The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade
Open accessAbstract
AMPK (AMP-activated protein kinase) is activated allosterically by AMP and by phosphorylation of Thr172 within the catalytic α subunit. Here we show that mutations in the regulatory γ subunit reduce allosteric activation of the kinase by AMP. In addition to its allosteric effect, AMP significantly reduces the dephosphorylation of Thr172 by PP (protein phosphatase)2Cα. Moreover, a mutation in the γ subunit almost completely abolishes the inhibitory effect of AMP on dephosphorylation. We were unable to detect any effect of AMP on Thr172 phosphorylation by either LKB1 or CaMKKβ (Ca2+/calmodulin-dependent protein kinase kinase β) using recombinant preparations of the proteins. However, using partially purified AMPK from rat liver, there was an apparent AMP-stimulation of Thr172 phosphorylation by LKB1, but this was blocked by the addition of NaF, a PP inhibitor. Western blotting of partially purified rat liver AMPK and LKB1 revealed the presence of PP2Cα in the preparations. We suggest that previous studies reporting that AMP promotes phosphorylation of Thr172 were misinterpreted. A plausible explanation for this effect of AMP is inhibition of dephosphorylation by PP2Cα, present in the preparations of the kinases used in the earlier studies. Taken together, our results demonstrate that AMP activates AMPK via two mechanisms: by direct allosteric activation and by protecting Thr172 from dephosphorylation. On the basis of our new findings, we propose a simple model for the regulation of AMPK in mammalian cells by LKB1 and CaMKKβ. This model accounts for activation of AMPK by two distinct signals: a Ca2+-dependent pathway, mediated by CaMKKβ and an AMP-dependent pathway, mediated by LKB1.
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Kahn, B. B., Alquier, T., Carling, D., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.003 · Cited by 2,799
Self-citationShaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., & Cantley, L. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308061100 · Cited by 1,797
Bialojan, C., & Takai, A. (1988) · Biochemical Journal · doi:10.1042/bj2560283 · Cited by 1,691
Hawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Mäkelä, T. P., Alessi, D. R., & Hardie, D. G. (2003) · Journal of Biology · doi:10.1186/1475-4924-2-28 · Cited by 1,665
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G. D., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., & Carling, D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.031 · Cited by 1,650
Self-citationHawley, S. A., Pan, D. A., Mustard, K. J., Ross, L., Bain, J., Edelman, A. M., Frenguelli, B. G., & Hardie, D. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.009 · Cited by 1,589
THE AMP-ACTIVATED/SNF1 PROTEIN KINASE SUBFAMILY: Metabolic Sensors of the Eukaryotic Cell?
Hardie, D. G., Carling, D., & Carlson, M. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.821 · Cited by 1,435
Self-citationWoods, A., Dickerson, K., Heath, R., Hong, S.-P., Momcilovic, M., Johnstone, S. R., Carlson, M., & Carling, D. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.06.005 · Cited by 1,392
Self-citationHawley, S. A., Davison, M., Woods, A., Davies, S. P., Beri, R. K., Carling, D., & Hardie, D. G. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.44.27879 · Cited by 1,264
Self-citationThe AMP-activated protein kinase cascade – a unifying system for energy control
Carling, D. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.11.005 · Cited by 1,112
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Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943
Steinberg, G. R., & Kemp, B. E. (2009) · Physiological Reviews · doi:10.1152/physrev.00011.2008 · Cited by 1,637
Exercise, GLUT4, and skeletal muscle glucose uptake
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Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and Stress
Sengupta, S., Peterson, T. R., & Sabatini, D. M. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.026 · Cited by 1,241
Foretz, M., Hébrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F., & Viollet, B. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40671 · Cited by 1,181
Metadata
- Authors
- Sanders, M. J., Grondin, P. O., Hegarty, B. D., Snowden, M. A., & Carling, D.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2007-03-13
- Volume
- 403
- Issue
- 1
- Pages
- 139-148
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2074894911
- Cited by
- 666
- References
- 49
- FWCI
- 23.71
- Type
- journal article
- Language
- en
- Open access
- bronze
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