Ahsg-fetuin blocks the metabolic arm of insulin action through its interaction with the 95-kD β-subunit of the insulin receptor
Abstract
We previously have shown that Ahsg, a liver glycoprotein, inhibits insulin receptor (InsR) tyrosine kinase (TK) activity and the ERK1/2 mitogenic signaling arm of insulin signaling. Here we show that Ahsg blocks insulin-stimulated GLUT4 translocation and Akt activation in intact cells (mouse myoblasts). Furthermore, Ahsg inhibits InsR autophosphorylation of highly-purified insulin holoreceptors in a cell-free, ATP-dependent system, with an IC50 within the range of single-chain Ahsg concentrations in human serum. Binding of (125)I-insulin to living cells overexpressing the InsR shows a dissociation constant (KD) of 250pM, unaltered in the presence of 300 nM Ahsg. A mutant InsR cDNA encoding the signal peptide, the β-subunit and the furin processing site, but deleting the α-subunit, was stably expressed in HEK293 cells. Treatment with peroxovanadate, but not insulin, dramatically increased the 95 kD β-subunit tyrosine phosphoryation. The level of tyrosine phosphorylation of the 95-kD β-subunit can be driven down sharply by treatment of living HEK293 transfectant cells with physiological doses of Ahsg. Treatment of myogenic cells with Ahsg blunts insulin-stimulated InsR autophosphorylation and AKT phosphorylation. Taken together, we show that Ahsg antagonizes the metabolic functions initiated by InsR activation without interference in insulin binding. The experiments suggest a direct interaction of Ahsg with the InsR ectodomain β-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor's two complementing α-subunits.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Fetuin A directly induces insulin resistance.
“Fetuin A has been shown to directly induce insulin resistance [189], suppress production of adiponectin by adipocytes [148], and induce pancreatic β-cell toxicity [152].”
Cites
1 retracted
Differential endocytosis and signaling dynamics of insulin receptor variants IR-A and IR-B
Giudice, J., Leskow, F. C., Arndt‐Jovin, D. J., et al. (2011) · Journal of Cell Science · doi:10.1242/jcs.076869 · Cited by 36 · see citing works
RetractedMatthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., & Turner, R. C. (1985) · Diabetologia · doi:10.1007/bf00280883 · Cited by 31,502 · see citing works
Molecular and Cellular Endocrinology
Rainey, W. E., & Rodgers, R. J. (2004) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2004.10.007 · Cited by 1,309 · see citing works
Plasticity of the Differentiated State
Blau, H. M., Pavlath, G. K., Hardeman, E. C., Chiu, C., Silberstein, L., Webster, S. G., Miller, S. C., & Webster, C. (1985) · Science · doi:10.1126/science.2414846 · Cited by 840 · see citing works
Harris, R. S., & Thiman, K. V. (1948) · The American Journal of the Medical Sciences · doi:10.1097/00000441-194801000-00035 · Cited by 792 · see citing works
Protein Kinase B/Akt Participates in GLUT4 Translocation by Insulin in L6 Myoblasts
Wang, Q., Somwar, R., Bilan, P. J., Liu, Z., Jin, J., Woodgett, J. R., & Klip, A. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.6.4008 · Cited by 590 · see citing works
Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase.
Chen, H., & Guan, J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.21.10148 · Cited by 518 · see citing works
McClain, D. A., Maegawa, H., Lee, J., Dull, T. J., Ulrich, A. K., & Olefsky, J. M. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)47847-7 · Cited by 397 · see citing works
Improved Insulin Sensitivity and Resistance to Weight Gain in Mice Null for the Ahsg Gene
Mathews, S. T., Singh, G. P., Ranalletta, M., Cintrón, V. J., Qiang, X., Goustin, A. S., Jen, K. C., Charron, M. J., Jahnen‐Dechent, W., & Grunberger, G. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2450 · Cited by 343 · see citing works
Self-citationAuberger, P., Falquerho, L., Contreres, J. O., Pagès, G., Cam, G. L., Rossi, B., & Cam, A. L. (1989) · Cell · doi:10.1016/0092-8674(89)90098-6 · Cited by 321 · see citing works
Structure of the insulin receptor ectodomain reveals a folded-over conformation
McKern, N. M., Lawrence, M. C., Streltsov, V. A., Lou, M.-Z., Adams, T. E., Lovrecz, G. O., ELLEMAN, T. C., Richards, K. M., Bentley, J. D., Pilling, P. A., et al. (2006) · Nature · doi:10.1038/nature05106 · Cited by 306 · see citing works
Saturated Fatty Acids Induce c-Src Clustering within Membrane Subdomains, Leading to JNK Activation
Holzer, R. G., Park, E., Li, N., Tran, H., Chen, M. F., Choi, C., Solinas, G., & Karin, M. (2011) · Cell · doi:10.1016/j.cell.2011.08.034 · Cited by 283 · see citing works
Stimulation of clonal growth of normal fibroblasts with substrata coated with basic polymers.
McKeehan, W. L., & Ham, R. G. (1976) · The Journal of Cell Biology · doi:10.1083/jcb.71.3.727 · Cited by 255 · see citing works
Srinivas, P. R., Wagner, A. S., Reddy, L. V. K., Deutsch, D. D., Leon, M. A., Goustin, A. S., & Grunberger, G. (1993) · Molecular Endocrinology · doi:10.1210/mend.7.11.7906861 · Cited by 243 · see citing works
Self-citationMathews, S. T. (2000) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(00)00237-9 · Cited by 179 · see citing works
Ward, C. W., & Lawrence, M. C. (2009) · BioEssays · doi:10.1002/bies.200800210 · Cited by 156 · see citing works
Bogan, J. S., McKee, A. E., & Lodish, H. F. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.14.4785-4806.2001 · Cited by 152 · see citing works
Internalized insulin receptors are recycled to the cell surface in rat hepatocytes.
Fehlmann, M., Carpentier, J. L., OBBERGHEN, E. V., Freychet, P., Thamm, P., Saunders, D., Brandenburg, D., & Orci, L. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.19.5921 · Cited by 144 · see citing works
Quach, N. L., Biressi, S., Reichardt, L. F., Keller, C., & Rando, T. A. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-02-0175 · Cited by 144 · see citing works
Insulin receptor internalization and signalling
Guglielmo, G. M. D., Drake, P. G., Baass, P. C., Authier, F., Posner, B. I., & Bergeron, J. J. M. (1998) · Springer eBooks · doi:10.1007/978-1-4615-5647-3_6 · Cited by 131 · see citing works
Dynamics of Signaling during Insulin-stimulated Endocytosis of Its Receptor in Adipocytes
Kublaoui, B. M., Lee, J., & Pilch, P. F. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.1.59 · Cited by 129 · see citing works
Baron, V. T., Calleja, V., Ferrari, P., Alengrin, F., & OBBERGHEN, E. V. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.12.7162 · Cited by 107 · see citing works
Smith, B. J., Huang, K., Kong, G. K.-W., Chan, S. J., Nakagawa, S. H., Menting, J. G. T., Hu, S.-Q., Whittaker, J., Steiner, D. F., Katsoyannis, P. G., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001813107 · Cited by 106 · see citing works
Goustin, A. S., & Abou‐Samra, A. (2010) · Cellular Signalling · doi:10.1016/j.cellsig.2010.11.003 · Cited by 97 · see citing works
Self-citationRuff-Jamison, S., Chen, K., & Cohen, S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.2.1263 · Cited by 97 · see citing works
Reiland, J., Ott, V. L., Lebakken, C. S., Yeaman, C. A., McCarthy, J. B., & Rapraeger, A. C. (1996) · Biochemical Journal · doi:10.1042/bj3190039 · Cited by 94 · see citing works
Insulin receptor internalization and signalling
Guglielmo, G. M. D., Baass, P. C., Authier, F., Posner, B. I., & Bergeron, J. J. M. (1998) · Molecular and Cellular Biochemistry · doi:10.1023/a:1006883311233 · Cited by 91 · see citing works
(1994) · Elsevier eBooks · doi:10.1016/c2009-0-02383-6 · Cited by 77 · see citing works
RINGOLD, G. M., Dieckmann, B. S., & Lee, F. (1981) · PubMed · Cited by 76 · see citing works
Serum Fetuin-A is an Independent Marker of Insulin Resistance in Japanese Men
Ishibashi, A., Ikeda, Y., Ohguro, T., Kumon, Y., Yamanaka, S., Takata, H., Inoue, M., Suehiro, T., & Terada, Y. (2010) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.3830 · Cited by 71 · see citing works
Bovine fetuin is an inhibitor of insulin receptor tyrosine kinase
Mathews, S. T., Srinivas, P. R., Leon, M. A., & Grunberger, G. (1997) · Life Sciences · doi:10.1016/s0024-3205(97)00737-6 · Cited by 68 · see citing works
src kinase catalyzes the phosphorylation and activation of the insulin receptor kinase.
Yu, K. T., Werth, D. K., Pastan, I. H., et al. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)89098-6 · Cited by 66 · see citing works
Ou, H., Yang, Y., Wu, H., Wu, J., Lu, F., & Chang, C. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04070.x · Cited by 66 · see citing works
Ma, C., Looney, J. E., Leu, T., & Hamlin, J. L. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.6.2316 · Cited by 66 · see citing works
Janicot, M., Flores-Riveros, J. R., & Lane, M. D. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)92830-9 · Cited by 60 · see citing works
Reduced Expression of Focal Adhesion Kinase Disrupts Insulin Action in Skeletal Muscle Cells
Huang, D., Khoe, M., Ilić, D., & Bryer‐Ash, M. (2006) · Endocrinology · doi:10.1210/en.2005-0382 · Cited by 56 · see citing works
Insulin and IGF‐1 Receptor Trafficking and Signalling
Foti, M., Moukil, M. A., Dudognon, P., et al. (2004) · Novartis Foundation symposium · doi:10.1002/0470869976.ch8 · Cited by 51 · see citing works
Peroxovanadate induces tyrosine phosphorylation of phosphoinositide‐dependent protein kinase‐1
Grillo, S., Grémeaux, T., Casamayor, A., et al. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01759.x · Cited by 48 · see citing works
Rosenzweig, T., Aga‐Mizrachi, S., Bak, A., & Sampson, S. R. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2004.03.015 · Cited by 47 · see citing works
Bisht, B., & Dey, C. S. (2008) · BMC Cell Biology · doi:10.1186/1471-2121-9-48 · Cited by 47 · see citing works
Nakai, N., Kawano, F., Oke, Y., Nomura, S., Ohira, T., Fujita, R., & Ohira, Y. (2010) · Molecules and Cells · doi:10.1007/s10059-010-0147-3 · Cited by 33 · see citing works
Srinivas, P. R., Deutsch, D. D., Mathews, S. T., Goustin, A. S., Leon, M. A., & Grunberger, G. (1996) · Cellular Signalling · doi:10.1016/s0898-6568(96)00110-6 · Cited by 22 · see citing works
Self-citationBaculoviral Expression of a Natural Inhibitor of the Human Insulin Receptor Tyrosine Kinase
Srinivas, P. R., Goustin, A. S., & Grunberger, G. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.1417 · Cited by 19 · see citing works
Self-citationCintrón, V. J., Ko, M. S. H., Chi, K. D., Gross, J. P., Srinivas, P. R., Goustin, A. S., & Grunberger, G. (2000) · Journal of Diabetes Research · doi:10.1155/edr.2000.249 · Cited by 17 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278 · see citing works
Fetuin-A: A novel link between obesity and related complications
Trepanowski, J. F., Mey, J., & Varady, K. A. (2015) · International Journal of Obesity · doi:10.1038/ijo.2014.203 · Cited by 161 · see citing works
Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver
Jelenik, T., Kaul, K., Séquaris, G., Flögel, U., Phielix, E., Kotzka, J., Knebel, B., Fahlbusch, P., Hörbelt, T., Lehr, S., et al. (2017) · Diabetes · doi:10.2337/db16-1147 · Cited by 154 · see citing works
Role of exercise-induced hepatokines in metabolic disorders
Ennequin, G., Sirvent, P., & Whitham, M. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00433.2018 · Cited by 54 · see citing works
- Authors
- Goustin, A. S., Derar, N., & Abou-Samra, A. B.
- Affiliations
- Wayne State University (US)
- Corresponding author
- Goustin, Anton Scott
- Venue
- Cellular Signalling
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 25
- Issue
- 4
- Pages
- 981-988
- ISSN
- 0898-6568 (ISSN-L)
- OpenAlex
- W2045965212
- Cited by
- 51
- References
- 44
- Citations by year
- 2025: 2 · 2024: 7 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 3 · 2018: 2 · 2017: 7 · 2016: 3 · 2015: 1 · 2014: 5
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cellular Signalling (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5T32DK080657-02, DK062286-06)
- King Abdullah's International Scholarship Program (Saudi Arabia)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- fetuin-A, insulin receptor, insulin receptor beta-subunit, insulin receptor tyrosine kinase, insulin signaling, GLUT4 translocation, Akt phosphorylation, insulin receptor autophosphorylation, insulin binding, ERK signaling, insulin resistance, myoblasts
- MeSH terms
- Adenosine Triphosphate, Animals, Cell Line, Cell-Free System, Humans, Insulin, Kinetics, Mutation, Phosphorylation, Protein Binding, Receptor, Insulin, Transfection, Signal Transduction, Protein Subunits, Proto-Oncogene Proteins c-akt, Glucose Transporter Type 4, Mice, Rats, HEK293 Cells, alpha-2-HS-Glycoprotein
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
