Insulin-stimulated Phosphorylation of the Rab GTPase-activating Protein TBC1D1 Regulates GLUT4 Translocation
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Insulin stimulates the translocation of the glucose transporter GLUT4 from intracellular locations to the plasma membrane in adipose and muscle cells. Prior studies have shown that Akt phosphorylation of the Rab GTPase-activating protein, AS160 (160-kDa Akt substrate; also known as TBC1D4), triggers GLUT4 translocation, most likely by suppressing its Rab GTPase-activating protein activity. However, the regulation of a very similar protein, TBC1D1 (TBC domain family, member 1), which is mainly found in muscle, in insulin-stimulated GLUT4 translocation has been unclear. In the present study, we have identified likely Akt sites of insulin-stimulated phosphorylation of TBC1D1 in C2C12 myotubes. We show that a mutant of TBC1D1, in which several Akt sites have been converted to alanine, is considerably more inhibitory to insulin-stimulated GLUT4 translocation than wild-type TBC1D1. This result thus indicates that similar to AS160, Akt phosphorylation of TBC1D1 enables GLUT4 translocation. We also show that in addition to Akt activation, activation of the AMP-dependent protein kinase partially relieves the inhibition of GLUT4 translocation by TBC1D1. Finally, we show that the R125W variant of TBC1D1, which has been genetically associated with obesity, is equally inhibitory to insulin-stimulated GLUT4 translocation, as is wild-type TBC1D1, and that healthy and type 2 diabetic individuals express approximately the same level of TBC1D1 in biopsies of vastus lateralis muscle. In conclusion, phosphorylation of TBC1D1 is required for GLUT4 translocation. Thus, the regulation of TBC1D1 resembles that of its paralog, AS160.
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TBC1D1 expression is normal in skeletal muscle from type 2 diabetics.
“TBC1D1 expression is normal in skeletal muscle from type 2 diabetics [99], suggesting a possible explanation for normal glucose uptake during exercise in these subjects.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [99]
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- Authors
- Peck, G. R., Chavez, J. A., Roach, W. G., Budnik, B. A., Lane, W. S., Karlsson, H. K. R., Zierath, J. R., & Lienhard, G. E.
- Affiliations
- Dartmouth College (US)
- Harvard University (US)
- Karolinska Institutet (SE)
- Corresponding author
- Lienhard, Gustav E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 284
- Issue
- 44
- Pages
- 30016-30023
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2781555
- OpenAlex
- W1967821760
- Cited by
- 95
- References
- 26
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 6 · 2015: 5 · 2014: 8 · 2013: 6 · 2012: 9
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA023108)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK025336, DK-25336, R56DK042816, R56DK025336, DK42816, R01DK042816)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- TBC1D1, GLUT4 translocation, insulin signaling, Akt phosphorylation, Rab GTPase-activating protein, AS160, muscle glucose uptake, obesity, type 2 diabetes, vastus lateralis, C2C12 myotubes
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Insulin, Nuclear Proteins, Phosphorylation, Muscle, Skeletal, GTPase-Activating Proteins, Protein Transport, 3T3-L1 Cells, Proto-Oncogene Proteins c-akt, Glucose Transporter Type 4, Mice
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