Translocation of SLC2A4 (GLUT4) to the plasma membrane

Stable Identifier
R-HSA-1445148
Type
Pathway
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 (SLC2A4) glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011, Jaldin-Fincati et al. 2017). In myocytes muscle contraction alone can also cause translocation of GLUT4.
Though the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins.
Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane.

Literature References
PubMed ID Title Journal Year
28602209 Update on GLUT4 Vesicle Traffic: A Cornerstone of Insulin Action

Jaldin-Fincati, JR, Pavarotti, M, Frendo-Cumbo, S, Bilan, PJ, Klip, A

Trends Endocrinol. Metab. 2017
20417083 Biogenesis and regulation of insulin-responsive vesicles containing GLUT4

Bogan, JS, Kandror, KV

Curr Opin Cell Biol 2010
21405107 Endocytosis, recycling, and regulated exocytosis of glucose transporter 4

Foley, K, Boguslavsky, S, Klip, A

Biochemistry 2011
19389739 The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets

Leney, SE, Tavaré, JM

J Endocrinol 2009
21216617 Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis

Hoffman, NJ, Elmendorf, JS

Trends Endocrinol Metab 2011
21306486 The sugar is sIRVed: sorting Glut4 and its fellow travelers

Kandror, KV, Pilch, PF

Traffic 2011
18570632 Insulin action on glucose transporters through molecular switches, tracks and tethers

Zaid, H, Antonescu, C, Randhawa, VK, Klip, A

Biochem J 2008
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