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

Tan, Shi‐Xiong; Ng, Yi Zhen; Burchfield, James G.; Ramm, Georg; Lambright, David G.; Stöckli, Jacqueline; James, David E.

doi:10.1128/mcb.00761-12

Cited by 60 publications

(59 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We demonstrated that Akt provides the fidelity of spatial release of GLUT4 on the cell surface, and our findings support previous work that Akt signaling at the plasma membrane is required for the last step of GLUT4 exocytosis (Koumanov et al, 2005). Moreover, a downstream target of Akt, AS160, is mobilized to the plasma membrane and regulates GLUT4 vesicle exocytosis (Tan et al, 2012). Therefore, it is conceivable that locally activated Akt might recruit AS160 and its downstream Rab proteins, as well as the exocyst complex (Chen et al, 2011), to control the spatial release of GLUT4 into the plasma membrane.…”

Section: Discussionsupporting

confidence: 78%

Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action

Nan

Fan

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

Glucose transporter 4 (GLUT4; also known as SLC2A4) resides on intracellular vesicles in muscle and adipose cells, and translocates to the plasma membrane in response to insulin. The phosphoinositide 3-kinase (PI3K)-Akt signaling pathway plays a major role in GLUT4 translocation; however, a challenge has been to unravel the potentially distinct contributions of PI3K and Akt (of which there are three isoforms, Akt1-Akt3) to overall insulin action. Here, we describe new optogenetic tools based on CRY2 and the N-terminus of CIB1 (CIBN). We used these 'Opto' modules to activate PI3K and Akt selectively in time and space in 3T3-L1 adipocytes. We validated these tools using biochemical assays and performed live-cell kinetic analyses of IRAP-pHluorin translocation (IRAP is also known as LNPEP and acts as a surrogate marker for GLUT4 here). Strikingly, Opto-PIP 3 largely mimicked the maximal effects of insulin stimulation, whereas Opto-Akt only partially triggered translocation. Conversely, drug-mediated inhibition of Akt only partially dampened the translocation response of Opto-PIP 3 . In spatial optogenetic studies, focal targeting of Akt to a region of the cell marked the sites where IRAP-pHluorin vesicles fused, supporting the idea that local Aktmediated signaling regulates exocytosis. Taken together, these results indicate that PI3K and Akt play distinct roles, and that PI3K stimulates Akt-independent pathways that are important for GLUT4 translocation.

show abstract

Section: Discussionsupporting

confidence: 78%

Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action

Nan

Fan

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…So far, Rab2, Rab8b, Rab10, and Rab14 have been identified as substrates for recombinant GAP domains of TBC1D1 and TBC1D4 in vitro (4,16), but the significance of these findings for GLUT4 translocation in adipose and muscle cells in vivo remains to be further investigated. Moreover, the phosphotyrosine-binding domains may also be involved in TBC1D1/TBC1D4 signaling (17)(18)(19). Previous studies of isolated L6 muscle cells and 3L3-L1 adipocytes demonstrated that ablation of either Tbc1d1 or Tbc1d4, or overexpression of mutated proteins, resulted in reduced insulin-stimulated translocation of GLUT4 (20)(21)(22).…”

mentioning

confidence: 99%

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport

et al. 2014

View full text Add to dashboard Cite

The Rab-GTPase-activating proteins TBC1D1 and TBC1D4 (AS160) were previously shown to regulate GLUT4 translocation in response to activation of AKT and AMPdependent kinase. However, knockout mice lacking either Tbc1d1 or Tbc1d4 displayed only partially impaired insulin-stimulated glucose uptake in fat and muscle tissue. The aim of this study was to determine the impact of the combined inactivation of Tbc1d1 and Tbc1d4 on glucose metabolism in double-deficient (D1/4KO) mice. D1/4KO mice displayed normal fasting glucose concentrations but had reduced tolerance to intraperitoneally administered glucose, insulin, and AICAR. D1/4KO mice showed reduced respiratory quotient, indicating increased use of lipids as fuel. These mice also consistently showed elevated fatty acid oxidation in isolated skeletal muscle, whereas insulin-stimulated glucose uptake in muscle and adipose cells was almost completely abolished. In skeletal muscle and white adipose tissue, the abundance of GLUT4 protein, but not GLUT4 mRNA, was substantially reduced. Cell surface labeling of GLUTs indicated that RabGAP deficiency impairs retention of GLUT4 in intracellular vesicles in the basal state. Our results show that TBC1D1 and TBC1D4 together play essential roles in insulin-stimulated glucose uptake and substrate preference in skeletal muscle and adipose cells.

show abstract

“…The suggested mechanism for TBC1D1 regulation is primarily based on the wellknown regulation of its close homolog AS160. TBC1D1 interacts with IRAP (18), inactivates the same Rabs as AS160 (13), and binds 14-3-3 upon phosphorylation (16,19). Although Akt mediates AS160 phosphorylation on the crucial 14-3-3 binding sites, linking AS160 to insulin signaling, TBC1D1 binds 14-3-3 in response to AMPK activation, a kinase activated by exercise (2).…”

Section: /2mentioning

confidence: 99%

The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

et al. 2015

Self Cite

View full text Add to dashboard Cite

Insulin and exercise stimulate glucose uptake into skeletal muscle via different pathways. Both stimuli converge on the translocation of the glucose transporter GLUT4 from intracellular vesicles to the cell surface. Two Rab guanosine triphosphatases-activating proteins (GAPs) have been implicated in this process: AS160 for insulin stimulation and its homolog, TBC1D1, are suggested to regulate exercise-mediated glucose uptake into muscle. TBC1D1 has also been implicated in obesity in humans and mice. We investigated the role of TBC1D1 in glucose metabolism by generating TBC1D1 2/2 mice and analyzing body weight, insulin action, and exercise. TBC1D12/2 mice showed normal glucose and insulin tolerance, with no difference in body weight compared with wild-type littermates. GLUT4 protein levels were reduced by ∼40% in white TBC1D1 2/2 muscle, and TBC1D1 2/2 mice showed impaired exercise endurance together with impaired exercise-mediated 2-deoxyglucose uptake into white but not red muscles. These findings indicate that the RabGAP TBC1D1 plays a key role in regulating GLUT4 protein levels and in exercise-mediated glucose uptake in nonoxidative muscle fibers.

show abstract

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

Cited by 60 publications

References 46 publications

Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action

Optogenetic activation reveals distinct roles of PIP3 and Akt in adipocyte insulin action

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport

The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

Contact Info

Product

Resources

About