RabGAP promotes lysosomal degradation of GLUT4. Skeletal muscle-specific AS160 deletion causes postprandial hyperglycemia and hyperinsulinemia. RabGAP-dead knockin mouse (R917K), skeletal muscle-specific AS160 KO, lysosomal inhibitor rescue of GLUT4 protein, postprandial glucose/insulin measurements Diabetes High 27554475
2009 Receptor-interacting protein 140 (RIP140), exported to the cytoplasm after PKCε phosphorylation and arginine methylation, interacts directly with AS160 and impedes its phosphorylation by Akt, thereby reducing GLUT4 trafficking and glucose uptake in adipocytes. Co-IP of RIP140 and AS160, phosphorylation assay, RIP140 cytoplasmic targeting, glucose uptake measurement, GLUT4 surface quantification in 3T3-L1 adipocytes and epididymal adipocytes from diet-induced obese mice Cell metabolism High 19945409
2010 Protein kinase WNK1 phosphorylates TBC1D4 in vitro and increases its binding to 14-3-3 proteins while reducing TBC1D4–Rab8A interaction; WNK1 expression levels regulate cell surface expression of GLUT1 via TBC1D4 in HEK293 cells, and these effects require WNK1 catalytic activity. Co-IP of WNK1–TBC1D4 complex, in vitro kinase assay, kinase-dead WNK1 mutant, 14-3-3 binding assay, Rab8A co-IP, surface GLUT1 quantification The Journal of biological chemistry High 20937822
2012 ClipR-59 interacts with AS160 through its ankyrin repeats and facilitates Akt-mediated AS160 phosphorylation and GLUT4 membrane translocation in adipocytes; the ankyrin repeat-deleted mutant (ΔANK-ClipR-59) fails to bind AS160 and does not promote AS160 phosphorylation or GLUT4 translocation, establishing ClipR-59 as a scaffold enhancing Akt–AS160 interaction. Co-IP of ClipR-59 and AS160, ΔANK mutant functional assay, GLUT4 surface quantification, AS160 phosphorylation measurement in 3T3-L1 adipocytes The Journal of biological chemistry Medium 22689584
2009 RUVBL2 is identified as an AS160-interacting protein; its depletion in adipocytes inhibits insulin-stimulated GLUT4 translocation and glucose uptake by reducing AS160 phosphorylation; reintroduction of RUVBL2 reverses this inhibitory effect. Tandem affinity purification combined with mass spectrometry, siRNA knockdown, GLUT4 translocation assay, AS160 phosphorylation measurement, rescue with human RUVBL2 in 3T3-L1 adipocytes Cell research Medium 19532121
2007 Rip11 forms a complex with AS160 independently of Rab11, and insulin induces dissociation of AS160 from Rip11 in 3T3-L1 adipocytes. Rip11 knockdown inhibits insulin-stimulated glucose uptake and overexpression blocks insulin-stimulated GLUT4 vesicle insertion into the plasma membrane. Co-IP of Rip11 and AS160, siRNA knockdown of Rip11, 2-deoxyglucose uptake assay, GLUT4 translocation assay, insulin stimulation Journal of cell science Medium 18003705
2016 Rab28 is a substrate for both TBC1D1 and TBC1D4 GAP domains in vitro; in intact skeletal muscle, Rab28 GTP-loading state is acutely regulated by insulin; Rab28 siRNA knockdown in muscle decreases basal glucose uptake; and constitutively active Rab28-Q72L overexpression in adipocytes increases basal surface GLUT4. In vitro GAP assay, insulin stimulation of mouse muscle, siRNA knockdown of Rab28 in muscle, constitutively active Rab28-Q72L in adipocytes, surface HA-GLUT4 quantification FEBS letters Medium 27929607
2016 AS160 regulates cell cycle progression in a glucose-independent manner: AS160 knockdown arrests multiple cell types in G1 via upregulation of the CDK inhibitor p21, and p21 silencing rescues the AS160 KD cell cycle arrest, establishing an AS160→p21 pathway governing cell proliferation. siRNA knockdown of AS160, cell cycle analysis, p21 immunoblotting, double-knockdown of AS160 and p21, AS160 overexpression rescue Cell cycle Medium 27152871
2017 FKBP51 associates with AS160 and restrains its phosphorylation by AKT2; pharmacological or genetic FKBP51 antagonism increases AS160 phosphorylation, increases GLUT4 at the plasma membrane, and enhances glucose uptake in skeletal myotubes. Co-IP of FKBP51 and AS160, FKBP5 KO mice, SAFit2 FKBP51 antagonist treatment, AS160 phosphorylation and GLUT4 surface quantification in myotubes Nature communications High 29170369
2016 Protein phosphatase 1-α (PP1-α) co-immunoprecipitates with AS160 and specifically dephosphorylates AS160 at Ser588 and Thr642 in skeletal muscle; PP1-α knockdown (but not PP1-β or PP1-γ1 KD) increases AS160 phosphorylation without altering Akt phosphorylation; recombinant inhibitor-2 protein (selective PP1 inhibitor) delays AS160 dephosphorylation in cell-free assays. Co-IP of PP1-α with AS160, siRNA knockdown of PP1 isoforms, recombinant inhibitor-2 treatment, AS160 dephosphorylation cell-free assay, okadaic acid dose-response Diabetes High 27246912
2021 Full-length TBC1D4 forms oligomers of ~600 kDa and displays higher specific GAP activity toward Rab10 than the truncated GAP domain. AKT preferentially phosphorylates Ser324 (KM ~6 μM) and Thr649 (KM ~25 μM); AMPK preferentially phosphorylates Ser348, Ser577, Ser595, Ser711, and Ser764. Phosphorylation by either kinase does not alter intrinsic RabGAP activity but disrupts interaction with IRAP, suggesting that phosphorylation regulates TBC1D4 by releasing it from GSVs rather than by modulating enzymatic activity. Baculovirus-expressed full-length recombinant TBC1D4, size-exclusion chromatography, co-IP, high-resolution mass spectrometry phosphosite mapping, Michaelis-Menten kinetics with stable isotope-labeled γ-[18O4]-ATP, in vitro kinase assays, IRAP co-IP The Journal of biological chemistry High 33872597
2023 TBC1D4-Ser711 phosphorylation (mediated by AMPK) is required for the insulin-sensitizing effect of exercise on skeletal muscle glucose uptake: TBC1D4-S711A knockin mice show normal basal glucose metabolism and contraction-stimulated glucose uptake but lack the post-exercise improvement in whole-body and muscle insulin sensitivity. TBC1D4-S711A knock-in mouse, hyperinsulinemic clamp, ex vivo glucose uptake in isolated muscles after contraction, AMPK activity measurement, exercise protocol Diabetes High 37074686
2023 TBC1D4 is essential for insulin-stimulated cardiac glucose uptake: Tbc1d4-knockout abolishes insulin-stimulated GLUT4-mediated glucose uptake in left ventricular muscle and in vivo cardiac glucose uptake; Tbc1d4-deficiency also causes baseline ER stress (via ATF4/eIF2α), increased cardiac extracellular matrix deposition, and aggravated infarction after ischemia/reperfusion. Tbc1d4 KO mice, [18F]-FDG PET imaging in vivo, ex vivo [3H]-2-deoxyglucose uptake in LV papillary muscle, echocardiography, cardiac I/R model, whole-heart transcriptomics, transmission electron microscopy Cardiovascular diabetology High 36707786
2022 AS160 expression in skeletal muscle is essential for the post-exercise improvement in insulin-stimulated glucose uptake: AS160-KO rats lack post-exercise enhancement of glucose uptake; AAV rescue of AS160 expression restores this effect; restoring GLUT4 alone without AS160 does not; and AS160 phosphorylation on Ser588, Thr642, and Ser704 is not required for the full post-exercise effect (though Ser588/Thr642/Ser704 phosphorylation contributes). AS160-KO rat, AAV-mediated rescue of AS160 expression, AAV-mediated GLUT4 rescue, phospho-site triple-mutant (S588A/T642A/S704A) AAV delivery, post-exercise insulin-stimulated glucose uptake in isolated muscle Diabetes High 34753801
2018 When both TBC1D1 and AS160 are expressed, TBC1D1 functionally dominates AS160 in GLUT4 release; AS160 modulates sensitivity to stimuli in TBC1D1-mediated GLUT4 release. Synergizing actions rely on the PTB1 and calmodulin-binding domains of TBC1D1 and key phosphorylation sites on both proteins (AS160-Thr642, TBC1D1-Ser237, and TBC1D1-Thr596). GLUT4 nanometry, cell-based reconstitution with varying expression ratios, systematic mutagenesis of domains and phosphorylation sites, AICAR and Ca2+ stimulation The Journal of biological chemistry High 30482843
2019 Chlamydia trachomatis activates the Akt/AS160/Rab14 axis to hijack sphingolipid delivery to chlamydial inclusions: infection promotes Akt phosphorylation, inactivates AS160 GAP activity (via pAS160), and thereby maintains Rab14 in its GTP-bound state to deliver sphingolipids. Akt inhibition or AS160 depletion reduces Rab14 at inclusions and impairs chlamydial replication. Akt inhibitor treatment, AS160 siRNA knockdown, pAkt/pAS160 localization, Rab14 recruitment quantification, sphingolipid trafficking assay, electron microscopy of bacteria Frontiers in microbiology Medium 31001235
2019 WNK1 phosphorylates TBC1D4 at Ser704 (identified by mass spectrometry), and phosphomimetic vs. unphosphorylatable mutants at this site alter GLUT1 surface expression; WNK1 knockdown reduces plasma membrane GLUT1 by ~2-fold and decreases glucose uptake ~60% in HEK293 cells. WNK1 siRNA knockdown, mass spectrometry phosphosite identification, phosphomimetic/unphosphorylatable TBC1D4 mutant transfection, surface GLUT1 quantification, glucose uptake assay Archives of biochemistry and biophysics Medium 31816312

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. American journal of physiology. Endocrinology and metabolism 360 18477703
2005 AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. The Biochemical journal 343 15971998
2005 Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. The Journal of biological chemistry 330 16154996
2014 A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature 318 25043022
2007 Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell metabolism 296 17403373
2006 Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 265 16804077
2005 Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein. Cell metabolism 262 16213228
2005 Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes 232 15919790
2006 AS160 regulates insulin- and contraction-stimulated glucose uptake in mouse skeletal muscle. The Journal of biological chemistry 229 16935857
2006 AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits. Diabetes 219 16804075
2005 Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity. Diabetes 215 15616009
2007 The Rab GTPase-activating protein AS160 integrates Akt, protein kinase C, and AMP-activated protein kinase signals regulating GLUT4 traffic. Diabetes 192 17259386
2004 Insulin stimulation of GLUT4 exocytosis, but not its inhibition of endocytosis, is dependent on RabGAP AS160. Molecular biology of the cell 186 15254270
2006 A role for 14-3-3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160. The Journal of biological chemistry 178 16880201
2008 Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. The Biochemical journal 169 17995453
2007 Effects of endurance exercise training on insulin signaling in human skeletal muscle: interactions at the level of phosphatidylinositol 3-kinase, Akt, and AS160. Diabetes 153 17513702
2007 Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF, PMA and AICAR. The Biochemical journal 152 17617058
2011 Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking. Cell metabolism 145 21195350
2006 Rabs 8A and 14 are targets of the insulin-regulated Rab-GAP AS160 regulating GLUT4 traffic in muscle cells. Biochemical and biophysical research communications 125 17208202
2014 Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia 120 25280670
2006 AS160 phosphorylation is associated with activation of alpha2beta2gamma1- but not alpha2beta2gamma3-AMPK trimeric complex in skeletal muscle during exercise in humans. American journal of physiology. Endocrinology and metabolism 112 17077344
2014 Rab8a-AS160-MSS4 regulatory circuit controls lipid droplet fusion and growth. Developmental cell 104 25158853
2009 Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle. Diabetologia 104 19252894
2010 Impaired insulin-induced site-specific phosphorylation of TBC1 domain family, member 4 (TBC1D4) in skeletal muscle of type 2 diabetes patients is restored by endurance exercise-training. Diabetologia 103 20938636
2006 Exercise-induced phosphorylation of the novel Akt substrates AS160 and filamin A in human skeletal muscle. Diabetes 102 16731842
2009 Increased AS160 phosphorylation, but not TBC1D1 phosphorylation, with increased postexercise insulin sensitivity in rat skeletal muscle. American journal of physiology. Endocrinology and metabolism 101 19435856
2012 Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase. Journal of lipid research 99 22315395
2012 Electrical stimuli release ATP to increase GLUT4 translocation and glucose uptake via PI3Kγ-Akt-AS160 in skeletal muscle cells. Diabetes 99 23274898
2017 Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function. Nature communications 95 29170369
2008 GLUT4 vesicle recruitment and fusion are differentially regulated by Rac, AS160, and Rab8A in muscle cells. The Journal of biological chemistry 95 18650435
2006 Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle. American journal of physiology. Endocrinology and metabolism 94 17179389
2012 Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis. American journal of physiology. Endocrinology and metabolism 92 23011063
2009 A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proceedings of the National Academy of Sciences of the United States of America 92 19470471
2009 Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle. American journal of physiology. Cell physiology 87 19923418
2006 Interaction of the Akt substrate, AS160, with the glucose transporter 4 vesicle marker protein, insulin-regulated aminopeptidase. Molecular endocrinology (Baltimore, Md.) 80 16762977
2014 “Deletion of both Rab-GTPase–activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport [corrected]. Diabetes 77 25249576
2013 AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues. The Biochemical journal 74 23078342
2014 Postexercise improvement in insulin-stimulated glucose uptake occurs concomitant with greater AS160 phosphorylation in muscle from normal and insulin-resistant rats. Diabetes 72 24608437
2007 Direct quantification of fusion rate reveals a distal role for AS160 in insulin-stimulated fusion of GLUT4 storage vesicles. The Journal of biological chemistry 72 18063571
2009 Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation. American journal of physiology. Endocrinology and metabolism 69 19366875
2012 The Rab GTPase-activating protein TBC1D4/AS160 contains an atypical phosphotyrosine-binding domain that interacts with plasma membrane phospholipids to facilitate GLUT4 trafficking in adipocytes. Molecular and cellular biology 59 23045393
2008 Regulation of glucose transporter 4 translocation by the Rab guanosine triphosphatase-activating protein AS160/TBC1D4: role of phosphorylation and membrane association. Molecular endocrinology (Baltimore, Md.) 59 18801932
2009 Inhibition of contraction-stimulated AMP-activated protein kinase inhibits contraction-stimulated increases in PAS-TBC1D1 and glucose transport without altering PAS-AS160 in rat skeletal muscle. Diabetes 57 19208911
2017 Baicalin against obesity and insulin resistance through activation of AKT/AS160/GLUT4 pathway. Molecular and cellular endocrinology 54 28359800
2011 Clustering of GLUT4, TUG, and RUVBL2 protein levels correlate with myosin heavy chain isoform pattern in skeletal muscles, but AS160 and TBC1D1 levels do not. Journal of applied physiology (Bethesda, Md. : 1985) 52 21799128
2009 A negative regulatory pathway of GLUT4 trafficking in adipocyte: new function of RIP140 in the cytoplasm via AS160. Cell metabolism 48 19945409
2008 Rab GTPase-activating protein AS160 is a major downstream effector of protein kinase B/Akt signaling in pancreatic beta-cells. Diabetes 48 18276765
2007 Calmodulin-binding domain of AS160 regulates contraction- but not insulin-stimulated glucose uptake in skeletal muscle. Diabetes 45 17717281
2021 AKT ISOFORMS-AS160-GLUT4: The defining axis of insulin resistance. Reviews in endocrine & metabolic disorders 44 33928491
2016 Toward Precision Medicine: TBC1D4 Disruption Is Common Among the Inuit and Leads to Underdiagnosis of Type 2 Diabetes. Diabetes care 44 27561922
2007 Glucose infusion causes insulin resistance in skeletal muscle of rats without changes in Akt and AS160 phosphorylation. American journal of physiology. Endocrinology and metabolism 44 17785505
2015 Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice. American journal of physiology. Endocrinology and metabolism 42 26625902
2012 Sustained postexercise increases in AS160 Thr642 and Ser588 phosphorylation in skeletal muscle without sustained increases in kinase phosphorylation. Journal of applied physiology (Bethesda, Md. : 1985) 42 22936728
2011 Loss of AS160 Akt substrate causes Glut4 protein to accumulate in compartments that are primed for fusion in basal adipocytes. The Journal of biological chemistry 42 21613213
2010 AS160 modulates aldosterone-stimulated epithelial sodium channel forward trafficking. Molecular biology of the cell 41 20410134
2007 The effect of exercise and insulin on AS160 phosphorylation and 14-3-3 binding capacity in human skeletal muscle. American journal of physiology. Endocrinology and metabolism 40 18042670
2008 Identification of a novel AS160 splice variant that regulates GLUT4 translocation and glucose-uptake in rat muscle cells. Cellular signalling 38 18771725
2007 Rip11 is a Rab11- and AS160-RabGAP-binding protein required for insulin-stimulated glucose uptake in adipocytes. Journal of cell science 36 18003705
2016 The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia. Diabetes 35 27554475
2011 Emerging role of Akt substrate protein AS160 in the regulation of AQP2 translocation. American journal of physiology. Renal physiology 35 21511697
2010 AS160 associates with the Na+,K+-ATPase and mediates the adenosine monophosphate-stimulated protein kinase-dependent regulation of sodium pump surface expression. Molecular biology of the cell 35 20943949
2013 Insulin stimulation regulates AS160 and TBC1D1 phosphorylation sites in human skeletal muscle. Nutrition & diabetes 34 23752133
2011 Naturally occurring compensated insulin resistance selectively alters glucose transporters in visceral and subcutaneous adipose tissues without change in AS160 activation. Biochimica et biophysica acta 32 21352908
2015 [6]-Gingerol Affects Glucose Metabolism by Dual Regulation via the AMPKα2-Mediated AS160-Rab5 Pathway and AMPK-Mediated Insulin Sensitizing Effects. Journal of cellular biochemistry 31 25694332
2014 Insulin-sensitizing effect of LXR agonist T0901317 in high-fat fed rats is associated with restored muscle GLUT4 expression and insulin-stimulated AS160 phosphorylation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 31 24732673
2014 Sustained AS160 and TBC1D1 phosphorylations in human skeletal muscle 30 min after a single bout of exercise. Journal of applied physiology (Bethesda, Md. : 1985) 31 24876356
2012 Thr649Ala-AS160 knock-in mutation does not impair contraction/AICAR-induced glucose transport in mouse muscle. American journal of physiology. Endocrinology and metabolism 31 22318952
2007 Resistance exercise and insulin regulate AS160 and interaction with 14-3-3 in human skeletal muscle. Diabetes 31 17369524
2012 Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4 phosphorylation. Acta pharmacologica Sinica 29 23103623
2010 Protein kinase WNK1 promotes cell surface expression of glucose transporter GLUT1 by regulating a Tre-2/USP6-BUB2-Cdc16 domain family member 4 (TBC1D4)-Rab8A complex. The Journal of biological chemistry 29 20937822
2008 Contraction-stimulated glucose transport in rat skeletal muscle is sustained despite reversal of increased PAS-phosphorylation of AS160 and TBC1D1. Journal of applied physiology (Bethesda, Md. : 1985) 27 18818383
2018 Cooperative actions of Tbc1d1 and AS160/Tbc1d4 in GLUT4-trafficking activities. The Journal of biological chemistry 25 30482843
2022 Berberine regulates mesangial cell proliferation and cell cycle to attenuate diabetic nephropathy through the PI3K/Akt/AS160/GLUT1 signalling pathway. Journal of cellular and molecular medicine 24 35001506
2020 Protective role of Astragaloside IV in chronic glomerulonephritis by activating autophagy through PI3K/AKT/AS160 pathway. Phytotherapy research : PTR 24 32726508
2014 Augmented β-Cell Function and Mass in Glucocorticoid-Treated Rodents Are Associated with Increased Islet Ir-β /AKT/mTOR and Decreased AMPK/ACC and AS160 Signaling. International journal of endocrinology 24 25313308
2011 Fatty acid-binding protein 3 stimulates glucose uptake by facilitating AS160 phosphorylation in mouse muscle cells. Genes to cells : devoted to molecular & cellular mechanisms 24 21501347
2021 AKT/AMPK-mediated phosphorylation of TBC1D4 disrupts the interaction with insulin-regulated aminopeptidase. The Journal of biological chemistry 23 33872597
2011 Crystal structures of human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating protein (RabGAP) domains reveal critical elements for GLUT4 translocation. The Journal of biological chemistry 23 21454505
2010 Disruption of AMPKalpha1 signaling prevents AICAR-induced inhibition of AS160/TBC1D4 phosphorylation and glucose uptake in primary rat adipocytes. Molecular endocrinology (Baltimore, Md.) 23 20501641
2012 Leptin reduces the expression and increases the phosphorylation of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4 in muscle of ob/ob mice. PloS one 22 22253718
2018 Postexercise improvement in glucose uptake occurs concomitant with greater γ3-AMPK activation and AS160 phosphorylation in rat skeletal muscle. American journal of physiology. Endocrinology and metabolism 21 30130149
2009 RUVBL2, a novel AS160-binding protein, regulates insulin-stimulated GLUT4 translocation. Cell research 21 19532121
2017 Challenging of AS160/TBC1D4 Alters Intracellular Lipid milieu in L6 Myotubes Incubated With Palmitate. Journal of cellular physiology 20 27714805
2012 The association of ClipR-59 protein with AS160 modulates AS160 protein phosphorylation and adipocyte Glut4 protein membrane translocation. The Journal of biological chemistry 20 22689584
2020 Sex and fiber type independently influence AMPK, TBC1D1, and TBC1D4 at rest and during recovery from high-intensity exercise in humans. Journal of applied physiology (Bethesda, Md. : 1985) 19 31895596
2013 Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma. Cancer & metabolism 19 24280290
2020 LNK deficiency decreases obesity-induced insulin resistance by regulating GLUT4 through the PI3K-Akt-AS160 pathway in adipose tissue. Aging 18 32911464
2019 Akt/AS160 Signaling Pathway Inhibition Impairs Infection by Decreasing Rab14-Controlled Sphingolipids Delivery to Chlamydial Inclusions. Frontiers in microbiology 18 31001235
2016 Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking. FEBS letters 18 27929607
2016 AS160 controls eukaryotic cell cycle and proliferation by regulating the CDK inhibitor p21. Cell cycle (Georgetown, Tex.) 17 27152871
2004 Upregulation of the transcript level of GTPase activating protein KIAA0603 in T cells from patients with atopic dermatitis. FEBS letters 17 15304337
2020 Resistance exercise-induced increase in muscle 5α-dihydrotestosterone contributes to the activation of muscle Akt/mTOR/p70S6K- and Akt/AS160/GLUT4-signaling pathways in type 2 diabetic rats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 32627878
2019 WNK1 phosphorylation sites in TBC1D1 and TBC1D4 modulate cell surface expression of GLUT1. Archives of biochemistry and biophysics 16 31816312
2016 Protein Phosphatase 1-α Regulates AS160 Ser588 and Thr642 Dephosphorylation in Skeletal Muscle. Diabetes 16 27246912
2010 Membrane Trafficking of Collecting Duct Water Channel Protein AQP2 Regulated by Akt/AS160. Electrolyte & blood pressure : E & BP 16 21468198
2008 Reduced phosphorylation of AS160 contributes to glucocorticoid-mediated inhibition of glucose uptake in human and murine adipocytes. Molecular and cellular endocrinology 16 19013499
2023 TBC1D4-S711 Controls Skeletal Muscle Insulin Sensitization After Exercise and Contraction. Diabetes 15 37074686
2022 Exercise-Induced Improvement in Insulin-Stimulated Glucose Uptake by Rat Skeletal Muscle Is Absent in Male AS160-Knockout Rats, Partially Restored by Muscle Expression of Phosphomutated AS160, and Fully Restored by Muscle Expression of Wild-Type AS160. Diabetes 15 34753801
2018 Estrogen replacement enhances insulin-induced AS160 activation and improves insulin sensitivity in ovariectomized rats. American journal of physiology. Endocrinology and metabolism 15 30179516
2023 Deletion of Tbc1d4/As160 abrogates cardiac glucose uptake and increases myocardial damage after ischemia/reperfusion. Cardiovascular diabetology 14 36707786