AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain
Open accessAbstract
Recently, we described a 160 kDa protein (designated AS160, for Akt substrate of 160 kDa) with a predicted Rab GAP (GTPase-activating protein) domain that is phosphorylated on multiple sites by the protein kinase Akt. Phosphorylation of AS160 in adipocytes is required for insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane. The aim of the present study was to determine whether AS160 is in fact a GAP for Rabs, and, if so, what its specificity is. We first identified a group of 16 Rabs in a preparation of intracellular vesicles containing GLUT4 by MS. We then prepared the recombinant GAP domain of AS160 and examined its activity against many of these Rabs, as well as several others. The GAP domain was active against Rabs 2A, 8A, 10 and 14. There was no significant activity against 14 other Rabs. GAP activity was further validated by the finding that the recombinant GAP domain with the predicted catalytic arginine residue replaced by lysine was inactive. Finally, it was found by immunoblotting that Rabs 2A, 8A and 14 are present in GLUT4 vesicles. These results indicate that AS160 is a Rab GAP, and suggest novel Rabs that may participate in GLUT4 translocation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Following a single exercise bout, improved insulin action involves coordinated effects on vasodilation, capillary perfusion, and GLUT4 translocation to the muscle surface membrane.
“Following a single exercise bout, the mechanisms underlying improved insulin action involve a coordinated effect of insulin action on vasodilation, augmented capillary perfusion, and increased glucose transporter 4 (GLUT4) translocation to the muscle surface membrane 55, 56.”
From Effect of exercise training on insulin-stimulated glucose disposal: A systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [56]
The Introduction (page not provided) states that insulin stimulates GLUT4 movement to the cell surface in fat and muscle cells. It does not address improved insulin action following a single exercise bout, vasodilation, or augmented capillary perfusion; searches for exercise and perfusion found no supporting passage. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Rab proteins as membrane organizers
Zerial, M., & McBride, H. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35052055 · Cited by 3,381 · see citing works
Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation
Sano, H., Kane, S., Sano, E., Mı̂inea, C. P., Asara, J. M., Lane, W. S., Garner, C. W., & Lienhard, G. E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300063200 · Cited by 964 · see citing works
Self-citationBasu, S., Totty, N. F., Irwin, M. S., Sudol, M., & Downward, J. (2003) · Molecular Cell · doi:10.1016/s1097-2765(02)00776-1 · Cited by 843 · see citing works
Evolution of the rab family of small GTP-binding proteins
Pereira‐Leal, J. B., & Seabra, M. C. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2001.5072 · Cited by 770 · see citing works
A Method to Identify Serine Kinase Substrates
Kane, S., Sano, H., Liu, S. C. H., Asara, J. M., Lane, W. S., Garner, C. C., & Lienhard, G. E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200198200 · Cited by 529 · see citing works
Self-citationRegulated Membrane Trafficking of the Insulin-Responsive Glucose Transporter 4 in Adipocytes
Watson, R. T., Kanzaki, M., & Pessin, J. E. (2004) · Endocrine Reviews · doi:10.1210/er.2003-0011 · Cited by 448 · see citing works
Jiang, Z. Y., Zhou, Q. L., Coleman, K. A., Chouinard, M., Boese, Q., & Czech, M. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1332633100 · Cited by 378 · see citing works
The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin
Inoue, M., Chang, L. C., Hwang, J., Chiang, S.-H., & Saltiel, A. R. (2003) · Nature · doi:10.1038/nature01533 · Cited by 355 · see citing works
Keller, S. R., Scott, H. M., Mastick, C. C., Aebersold, R. H., & Lienhard, G. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.40.23612 · Cited by 325 · see citing works
Self-citationIsoform-specific Regulation of Insulin-dependent Glucose Uptake by Akt/Protein Kinase B
Bae, S. S., Cho, H., Mu, J., & Birnbaum, M. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306782200 · Cited by 312 · see citing works
The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5
Lanzetti, L., Rybin, V., Malabarba, M. G., Christoforidis, S., Scita, G., Zerial, M., & Fiore, P. P. D. (2000) · Nature · doi:10.1038/35042605 · Cited by 284 · see citing works
Cain, C. C., Trimble, W. S., & Lienhard, G. E. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)49748-2 · Cited by 274 · see citing works
Self-citationThe Exocyst Complex in Polarized Exocytosis
Hsu, S.-C., Terbush, D. R., Abraham, M., & Guo, W. (2004) · International review of cytology · doi:10.1016/s0074-7696(04)33006-8 · Cited by 266 · see citing works
Peränen, J., Auvinen, P., Virta, H., Wepf, R. A., & Simons, K. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.135.1.153 · Cited by 247 · see citing works
Self-citationRidley, A. J., Self, A. J., Kasmi, F., Paterson, H. F., Hall, A., Marshall, C. J., & Ellis, C. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb06210.x · Cited by 238 · see citing works
Insulin regulation of the two glucose transporters in 3T3-L1 adipocytes.
Calderhead, D. M., Kitagawa, K., Tanner, L. I., Holman, G. D., & Lienhard, G. E. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)77419-x · Cited by 234 · see citing works
Self-citationZeigerer, A., McBrayer, M. K., & McGraw, T. E. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-04-0333 · Cited by 226 · see citing works
Ang, A. L., Fölsch, H., Koivisto, U.-M., et al. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200307046 · Cited by 222 · see citing works
Katome, T., Obata, T., Matsushima, R., Masuyama, N., Cantley, L. C., Gotoh, Y., Kishi, K., Shiota, H., & Ebina, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302094200 · Cited by 212 · see citing works
Shewan, A. M., van Dam, E. M., Martin, S., Luen, T., Hong, W., Bryant, N. J., & James, D. E. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-06-0315 · Cited by 210 · see citing works
Rab14 Is Involved in Membrane Trafficking between the Golgi Complex and Endosomes
Junutula, J. R., Mazière, A. M. G. L. D., Peden, A. A., Ervin, K. E., Advani, R. J., van Dijk, S., Klumperman, J., & Scheller, R. H. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-10-0777 · Cited by 198 · see citing works
Characterization of the Insulin-regulated Membrane Aminopeptidase in 3T3-L1 Adipocytes
Ross, S. A., Scott, H. M., Morris, N. J., Leung, W., Mao, F., Lienhard, G. E., & Keller, S. R. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.6.3328 · Cited by 151 · see citing works
Self-citationInsulin and okadaic acid induce Rab4 redistribution in adipocytes.
Cormont, M., Tanti, J., Zahraoui, A., OBBERGHEN, E. V., Tavitian, A., & MARCHAND‐BRUSTEL, Y. L. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)36542-1 · Cited by 150 · see citing works
Chen, Y., Holcomb, C. L., & Moore, H. P. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.14.6508 · Cited by 147 · see citing works
Cuif, M., Possmayer, F., Zander, H., Bordes, N., Jollivet, F., Couëdel-Courteille, A., Janoueix‐Lerosey, I., Langsley, G., Bornens, M., & Goud, B. (1999) · The EMBO Journal · doi:10.1093/emboj/18.7.1772 · Cited by 145 · see citing works
Rab2 Is Essential for the Maturation of Pre-Golgi Intermediates
Tisdale, E. J., & Balch, W. E. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.46.29372 · Cited by 139 · see citing works
Rab11 is associated with GLUT4-containing vesicles and redistributes in response to insulin
Kessler, A., Tomás, E., Immler, D., Meyer, H. E., Zorzano, A., & Eckel, J. (2000) · Diabetologia · doi:10.1007/s001250051563 · Cited by 99 · see citing works
PRC17, a novel oncogene encoding a Rab GTPase-activating protein, is amplified in prostate cancer.
Pei, L., Yue, P., Yang, Y., Ling, X. B., van Eyndhoven, W., Nguyen, K. C. Q., Rubin, M. A., Hoey, T., Powers, S., & Li, J. (2002) · PubMed · Cited by 96 · see citing works
Du, L., & Novick, P. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.5.1215 · Cited by 79 · see citing works
Rab8 Regulates the Actin-based Movement of Melanosomes
Chabrillat, M. L., Wilhelm, C., Wasmeier, C., Sviderskaya, E. V., Louvard, D., & Coudrier, E. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-09-0770 · Cited by 65 · see citing works
Catalytic Domain of the p120 Ras GAP Binds to Rab5 and Stimulates Its GTPase Activity
Liu, K., & Li, G. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10087 · Cited by 56 · see citing works
Evidence for a Role of the Exocyst in Insulin-stimulated Glut4 Trafficking in 3T3-L1 Adipocytes
Ewart, M., Clarke, M., Kane, S., Chamberlain, L. H., & Gould, G. W. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409928200 · Cited by 54 · see citing works
Self-citationBiochemical Characterization of Gyp6p, a Ypt/Rab-specific GTPase-activating Protein from Yeast
Will, E., & Gallwitz, D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011451200 · Cited by 51 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Rab GTPases as coordinators of vesicle traffic
Stenmark, H. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2728 · Cited by 3,413 · see citing works
Exercise, GLUT4, and skeletal muscle glucose uptake
Richter, E. A., & Hargreaves, M. (2013) · Physiological Reviews · doi:10.1152/physrev.00038.2012 · Cited by 1,407 · see citing works
Molecular mechanisms of ROS production and oxidative stress in diabetes
Newsholme, P., Cruzat, V. F., Keane, K. N., Carlessi, R., & de Bittencourt, P. I. H. (2016) · Biochemical Journal · doi:10.1042/bcj20160503c · Cited by 878 · see citing works
Biochemical and cellular properties of insulin receptor signalling
Haeusler, R. A., McGraw, T. E., & Accili, D. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.89 · Cited by 739 · see citing works
Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease
Chadt, A., & Al-Hasani, H. (2020) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-020-02417-x · Cited by 510 · see citing works
Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic
Sakamoto, K., & Holman, G. D. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90331.2008 · Cited by 481 · see citing works
Insulin signaling in health and disease
Saltiel, A. R. (2021) · Journal of Clinical Investigation · doi:10.1172/jci142241 · Cited by 446 · see citing works
The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia
Sylow, L., Tokarz, V. L., Richter, E. A., & Klip, A. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.03.020 · Cited by 366 · see citing works
Kramer, H. F., Witczak, C. A., Fujii, N., Jessen, N., Taylor, E. B., Arnolds, D. E., Sakamoto, K., Hirshman, M. F., & Goodyear, L. J. (2006) · Diabetes · doi:10.2337/db06-0150 · Cited by 315 · see citing works
Ishiki, M., & Klip, A. (2005) · Endocrinology · doi:10.1210/en.2005-0850 · Cited by 281 · see citing works
O’Gorman, D. J., Karlsson, H. K. R., McQuaid, S., Yousif, O., Rahman, Y., Gasparro, D., Glund, S., Chibalin, A. V., Zierath, J. R., & Nolan, J. J. (2006) · Diabetologia · doi:10.1007/s00125-006-0457-3 · Cited by 226 · see citing works
TBC proteins: GAPs for mammalian small GTPase Rab?
Fukuda, M. (2011) · Bioscience Reports · doi:10.1042/bsr20100112 · Cited by 207 · see citing works
Self-citationGeraghty, K. M., Chen, S., Harthill, J. E., Ibrahim, A. F., Toth, R., Morrice, N. A., Vandermoere, F., Moorhead, G. B., Hardie, D. G., & MacKintosh, C. (2007) · Biochemical Journal · doi:10.1042/bj20070649 · Cited by 181 · see citing works
Insulin signaling and glucose transport in insulin resistant human skeletal muscle
Karlsson, H. K. R., & Zierath, J. R. (2007) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-007-0030-9 · Cited by 159 · see citing works
Ge, P., Lei, Z., Yu, Y., Lu, Z., Qiang, L., Chai, Q., Zhang, Y., Zhao, D., Li, B., Pang, Y., et al. (2022) · Autophagy · doi:10.1080/15548627.2021.1938912 · Cited by 132 · see citing works
Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle
Treebak, J. T., Frøsig, C., Pehmøller, C., Chen, S., Maarbjerg, S. J., Brandt, N., MacKintosh, C., Zierath, J. R., Hardie, D. G., Kiens, B., et al. (2009) · Diabetologia · doi:10.1007/s00125-009-1294-y · Cited by 119 · see citing works
Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle
Arias, E. B., Kim, J., Funai, K., & Cartee, G. D. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00602.2006 · Cited by 118 · see citing works
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. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.035568 · Cited by 95 · see citing works
Self-citationThyfault, J. P., Cree, M. G., Zheng, D., Zwetsloot, J. J., Tapscott, E. B., Koves, T. R., Ilkayeva, O., Wolfe, R. R., Muoio, D. M., & Dohm, G. L. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00311.2006 · Cited by 87 · see citing works
Funai, K., & Cartee, G. D. (2009) · Diabetes · doi:10.2337/db08-1477 · Cited by 76 · see citing works
Frøsig, C., Pehmøller, C., Birk, J. B., Richter, E. A., & Wojtaszewski, J. F. P. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.194811 · Cited by 73 · see citing works
Funai, K., Schweitzer, G. G., Castorena, C. M., Kanzaki, M., & Cartee, G. D. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00758.2009 · Cited by 63 · see citing works
Thyfault, J. P. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00924.2007 · Cited by 53 · see citing works
Targeting Small GTPases and Their Prenylation in Diabetes Mellitus
Gendaszewska-Darmach, E., Garstka, M. A., & Błażewska, K. M. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00410 · Cited by 35 · see citing works
Park, S.-Y., Jin, W., Woo, J. R., & Shoelson, S. E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.217323 · Cited by 25 · see citing works
Rebello, C. J., Zhang, D., Kirwan, J. P., Lowe, A. C., Emerson, C. J., Kracht, C. L., Steib, L. C., Greenway, F. L., Johnson, W. D., & Brown, J. C. (2023) · International Journal of Obesity · doi:10.1038/s41366-023-01283-8 · Cited by 16 · see citing works
“Following a single exercise bout, the mechanisms underlying improved insulin action involve a coordinated effect of insulin action on vasodilation, augmented capillary perfusion, and increased glucose transporter 4 (GLUT4) translocation to the muscle surface membrane [55, 56].”
Background
- Authors
- Mîinea, C. P., Sano, H., Kane, S., Sano, E., Fukuda, M., Peränen, J., Lane, W. S., & Lienhard, G. E.
- Affiliations
- Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, U.S.A.
- Dartmouth College (US)
- RIKEN (JP)
- University of Helsinki (FI)
- Harvard University (US)
- Corresponding author
- Sano, Hiroyuki
- Kane, Susan
- Sano, Eiko
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2005-09-26
- Volume
- 391
- Issue
- 1
- Pages
- 87-93
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1237142
- OpenAlex
- W2097210443
- Semantic Scholar
- 58432369bfd27c34fb0623573c09a1a30ef68291
- Cited by
- 449
- References
- 33
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 20 · 2023: 17 · 2022: 15 · 2021: 24 · 2020: 17 · 2019: 26 · 2018: 19 · 2017: 19 · 2016: 19 · 2015: 25 · 2014: 21 · 2013: 18 · 2012: 38
- FWCI
- 9.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK025336)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK025336, DK025336, R56DK025336)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- AS160, Rab GTPase-activating protein, Rab GTPases, GLUT4 translocation, insulin signaling, Akt phosphorylation, RAB2A, Rab8a, Rab14, GLUT4 vesicles, adipocytes, glucose transport
- MeSH terms
- Animals, Cell Line, Dogs, Enzyme Activation, Humans, Recombinant Proteins, Protein Structure, Tertiary, Adipocytes, GTPase-Activating Proteins, rab GTP-Binding Proteins, Protein Transport, Transport Vesicles, Proto-Oncogene Proteins c-akt, Glucose Transporter Type 4, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
