Affinage

TBC1D1

TBC1 domain family member 1 · UniProt Q86TI0

Length
1168 aa
Mass
133.1 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBC1D1 is a Rab-GTPase-activating protein (RabGAP) that serves as the principal signaling node coupling AMPK and Akt kinase pathways to GLUT4 vesicle trafficking and fatty acid oxidation in skeletal muscle. In its unphosphorylated state, TBC1D1 inactivates Rab8a, Rab10, Rab14, and Rab28, retaining GLUT4 in intracellular storage vesicles; AMPK phosphorylates TBC1D1 primarily on Ser237 (and additional AMPK sites Ser231, Ser660, Ser700) in response to contraction, while Akt phosphorylates Thr590/596 in response to insulin, with both events promoting 14-3-3 binding and disrupting TBC1D1 interaction with the GLUT4-vesicle-resident protein IRAP rather than directly inhibiting intrinsic GAP catalytic activity (PMID:30275018, PMID:17995453, PMID:20701589). The PTB1 and PTB2 domains scaffold AMPKα1-containing heterotrimers to facilitate Ser237 phosphorylation, and the obesity-associated R125W mutation in PTB1 disrupts this association, abolishing exercise-primed acquisition of insulin responsiveness (PMID:30135087, PMID:23325788). Loss of TBC1D1 in mice impairs contraction-stimulated glucose uptake specifically in glycolytic muscle fibers, reduces GLUT4 protein abundance, increases fatty acid oxidation and resting metabolic rate, and protects against diet-induced obesity (PMID:18931681, PMID:25576050, PMID:23892475).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 High

    Establishing TBC1D1 as a functional RabGAP that inhibits GLUT4 translocation resolved whether this AS160 paralog independently controls glucose transporter trafficking.

    Evidence In vitro GAP assay and overexpression/GAP-dead mutant in 3T3-L1 adipocytes with GLUT4 translocation readout

    PMID:17274760

    Open questions at the time
    • Endogenous role in muscle not yet tested
    • Rab substrate specificity established only by shared homology with AS160
    • Insulin-stimulated phosphosite identity not fully mapped
  2. 2008 High

    Identification of TBC1D1 as the dominant Akt/AMPK substrate in skeletal muscle, with distinct phosphosite clusters mediating 14-3-3 binding, established its dual-kinase regulation and muscle-specific importance.

    Evidence Mass spectrometry phosphosite mapping, in vitro kinase assays with purified AMPK and Akt, 14-3-3 binding assays in L6 myotubes and HEK-293 cells, and immunodepletion-MS identification in mouse muscle

    PMID:17995453 PMID:18215134 PMID:18276596

    Open questions at the time
    • In vivo kinase requirement not yet genetically confirmed
    • Relative contribution of each phosphosite to GLUT4 trafficking unknown
    • Mechanism linking phosphorylation to GAP inactivation unresolved
  3. 2008 High

    Discovery that a natural Tbc1d1 truncation confers leanness and increased fatty acid oxidation revealed TBC1D1 as a regulator of whole-body energy substrate partitioning, not only glucose uptake.

    Evidence Genetic mapping in SJL mice, congenic mouse metabolic phenotyping, siRNA in muscle cells with fatty acid oxidation assay

    PMID:18931681

    Open questions at the time
    • Molecular mechanism linking TBC1D1 GAP activity to fatty acid oxidation unclear
    • Whether CD36 trafficking is involved not yet tested
    • Contribution of individual domains to metabolic phenotype unknown
  4. 2009 High

    Genetic and pharmacological epistasis experiments in intact muscle demonstrated that AMPK is the primary kinase for contraction-stimulated TBC1D1 phosphorylation and glucose transport, while PI3K/Akt mediates the insulin pathway.

    Evidence AMPK kinase-dead transgenic mice, compound C and wortmannin inhibitors in isolated rat muscle, site-specific phospho-antibodies, 14-3-3 pull-down

    PMID:19208911 PMID:19531644

    Open questions at the time
    • Whether AMPK is sufficient or merely necessary for contraction-stimulated glucose uptake not resolved
    • Downstream Rab targets in intact muscle not identified
    • Redundancy with AS160 in contraction pathway not addressed
  5. 2010 High

    Systematic mapping of AMPK-specific phosphosites (Ser231, Ser660, Ser700) using AMPKα2-inactive mice and in vivo glucose uptake with 4P-mutant TBC1D1 established the multisite AMPK phosphorylation code required for contraction-stimulated glucose transport, while the R125W mutation selectively impaired insulin-stimulated transport.

    Evidence AMPKα2-inactive and Akt2 KO transgenic mice, site-specific phospho-antibodies, in vivo electroporation of mutant constructs with glucose uptake measurement, combined R125W+GAP-dead double mutant

    PMID:20299473 PMID:20701589 PMID:20837646

    Open questions at the time
    • Structural basis for how multisite phosphorylation alters TBC1D1 conformation unknown
    • Whether 14-3-3 binding is the sole effector mechanism of phosphorylation not tested
    • Human in vivo relevance of individual phosphosites beyond Ser237 not confirmed
  6. 2011 High

    Crystal structure of the TBC1D1 RabGAP domain at 2.2 Å resolution, combined with alanine-scanning mutagenesis, identified Met930 as a catalytically critical residue outside the canonical contact surface, providing the first structural framework for understanding GAP function.

    Evidence X-ray crystallography, alanine-scanning mutagenesis, in vitro RabGAP assay, GLUT4 translocation assay

    PMID:21454505

    Open questions at the time
    • No structure of full-length TBC1D1 or PTB domains
    • No Rab-bound co-crystal structure
    • How phosphorylation-induced conformational changes propagate to the GAP domain unknown
  7. 2013 High

    Demonstration that TBC1D1 acquires insulin responsiveness only after AMPK-mediated Ser237 phosphorylation, dependent on an intact PTB1 domain, explained the exercise-priming phenomenon and how the R125W obesity variant uncouples exercise from subsequent insulin sensitivity.

    Evidence GLUT4 nanometry with cell-based reconstitution, AICAR pretreatment, site-directed mutagenesis of Ser237 and PTB1 domain, R125W variant analysis

    PMID:23325788

    Open questions at the time
    • Identity of PTB1-binding partner that enables insulin responsiveness unknown
    • Whether this priming mechanism operates in human muscle not directly tested
    • Temporal dynamics of the primed state undefined
  8. 2014 High

    Double knockout of TBC1D1 and TBC1D4 nearly abolished insulin-stimulated glucose uptake in muscle and adipose tissue and reduced GLUT4 protein without altering mRNA, establishing that both RabGAPs are collectively essential for maintaining the intracellular GLUT4 storage compartment.

    Evidence Double KO mouse, euglycemic clamp, isolated muscle glucose uptake, GLUT4 protein and mRNA quantification, cell surface GLUT4 labeling

    PMID:25249576

    Open questions at the time
    • Mechanism by which RabGAP loss reduces GLUT4 protein stability not identified
    • Individual Rab contributions to GLUT4 retention in double KO not dissected
    • Whether RabGAP-independent GLUT4 trafficking pathways exist is unresolved
  9. 2018 High

    Reconstitution with full-length TBC1D1 resolved a longstanding paradox: phosphorylation by AMPK or Akt does not inhibit intrinsic GAP catalytic activity but instead disrupts TBC1D1 binding to IRAP on GLUT4 vesicles, establishing vesicle dissociation as the regulatory mechanism.

    Evidence Full-length recombinant TBC1D1 from baculovirus/Sf9, in vitro RabGAP assay with Rab8a/Rab10/Rab14, AKT/AMPK phosphorylation, 14-3-3 binding, Co-IP with IRAP cytoplasmic tail

    PMID:30275018

    Open questions at the time
    • Whether IRAP dissociation is sufficient for GLUT4 release in intact cells not confirmed
    • Structural basis of PTB–IRAP interaction unknown
    • Role of 14-3-3 binding beyond a correlative marker not mechanistically separated from IRAP dissociation
  10. 2018 High

    Identification that AMPKα1 (not α2) forms a stable scaffolded complex with TBC1D1 via both PTB domains, disrupted by R125W, explained isoform-specific AMPK signaling and the molecular basis of the obesity-associated variant.

    Evidence Reciprocal Co-IP, in vitro binding with isoform-specific AMPK constructs, pharmacological activation, R125W mutant analysis, Ser237 phosphorylation measurement

    PMID:30135087

    Open questions at the time
    • Whether AMPKα1 scaffolding is required in vivo for contraction signaling not tested genetically
    • Structural basis of PTB–AMPKα1 selectivity unknown
    • Whether R125W affects additional PTB1-dependent interactions beyond AMPKα1 not explored
  11. 2020 Medium

    Identification of VPS13A/C, EHBP1L1, MICAL1, and SERCA1 as PTB-domain interactors expanded TBC1D1's role beyond Rab regulation; depletion of VPS13A/C enhanced AMPK-stimulated GLUT4 surface expression, suggesting these lipid transport proteins constrain GLUT4 trafficking.

    Evidence Quantitative AP-MS in C2C12 myotubes, siRNA depletion of VPS13A/C, cell surface GLUT4 measurement

    PMID:33087848

    Open questions at the time
    • VPS13A/C interaction not validated by reciprocal pull-down or in vivo model
    • Mechanism by which VPS13 proteins constrain GLUT4 trafficking unknown
    • Whether these interactions are conserved across species not tested
  12. 2022 Medium

    Extension of TBC1D1-AMPK signaling to hepatic lipid metabolism via Rab2A-mediated PPARγ stabilization revealed a non-muscle, non-GLUT4 role for TBC1D1, as S231A knockin mice develop fatty liver with aging.

    Evidence TBC1D1 S231A knockin mice, GTP-Rab2A pulldown, Rab2A knockdown in NAFLD models, PPARγ stability assays

    PMID:35061665

    Open questions at the time
    • Whether TBC1D1 directly acts as a GAP for Rab2A not demonstrated in vitro
    • Contribution of TBC1D1 versus TBC1D4 in liver not dissected
    • Single-lab finding not yet independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of TBC1D1 (including PTB domains and their conformational coupling to the GAP domain), the precise mechanism by which IRAP dissociation triggers GLUT4 vesicle release, the identity of all physiologically relevant Rab substrates in intact muscle fibers, and the molecular basis of TBC1D1's regulation of fatty acid oxidation and CD36 trafficking.
  • No full-length TBC1D1 structure available
  • IRAP dissociation mechanism in intact cells unvalidated
  • In vivo Rab substrate hierarchy in muscle not established
  • Molecular link between TBC1D1 and β-HAD activity/fatty acid oxidation pathway not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0003924 GTPase activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-382551 Transport of small molecules 8 R-HSA-162582 Signal Transduction 7 R-HSA-9609507 Protein localization 5 R-HSA-1430728 Metabolism 3
Partners
AKT2APPL2IRAPPRKAA1PRKAA2VPS13AVPS13CYWHAZ

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 TBC1D1 RabGAP domain exhibits the same Rab substrate specificity as AS160 (TBC1D4), and ectopic expression of TBC1D1 in 3T3-L1 adipocytes blocks insulin-stimulated GLUT4 translocation to the plasma membrane in a GAP-activity-dependent manner; a point mutant with inactive GAP domain had no effect. Insulin treatment leads to phosphorylation of TBC1D1 on an Akt-consensus site conserved with AS160. In vitro RabGAP activity assay, overexpression in 3T3-L1 adipocytes with GLUT4 translocation assay, phosphorylation analysis, GAP-dead mutant (point mutation) The Biochemical journal High 17274760
2008 TBC1D1 is identified as the dominant phospho-Akt substrate (PAS) immunoreactive protein at ~160 kDa in tibialis anterior and EDL skeletal muscle. Both purified Akt and AMPK phosphorylate TBC1D1 in vitro; AMPK causes greater overall phosphorylation and shifts TBC1D1 electrophoretic mobility. In vivo, insulin, AICAR, and muscle contraction all increase TBC1D1 PAS phosphorylation in skeletal muscle. Immunodepletion, mass spectrometry identification, in vitro kinase assay (purified Akt and AMPK), in vivo phosphorylation after insulin/AICAR/contraction The Journal of biological chemistry High 18276596
2008 TBC1D1 has two clusters of phosphorylated residues with distinct 14-3-3 binding sites: AMPK activation drives 14-3-3 binding primarily via pSer237, whereas IGF-1/EGF/insulin-like stimuli drive binding via pThr596. AMPK activators (AICAR, phenformin, A-769662) strongly phosphorylate Ser237 and promote 14-3-3 binding in L6 myotubes, whereas insulin promotes pThr596 but not 14-3-3 binding in L6 cells, contrasting with AS160. Mass spectrometry phosphosite mapping, in vitro phosphorylation assays, 14-3-3 binding assays, pharmacological inhibitors in HEK-293 and L6 myotubes The Biochemical journal High 17995453
2008 TBC1D1 is ~20-fold less abundant than AS160 in 3T3-L1 adipocytes; knockdown of endogenous TBC1D1 has no effect on insulin-stimulated GLUT4 translocation in adipocytes. Overexpressed TBC1D1 inhibits GLUT4 translocation even with activated Akt, indicating Akt phosphorylation alone (at the single canonical Akt site) is insufficient to suppress TBC1D1 GAP activity. AICAR (AMPK activation) partially reverses TBC1D1-mediated inhibition. siRNA knockdown, overexpression, activated Akt co-expression, GLUT4 translocation assay in 3T3-L1 adipocytes The Journal of biological chemistry High 18258599
2008 TBC1D1 is identified as an Akt substrate phosphorylated at Thr590 in adipocytes. RNAi-mediated silencing of TBC1D1 in 3T3-L1 adipocytes elevates basal glucose uptake ~61% and strongly increases GLUT1 (not GLUT4) expression. This increase in GLUT1 is mediated through mTOR-p70 S6 kinase pathway activation, as rapamycin blocks it. Overexpression of TBC1D1-T590A (non-phosphorylatable) inhibits insulin-stimulated p70 S6 kinase phosphorylation. Mass spectrometry identification of Akt substrate, siRNA knockdown, glucose uptake assay, rapamycin treatment, Western blotting in 3T3-L1 adipocytes The Biochemical journal High 18215134
2008 A naturally occurring truncating mutation in the Tbc1d1 gene (SJL mouse strain) lacking the TBC RabGAP domain confers leanness and protects from diet-induced obesity. Knockdown of TBC1D1 in skeletal muscle cells increased fatty acid uptake and oxidation; overexpression had the opposite effect. Congenic mice lacking TBC1D1 show reduced respiratory quotient, increased fatty acid oxidation, and reduced glucose uptake in isolated skeletal muscle. Genetic mapping, loss-of-function mouse model, siRNA knockdown in muscle cells, metabolic phenotyping, fatty acid oxidation assay, isolated muscle glucose uptake Nature genetics High 18931681
2009 Phosphorylation of TBC1D1 by Akt on multiple sites is required for insulin-stimulated GLUT4 translocation in C2C12 myotubes: a TBC1D1 Akt-site Ala mutant (multiple sites) is considerably more inhibitory than wild-type TBC1D1. AMPK activation (AICAR) partially relieves TBC1D1-mediated inhibition. The obesity-associated R125W variant is equally inhibitory to GLUT4 translocation as wild-type. Site-directed mutagenesis, overexpression in C2C12 myotubes, GLUT4 translocation assay, AICAR treatment, mass spectrometry phosphosite identification The Journal of biological chemistry High 19740738
2009 In intact skeletal muscle, contraction increases 14-3-3 binding to TBC1D1 as well as phosphorylation of Ser237 and Thr596 in an AMPK-dependent manner. Using AMPK kinase-dead (KD) transgenic mice, both contraction- and AICAR-stimulated Ser237 phosphorylation and 14-3-3 binding are abolished. Insulin increases Thr596 phosphorylation but not Ser237 phosphorylation or 14-3-3 binding, and this insulin-stimulated Thr596 phosphorylation is also fully abolished in AMPK KD mice. AMPK kinase-dead transgenic mouse model, site-specific phospho-antibodies, 14-3-3 pull-down, ex vivo muscle contraction and AICAR treatment American journal of physiology. Endocrinology and metabolism High 19531644
2009 Contraction-stimulated PAS-TBC1D1 phosphorylation and glucose transport (but not PAS-AS160) are inhibited by compound C (AMPK inhibitor) in rat epitrochlearis muscle. Wortmannin (PI3K/Akt inhibitor) abolishes insulin-stimulated TBC1D1 phosphorylation and glucose transport but does not alter contraction-stimulated PAS-TBC1D1 or glucose transport. This places AMPK as the primary kinase for contraction-stimulated TBC1D1 phosphorylation. Pharmacological inhibitors (compound C, wortmannin), isolated rat epitrochlearis muscle, glucose transport assay, phospho-specific immunoblotting Diabetes High 19208911
2010 Muscle contraction increases TBC1D1 phosphorylation on AMPK sites Ser231 and Ser660 (and tends to increase Ser700), but not on the Akt site Thr590. AICAR mirrors contraction on AMPK sites; insulin only increases Thr590. Basal and contraction-stimulated Ser231, Ser660, Ser700 phosphorylation are greatly reduced in AMPKα2-inactive transgenic mice. Akt2 KO mice show blunted insulin-stimulated Thr590 phosphorylation. In vivo glucose uptake is significantly decreased in muscle overexpressing TBC1D1 mutated on four AMPK sites. AMPKα2-inactive transgenic mice, Akt2 KO mice, site-specific phospho-antibodies, in vivo electroporation/overexpression, glucose uptake assay The Biochemical journal High 20701589
2010 TBC1D1 regulates both insulin- and contraction-stimulated glucose transport in vivo via distinct mechanisms. The obesity-associated R125W mutation impairs insulin-stimulated glucose transport (reversed by GAP-domain inactivation). A phosphorylation-deficient TBC1D1 (4P mutant, Ala substitution at four AMPK/Akt sites) does not affect insulin-stimulated glucose transport but decreases contraction-stimulated glucose transport (prevented by concurrent GAP-domain disruption). In vivo electroporation of wild-type and mutant TBC1D1 constructs in mouse tibialis anterior, in vivo glucose transport measurement, combined R125W+GAP-dead double mutant Diabetes High 20299473
2010 Exercise in human skeletal muscle increases TBC1D1 Ser237 phosphorylation and 14-3-3 protein binding capacity. In vitro, recombinant AMPK induces both Ser237 phosphorylation and 14-3-3 binding on human TBC1D1. In AMPKα2 knockout mouse EDL muscle, both basal and contraction-stimulated Ser237 phosphorylation are reduced (~60%), and TBC1D1 protein content is also reduced (~50%), identifying AMPKα2 as the primary isoform regulating TBC1D1 Ser237 in EDL. Human muscle biopsies post-exercise, in vitro AMPK kinase assay, AMPKα1 and α2 KO mouse models, 14-3-3 binding assay The Journal of physiology High 20837646
2011 Crystal structures of human TBC1D1 and TBC1D4 RabGAP domains solved at 2.2 Å and 3.5 Å resolution, respectively. Both domains have 16 α-helices and no β-sheet. Ala-scanning mutagenesis identified TBC1D1 Met930 as critical for catalytic efficiency (outside the canonical Gyp1p/Rab33B contact surface). GLUT4 translocation assays confirmed that substitutions reducing RabGAP activity (including catalytically dead RK mutant and Met930/Leu1019 mutations) impair biological activity. X-ray crystallography (2.2 Å), Ala-scanning mutagenesis, in vitro RabGAP activity assay, GLUT4 translocation assay The Journal of biological chemistry High 21454505
2012 TBC1D1-deficient (Nob1.10SJL) mice show impaired glucose transport in response to insulin, AICAR, and contraction specifically in EDL (glycolytic) but not soleus muscle, partially explained by ~50% reduction in GLUT4 protein. Proximal signaling (Akt, AMPK, ACC) is unaltered, implicating TBC1D1 in distal GLUT4 regulation. Fatty acid oxidation is increased in TBC1D1-deficient muscle. TBC1D1-deficient mouse model, isolated muscle glucose transport assay, GLUT4 protein quantification, AMPK/Akt signaling analysis American journal of physiology. Endocrinology and metabolism High 22693207
2013 Conventional Tbc1d1 knockout mice show severely impaired insulin- and AICAR-stimulated glucose uptake in glycolytic EDL muscle and substantially increased fatty acid oxidation in oxidative soleus muscle, with reduced respiratory quotient and elevated resting metabolic rate. Conventional Tbc1d1 KO mouse generation, ex vivo isolated muscle glucose uptake, fatty acid oxidation assay, whole-body metabolic phenotyping Endocrinology High 23892475
2013 TBC1D1 acquires insulin responsiveness (triggering GLUT4 trafficking) only after an exercise-mimetic stimulus (AICAR pretreatment). This regulatory mode shift requires Ser237 phosphorylation and an intact PTB1 domain. The obesity-associated R125W mutation in PTB1 abolishes this acquisition of insulin responsiveness while leaving AICAR-responsive GLUT4-liberation activity intact. GLUT4 nanometry, cell-based reconstitution model, AICAR pretreatment, site-directed mutagenesis of Ser237 and PTB1 domain, R125W variant analysis Molecular biology of the cell High 23325788
2014 Double knockout of TBC1D1 and TBC1D4 (AS160) in mice almost completely abolishes insulin-stimulated glucose uptake in skeletal muscle and adipose cells. GLUT4 protein abundance is substantially reduced in skeletal muscle and white adipose tissue of double-KO mice (but GLUT4 mRNA is unchanged). Cell surface labeling indicates that RabGAP deficiency impairs intracellular GLUT4 retention in the basal state. Double KO mouse model, euglycemic clamp, isolated muscle glucose uptake, GLUT4 protein quantification by Western blot, cell surface GLUT4 labeling Diabetes High 25249576
2014 The adaptor protein APPL2 interacts with TBC1D1 via TBC1D1 phosphorylation on Ser235. Insulin stimulates TBC1D1 pSer235, which enhances TBC1D1 binding to the BAR domain of APPL2, which in turn suppresses insulin-evoked TBC1D1 phosphorylation on Thr596 in myotubes. APPL2 overexpression impairs GLUT4 trafficking and glucose uptake; conditional muscle APPL2 deletion enhances insulin sensitivity. The S235A mutation diminishes APPL2-mediated inhibition of Thr596 phosphorylation. Co-immunoprecipitation, APPL2 overexpression and knockdown, conditional muscle APPL2 KO mice, site-directed mutagenesis, GLUT4 translocation assay, glucose uptake in myotubes Diabetes High 24879834
2015 TBC1D1 knockout mice have impaired exercise-mediated 2-deoxyglucose uptake and impaired exercise endurance specifically in white (non-oxidative) but not red muscles. GLUT4 protein levels are reduced ~40% in white TBC1D1-/- muscle. Insulin tolerance and basal glucose homeostasis are normal. TBC1D1 KO mouse generation, in vivo exercise glucose uptake measurement, GLUT4 protein quantification, treadmill exercise tolerance test Diabetes High 25576050
2016 A Tbc1d1 Ser231Ala knockin mutation partially impairs AICAR-stimulated (but not exercise-induced) muscle glucose uptake and cell surface GLUT4 content at submaximal AICAR doses. Muscle-specific AMPKα1/α2 double KO completely prevents AICAR-induced hypoglycemia and glucose uptake. This places TBC1D1 Ser231 phosphorylation downstream of AMPK in the AICAR-stimulated but not contraction-stimulated glucose uptake pathway. Knockin mouse model (Ser231Ala), skeletal muscle-specific AMPK double KO, isolated muscle glucose uptake, cell surface GLUT4 labeling, AICAR treatment Diabetologia High 27826658
2017 Rat TBC1D1 KO model shows that TBC1D1 ablation does not alter insulin-induced GLUT4 plasma membrane recruitment or whole-body insulin tolerance, but impairs contraction-induced sarcolemmal GLUT4 content and glucose uptake specifically in white gastrocnemius. TBC1D1 KO rats show increased fat oxidation and impaired exercise tolerance. Maximal ADP-stimulated mitochondrial respiration is higher in KO permeabilized muscle fibers. Rat TBC1D1 KO model, sarcolemmal GLUT4 content measurement, ex vivo muscle contraction, insulin tolerance test, mitochondrial respiration in permeabilized fibers, treadmill exercise The Journal of biological chemistry High 28808062
2018 Full-length recombinant TBC1D1 shows RabGAP activity toward Rab8a, Rab10, and Rab14 (GLUT4-associated Rabs), with markedly higher catalytic activity than the truncated GAP domain alone. In vitro phosphorylation of TBC1D1 by AKT or AMPK increases 14-3-3 binding but does not alter intrinsic RabGAP activity. However, TBC1D1 interacts through its N-terminal PTB domains with the cytoplasmic tail of IRAP (insulin-regulated aminopeptidase, a resident protein of GLUT4 storage vesicles), and this interaction is disrupted by AKT or AMPK phosphorylation of TBC1D1. Baculovirus/Sf9 expression of full-length recombinant TBC1D1, in vitro RabGAP assay, in vitro AKT/AMPK phosphorylation, 14-3-3 binding assay, Co-immunoprecipitation with IRAP The Journal of biological chemistry High 30275018
2018 AMPKα1-containing heterotrimers (but not α2) form a stable, direct association with TBC1D1 via a dual interaction mechanism involving both PTB domains of TBC1D1. This interaction is increased by AMPK activators (AICAR, A769662) and enhances AMPK-mediated phosphorylation of TBC1D1 on Ser237. The obesity-associated R125W mutation in PTB1 reduces this α1-AMPK association and concomitantly reduces Ser237 phosphorylation. Co-immunoprecipitation, in vitro binding assays, isoform-specific AMPK constructs, pharmacological AMPK activation, R125W mutant analysis, Ser237 phosphorylation measurement The Biochemical journal High 30135087
2018 When both TBC1D1 and AS160 are present, TBC1D1 functionally dominates AS160 in GLUT4 regulation, with stimuli-inducible GLUT4 release relying on TBC1D1-evoking proximal stimuli (AICAR, intracellular Ca2+). AS160 modulates the sensitivity to external stimuli in TBC1D1-mediated GLUT4 release. These cooperative actions require TBC1D1 PTB1 and calmodulin-binding domains and phosphorylation at AS160 Thr642 and TBC1D1 Ser237/Thr596. GLUT4 nanometry, cell-based reconstitution with varying expression ratios of TBC1D1 and AS160, mutational analysis of PTB1, calmodulin-binding domain, and phosphosites The Journal of biological chemistry High 30482843
2016 Rab28 is a substrate for the GAP domains of both TBC1D1 and TBC1D4 in vitro. Rab28 GTP-binding state is acutely regulated by insulin in intact isolated mouse skeletal muscle. siRNA-mediated knockdown of Rab28 decreases basal glucose uptake; constitutively active Rab28-Q72L overexpression increases basal cell surface GLUT4 levels in adipocytes. In vitro RabGAP assay with recombinant proteins, siRNA knockdown of Rab28 in skeletal muscle, constitutively active Rab28 overexpression in adipocytes, cell surface GLUT4 measurement FEBS letters High 27929607
2019 WNK1 phosphorylates TBC1D1 on Ser565 (and TBC1D4 on Ser704) as identified by mass spectrometry. Phosphomimetic or unphosphorylatable TBC1D1 Ser565 mutants alter cell surface abundance of GLUT1. WNK1 downregulation decreases plasma membrane GLUT1 expression and glucose uptake by ~60% in HEK293 cells. Mass spectrometry phosphosite identification, WNK1 siRNA knockdown, phosphomimetic/unphosphorylatable TBC1D1 mutant transfection, cell surface GLUT1 quantification, glucose uptake assay Archives of biochemistry and biophysics Medium 31816312
2020 TBC1D1 interacts with VPS13A and VPS13C, the Rab-binding proteins EHBP1L1 and MICAL1, and the calcium pump SERCA1 via its PTB domains in C2C12 myotubes, as identified by quantitative proteomics. These interactions are not regulated by AMPK activation (unlike the AMPKα1 interaction). Depletion of VPS13A or VPS13C increases cellular GLUT4 protein and enhances cell surface GLUT4 in response to AMPK activation, specifically. Quantitative affinity-purification mass spectrometry, siRNA depletion of VPS13A/C, cell surface GLUT4 measurement in C2C12 myotubes Scientific reports Medium 33087848
2014 TBC1D1 overexpression in mouse soleus reduces palmitate oxidation and blunts AICAR-stimulated palmitate oxidation, increases glucose oxidation, and reduces β-HAD enzyme activity. This regulation of fatty acid oxidation is independent of changes in FAT/CD36, mitochondrial content, CPT1, AS160, ACC, or AMPK expression/phosphorylation. In vivo electrotransfection/overexpression in mouse soleus, palmitate and glucose oxidation assays, β-HAD enzyme activity assay American journal of physiology. Regulatory, integrative and comparative physiology Medium 25163918
2013 TBC1D1 is expressed in pancreatic β-cells and is phosphorylated in response to glucose stimulation. Knockdown of TBC1D1 in β-cells results in increased basal and glucose-stimulated insulin release and decreased proliferation, without change in apoptosis. Western blotting, phosphorylation analysis in human and rat β-cells, TBC1D1 siRNA knockdown, insulin secretion assay, proliferation/apoptosis assays FEBS letters Medium 24239544
2022 AMPK-TBC1D1 signaling regulates GTP-bound Rab2A levels: when AMPK-TBC1D1 phosphorylation is suppressed (nutrition repletion), GTP-Rab2A increases and stabilizes PPARγ protein, promoting hepatic lipid accumulation. Tbc1d1 S231A knock-in mice (blocking AMPK phosphorylation of TBC1D1) show increased GTP-bound Rab2A and develop fatty liver with aging. TBC1D1 S231A knockin mouse model, GTP-Rab2A pulldown assay, Rab2A knockdown in NAFLD models, PPARγ protein stability assays PLoS biology Medium 35061665
2020 Upon lipid/fatty acid overload, AMPK phosphorylates TBC1D1 (alongside PKCζ activation), leading to release of cytosolic CD36 and increased sarcolemmal CD36 translocation for fatty acid transport. Inhibition of TBC1D1 and PKCζ is synergistic in impairing CD36 redistribution. AMPK is upstream of PKCζ in this pathway. Gene knockdown and overexpression in L6 cells, Co-immunoprecipitation, kinase activity assay, surface CD36 detection, high fat diet mouse model Theranostics Medium 31938068

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
2015 R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 276 25568347
2010 Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proceedings of the National Academy of Sciences of the United States of America 239 20660762
2008 Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. The Journal of biological chemistry 211 18276596
2012 Structurally distinct bacterial TBC-like GAPs link Arf GTPase to Rab1 inactivation to counteract host defenses. Cell 177 22939626
2008 Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. The Biochemical journal 169 17995453
2008 Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nature genetics 169 18931681
2011 TBC proteins: GAPs for mammalian small GTPase Rab? Bioscience reports 155 21250943
2007 Substrate specificity and effect on GLUT4 translocation of the Rab GTPase-activating protein Tbc1d1. The Biochemical journal 153 17274760
2006 Screening for target Rabs of TBC (Tre-2/Bub2/Cdc16) domain-containing proteins based on their Rab-binding activity. Genes to cells : devoted to molecular & cellular mechanisms 134 16923123
2008 Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. The Journal of biological chemistry 133 18258599
2009 Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle. American journal of physiology. Endocrinology and metabolism 131 19531644
2010 TBC1D1 regulates insulin- and contraction-induced glucose transport in mouse skeletal muscle. Diabetes 123 20299473
2006 TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition. Human molecular genetics 122 16893906
2014 Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia 120 25280670
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
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
2009 Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus. Biochemical and biophysical research communications 92 19265681
2005 TBC domain family, member 15 is a novel mammalian Rab GTPase-activating protein with substrate preference for Rab7. Biochemical and biophysical research communications 88 16055087
2010 Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle. The Biochemical journal 83 20701589
2014 “Deletion of both Rab-GTPase–activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport [corrected]. Diabetes 77 25249576
2009 Insulin-stimulated phosphorylation of the Rab GTPase-activating protein TBC1D1 regulates GLUT4 translocation. The Journal of biological chemistry 74 19740738
2008 R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population. Human molecular genetics 74 18325908
2010 TBC-2 regulates RAB-5/RAB-7-mediated endosomal trafficking in Caenorhabditis elegans. Molecular biology of the cell 70 20462958
2012 The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism. American journal of physiology. Endocrinology and metabolism 68 22693207
2011 Autologous stem cell transplantation with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning in patients with CNS involvement by non-Hodgkin lymphoma. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 67 21749848
2001 Identification of EPI64, a TBC/rabGAP domain-containing microvillar protein that binds to the first PDZ domain of EBP50 and E3KARP. The Journal of cell biology 66 11285285
2015 The Evolutionarily Conserved Tre2/Bub2/Cdc16 (TBC), Lysin Motif (LysM), Domain Catalytic (TLDc) Domain Is Neuroprotective against Oxidative Stress. The Journal of biological chemistry 65 26668325
2004 The TBC (Tre-2/Bub2/Cdc16) domain protein TRE17 regulates plasma membrane-endosomal trafficking through activation of Arf6. Molecular and cellular biology 64 15509780
2010 Exercise-induced TBC1D1 Ser237 phosphorylation and 14-3-3 protein binding capacity in human skeletal muscle. The Journal of physiology 63 20837646
2013 Conventional knockout of Tbc1d1 in mice impairs insulin- and AICAR-stimulated glucose uptake in skeletal muscle. Endocrinology 59 23892475
2007 A Rab-GAP TBC domain protein binds hepatitis C virus NS5A and mediates viral replication. Journal of virology 59 17686842
2011 Exercise increases TBC1D1 phosphorylation in human skeletal muscle. American journal of physiology. Endocrinology and metabolism 58 21505148
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
2013 ACBD3 interaction with TBC1 domain 22 protein is differentially affected by enteroviral and kobuviral 3A protein binding. mBio 56 23572552
2009 C. elegans Rab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5. Development (Cambridge, England) 54 19542357
2015 The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle. Diabetes 52 25576050
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
2006 The EVI5 TBC domain provides the GTPase-activating protein motif for RAB11. Oncogene 50 17099728
1997 Translation of the chloroplast psbC mRNA is controlled by interactions between its 5' leader and the nuclear loci TBC1 and TBC3 in Chlamydomonas reinhardtii. Molecular and cellular biology 49 9154843
2016 Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia. American journal of human genetics 48 27040691
1998 NB4S, a member of the TBC1 domain family of genes, is truncated as a result of a constitutional t(1;10)(p22;q21) chromosome translocation in a patient with stage 4S neuroblastoma. Human molecular genetics 48 9618176
2008 Identification and characterization of a novel Tre-2/Bub2/Cdc16 (TBC) protein that possesses Rab3A-GAP activity. Genes to cells : devoted to molecular & cellular mechanisms 46 19077034
2010 Evaluation of the rapid MGIT TBc identification test for culture confirmation of Mycobacterium tuberculosis complex strain detection. Journal of clinical microbiology 44 21191055
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
2008 Akt substrate TBC1D1 regulates GLUT1 expression through the mTOR pathway in 3T3-L1 adipocytes. The Biochemical journal 38 18215134
2018 Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease - a new type of neuronal ceroid lipofuscinosis (CLN15)? Acta neuropathologica communications 37 30591081
2017 Ablating the protein TBC1D1 impairs contraction-induced sarcolemmal glucose transporter 4 redistribution but not insulin-mediated responses in rats. The Journal of biological chemistry 37 28808062
2010 Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis. Genes, chromosomes & cancer 37 20095038
2019 Specific TBC Domain-Containing Proteins Control the ER-Golgi-Plasma Membrane Trafficking of GPCRs. Cell reports 34 31291588
2013 Insulin stimulation regulates AS160 and TBC1D1 phosphorylation sites in human skeletal muscle. Nutrition & diabetes 34 23752133
2007 Identification of TBC7 having TBC domain as a novel binding protein to TSC1-TSC2 complex. Biochemical and biophysical research communications 34 17658474
2020 Lipid oversupply induces CD36 sarcolemmal translocation via dual modulation of PKCζ and TBC1D1: an early event prior to insulin resistance. Theranostics 33 31938068
2018 AKT and AMP-activated protein kinase regulate TBC1D1 through phosphorylation and its interaction with the cytosolic tail of insulin-regulated aminopeptidase IRAP. The Journal of biological chemistry 33 30275018
2016 A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice. Diabetologia 33 27826658
2001 Thiotepa, busulfan, cyclophosphamide (TBC) and autologous hematopoietic transplantation: an intensive regimen for the treatment of multiple myeloma. Bone marrow transplantation 33 11477439
1996 Influence of the mouse Bcg, Tbc-1 and xid genes on resistance and immune responses to tuberculosis infection and efficacy of bacille Calmette-Guérin (BCG) vaccination. Clinical and experimental immunology 33 8603530
2015 Basolateral Endocytic Recycling Requires RAB-10 and AMPH-1 Mediated Recruitment of RAB-5 GAP TBC-2 to Endosomes. PLoS genetics 32 26393361
2012 CED-10/Rac1 regulates endocytic recycling through the RAB-5 GAP TBC-2. PLoS genetics 32 22807685
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
2021 GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity. Nature communications 30 34853313
2010 Evaluation of the BD MGIT TBc Identification Test (TBc ID), a rapid chromatographic immunoassay for the detection of Mycobacterium tuberculosis complex from liquid culture. Journal of microbiological methods 29 21167879
2014 The adaptor protein APPL2 inhibits insulin-stimulated glucose uptake by interacting with TBC1D1 in skeletal muscle. Diabetes 28 24879834
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
2010 The porcine TBC1D1 gene: mapping, SNP identification, and association study with meat, carcass and production traits in Italian heavy pigs. Molecular biology reports 26 20730498
2002 Serological cloning of PARIS-1: a new TBC domain-containing, immunogenic tumor antigen from a prostate cancer cell line. Biochemical and biophysical research communications 26 11785977
2001 Genetic and functional analysis of the tbc operons for catabolism of alkyl- and chloroaromatic compounds in Burkholderia sp. strain JS150. Applied and environmental microbiology 26 11571188
2020 Benzyl Isothiocyanate Ameliorates High-Fat Diet-Induced Hyperglycemia by Enhancing Nrf2-Dependent Antioxidant Defense-Mediated IRS-1/AKT/TBC1D1 Signaling and GLUT4 Expression in Skeletal Muscle. Journal of agricultural and food chemistry 25 33301311
2018 Cooperative actions of Tbc1d1 and AS160/Tbc1d4 in GLUT4-trafficking activities. The Journal of biological chemistry 25 30482843
2016 Comparative transcriptome analysis between an evolved abscisic acid-overproducing mutant Botrytis cinerea TBC-A and its ancestral strain Botrytis cinerea TBC-6. Scientific reports 25 27892476
2009 A myosin II ATPase inhibitor reduces force production, glucose transport, and phosphorylation of AMPK and TBC1D1 in electrically stimulated rat skeletal muscle. American journal of physiology. Endocrinology and metabolism 25 19190254
1998 Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage: dose study and review of endothelin-based therapies in the literature on cerebral vasospasm. Neurosurgery 24 9848855
2015 Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT). Human genetics 23 26572137
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
2022 Rab2A regulates the progression of nonalcoholic fatty liver disease downstream of AMPK-TBC1D1 axis by stabilizing PPARγ. PLoS biology 22 35061665
2013 Regulatory mode shift of Tbc1d1 is required for acquisition of insulin-responsive GLUT4-trafficking activity. Molecular biology of the cell 22 23325788
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
2011 The oncogenic TBC domain protein USP6/TRE17 regulates cell migration and cytokinesis. Biology of the cell 22 22188517
2010 TBC-2 is required for embryonic yolk protein storage and larval survival during L1 diapause in Caenorhabditis elegans. PloS one 22 21203392
1980 Augmented induction of tumor-specific resistance by priming with Mycobacterium tuberculosis (TBC) and subsequent immunization with PPD-coupled syngeneic tumor cells. Journal of immunology (Baltimore, Md. : 1950) 20 6776192
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
2015 Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice. American journal of physiology. Endocrinology and metabolism 19 26015432
2016 Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking. FEBS letters 18 27929607
2014 Detection of SNPs in the TBC1D1 gene and their association with carcass traits in chicken. Gene 18 24979340
2004 The anti-inflammatory effects of a selectin ligand mimetic, TBC-1269, are not a result of competitive inhibition of leukocyte rolling in vivo. Journal of leukocyte biology 18 15466915
2013 Identification and Association of SNPs in TBC1D1 Gene with Growth Traits in Two Rabbit Breeds. Asian-Australasian journal of animal sciences 17 25049738
2021 Regulation of lipid homeostasis by the TBC protein dTBC1D22 via modulation of the small GTPase Rab40 to facilitate lipophagy. Cell reports 16 34469730
2020 Epidermal control of axonal attachment via β-spectrin and the GTPase-activating protein TBC-10 prevents axonal degeneration. Nature communications 16 31919407
2020 TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes. Scientific reports 16 33087848
2019 WNK1 phosphorylation sites in TBC1D1 and TBC1D4 modulate cell surface expression of GLUT1. Archives of biochemistry and biophysics 16 31816312
2018 Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity. The Biochemical journal 15 30135087
2014 TBC1D1 reduces palmitate oxidation by inhibiting β-HAD activity in skeletal muscle. American journal of physiology. Regulatory, integrative and comparative physiology 15 25163918
2013 Expression, phosphorylation and function of the Rab-GTPase activating protein TBC1D1 in pancreatic beta-cells. FEBS letters 15 24239544
2013 The TBC1D1 gene: structure, function, and association with obesity and related traits. Vitamins and hormones 14 23374713
2012 TBC: a clustering algorithm based on prokaryotic taxonomy. Journal of microbiology (Seoul, Korea) 14 22538644
2013 Exploratory study on association of genetic variation in TBC1D1 with antipsychotic-induced weight gain. Human psychopharmacology 13 23364847
2021 Tris (2,3-Dibromopropyl) Isocyanurate (TDBP-TAZTO or TBC) Shows Different Toxicity Depending on the Degree of Differentiation of the Human Neuroblastoma (SH-SY5Y) Cell Line. Neurotoxicity research 12 34342853
2020 Increased glucose metabolism in Arid5b-/- skeletal muscle is associated with the down-regulation of TBC1 domain family member 1 (TBC1D1). Biological research 12 33023658
2017 Vps34 and the Armus/TBC-2 Rab GAPs: Putting the brakes on the endosomal Rab5 and Rab7 GTPases. Cellular logistics 12 29296513
2007 Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways. The Biochemical journal 11 17376030