Thirty sweet years of GLUT4

Klip, Amira; McGraw, Timothy E.; James, David E.

doi:10.1074/jbc.rev119.008351

Cited by 262 publications

(287 citation statements)

References 154 publications

(119 reference statements)

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“…These data are the first direct evidence demonstrating that insulin signaling accelerates mobilization of GLUT4 from the perinuclear region. Insulin-stimulated GLUT4 translocation in adipocytes and muscle requires activation of AKT (1). Insulin regulation of GLUT4 mobilization from the perinuclear region is downstream of AKT in 3T3-L1 adipocytes, and as compared to insulin in the presence of DMSO (vehicle), insulin in the presence of AKT inhibitor MK2206 (44) could not promote the mobilization of HA-GLUT4-mEos3.2 from the perinuclear region (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We find insulin does not regulate GLUT4 recruitment to the perinuclear region. A large portion of GLUT4 in the PM is internalized by clathrin-mediated endocytosis together with constitutively recycling cargo such as TR (1). GLUT4-containing endosomes are sent to the TGN, and the observation that delivery of GLUT4 to the TGN is not regulated by insulin is not surprising given insulin stimulation has little effect on TR trafficking (1).…”

Section: Discussionmentioning

confidence: 99%

“…Regulation of glucose uptake by fat and muscle cells, essential for the maintenance of whole-body glucose homeostasis, is determined by the levels of glucose transporter 4 (GLUT4) in the plasma membranes (PM) of these cells (1). GLUT4 cycles between intracellular compartments and the PM, with the distribution determined by the rates of exocytosis and endocytosis (2–5).…”

Section: Introductionmentioning

confidence: 99%

“…GLUT4 cycles between intracellular compartments and the PM, with the distribution determined by the rates of exocytosis and endocytosis (2–5). The main effect of insulin is to stimulate GLUT4 exocytosis to increase the amount of PM GLUT4, thereby promoting increased glucose uptake (1).…”

Section: Introductionmentioning

confidence: 99%

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Insulin promoted mobilization of GLUT4 from a perinuclear storage site requires RAB10

Brumfield

Chaudhary

Molle

et al. 2020

Preprint

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25Insulin controls glucose uptake into muscle and fat cells by inducing a net redistribution of 26 GLUT4 from intracellular storage to the plasma membrane (PM). The TBC1D4-RAB10 signaling 27 module is required for insulin-stimulated GLUT4 translocation to the PM, although where it 28 intersects GLUT4 traffic was unknown. Here we demonstrate that TBC1D4-RAB10 functions to 29 control GLUT4 mobilization from a Trans Golgi Network (TGN) storage compartment, 30 establishing that insulin, in addition to regulating the PM proximal effects of GLUT4-containing 31 vesicles docking to and fusion with the PM, also directly regulates the behavior of GLUT4 32 deeper within the cell. We also show that GLUT4 is retained in an element/domain of the TGN 33 from which newly synthesized lysosomal proteins are targeted to the late endosomes and the 34 ATP7A copper transporter is translocated to the PM by elevated copper. Insulin does not 35 mobilize ATP7A nor does copper mobilize GLUT4. Consequently, GLUT4 intracellular 36 sequestration and mobilization by insulin is achieved, in part, through utilizing a region of the 37 TGN devoted to specialized cargo transport in general rather than being specific for GLUT4. 38Our results define GLUT4-containing region of the TGN as a sorting and storage site from which 39 different cargo are mobilized by distinct signals. 40 11) whose delivery to the PM is regulated by insulin (2). GLUT4 in the PM cycles back to the 51 TGN via the endosomal pathway (2, 12, 13). Targeting GLUT4 from endosomes to the TGN has 52 an important role in basal intracellular GLUT4 retention. Mutations in GLUT4 that disrupt its 53 traffic from endosomes to the TGN are poorly retained in basal conditions and are not properly 54 translocated to the PM upon insulin stimulation (6, 14-16). These results identify the TGN as the 55 site for formation of IRVs. The TGN is a main sorting compartment along the biosynthetic and 56 endocytic pathways. Cargoes to be targeted to distinct destinations are sorted and packaged 57 into the correct transport vesicles in the TGN. The relationship between the TGN containing 58 GLUT4 and the TGN involved in the traffic of other cargoes is not known (2, 6, 8, 12). 59Insulin signaling triggers multiple discrete molecular events that mediate efficient recruitment, 60 docking, and fusion of IRVs with the PM (17-19). These events lead to a decrease in the size of 61 the intracellular GLUT4 pool concomitant with an increase of GLUT4 in the PM. As GLUT4 in 62 the PM is in equilibrium with intracellular GLUT4, endocytosis of GLUT4 dynamically removes 63 GLUT4 from the PM. Thus, maintenance of the insulin-stimulated dynamic increase in GLUT4 64 in the PM requires the continual ferrying of GLUT4-containing IRVs to the PM. Insulin signaling 65 can add to the IRV pool by increasing the rate of GLUT4 mobilization from the TGN in nascent 66IRVs. Despite the biological importance, insulin regulation of GLUT4 trafficking at the 67 perinuclear region has not been thoroughly interrogated. 68A key aspect of insu...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Insulin promoted mobilization of GLUT4 from a perinuclear storage site requires RAB10

Brumfield

Chaudhary

Molle

et al. 2020

Preprint

Self Cite

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“…The process of regulating the subcellular localization of GLUT4 is exceedingly complex and has been reviewed recently (Klip et al 2019). A number of 21 kDa Rab GTPases have been implicated to be involved in GLUT4 vesicle traffic, and their activation state, GTP-bound or GDP-bound, is presumably regulated by the RabGAPs TBC1D1 and TBC1D4 (Zerial & McBride 2001).…”

Section: Skeletal Muscle Metabolism Is Crucial In Controlling Systemimentioning

confidence: 99%

RabGAPs in skeletal muscle function and exercise

Espelage

Al-Hasani

Chadt

2020

Journal of Molecular Endocrinology

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The two closely related RabGAPs TBC1D1 and TBC1D4 are key signaling factors of skeletal muscle substrate utilization. In mice, deficiency in both RabGAPs leads to reduced skeletal muscle glucose transport in response to insulin and lower GLUT4 abundance. Conversely, Tbc1d1 and Tbc1d4 deficiency results in enhanced lipid use as fuel in skeletal muscle, through yet unknown mechanisms. In humans, variants in TBC1D1 and TBC1D4 are linked to obesity, insulin resistance and type 2 diabetes. While the specific function in metabolism of each of the two RabGAPs remains to be determined, TBC1D1 emerges to be controlling exercise endurance and physical capacity, whereas TBC1D4 may rather be responsible for maintaining muscle insulin sensitivity, muscle contraction, and exercise. There is growing evidence that TBC1D1 also plays an important role in skeletal muscle development, since it has been found to be associated to meat production traits in several livestock species. In addition, TBC1D1 protein abundance in skeletal muscle is regulated by both, insulin receptor and insulin-like growth factor-1 (IGF-1) receptor signaling. This review focuses on the specific roles of the two key signaling factors TBC1D1 and TBC1D4 in skeletal muscle metabolism, development and exercise physiology.

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Akt may associate with insulin‐responsive vesicles via interaction with sortilin

Zaarur,

Meriin,

Singh

et al. 2023

FEBS Letters

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Insulin‐responsive vesicles (IRVs) deliver the glucose transporter Glut4 to the plasma membrane in response to activation of the insulin signaling cascade: insulin receptor–IRS–PI3 kinase–Akt–TBC1D4–Rab10. Previous studies have shown that Akt, TBC1D4, and Rab10 are compartmentalized on the IRVs. Although functionally significant, the mechanism of Akt association with the IRVs remains unknown. Using pull‐down assays, immunofluorescence microscopy, and cross‐linking, we have found that Akt may be recruited to the IRVs via the interaction with the juxtamembrane domain of the cytoplasmic C terminus of sortilin, a major IRV protein. Overexpression of full‐length sortilin increases insulin‐stimulated phosphorylation of TBC1D4 and glucose uptake in adipocytes, while overexpression of the cytoplasmic tail of sortilin has the opposite effect. Our findings demonstrate that the IRVs represent both a scaffold and a target of insulin signaling.

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Thirty sweet years of GLUT4

Cited by 262 publications

References 154 publications

Insulin promoted mobilization of GLUT4 from a perinuclear storage site requires RAB10

Insulin promoted mobilization of GLUT4 from a perinuclear storage site requires RAB10

RabGAPs in skeletal muscle function and exercise

Akt may associate with insulin‐responsive vesicles via interaction with sortilin

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