The Ca2+/Calmodulin-dependent Protein Kinase Kinases Are AMP-activated Protein Kinase Kinases*

By Rebecca L. Hurley, K. A. Anderson, J. Franzone, Bruce E. Kemp, A. Means, L. Witters. Journal of Biological Chemistry, 2005

1,039 citations recorded by the source corpus.

The AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism in response to metabolic stress and to other regulatory signals. AMPK activity is absolutely dependent upon phosphorylation of AMPKαThr-172 in its activation loop by one or more AMPK kinases (AMPKKs). The tumor suppressor kinase, LKB1, is a major AMPKK present in a variety of tissues and cells, but several lines of evidence point to the existence of other AMPKKs. We have employed three cell lines deficient in LKB1 to study AMPK regulation and phosphorylation, HeLa, A549, and murine embryo fibroblasts derived from LKB-/- mice. In HeLa and A549 cells, mannitol, 2-deoxyglucose, and ionomycin, but not 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), treatment activates AMPK by αThr-172 phosphorylation. These responses, as well as the downstream effects of AMPK on the phosphorylation of acetyl-CoA carboxylase,arelargelyinhibitedbytheCa2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor, STO-609. AMPKK activity in HeLa cell lysates measured in vitro is totally inhibited by STO-609 with an IC50 comparable with that of the known CaMKK isoforms, CaMKKα and CaMKKβ. Furthermore, 2-deoxyglucose- and ionomycin-stimulated AMPK activity, αThr-172 phosphorylation, and acetyl-CoA carboxylase phosphorylation are substantially reduced in HeLa cells transfected with small interfering RNAs specific for CaMKKα and CaMKKβ. Lastly, the activation of AMPK in response to ionomycin and 2-deoxyglucose is not impaired in LKB1-/- murine embryo fibroblasts. These data indicate that the CaMKKs function in intact cells as AMPKKs, predicting wider roles for these kinases in regulating AMPK activity in vivo.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/7f8ad18df8c784c935d4502a86e6d15c122b403f

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In Molecular Biology

1. D. Hardie
2. R. Shaw
3. G. Steinberg
4. Bruce E. Kemp
5. S. Hawley
6. J. Villén
7. Fiona A. Ross
8. Steven P. Gygi

In Surgery

1. D. Hardie
2. R. Shaw
3. S. Hawley
4. G. Steinberg
5. Bruce E. Kemp
6. Fiona A. Ross
7. M. Towler
8. K. Green

Citations in the corpus

• AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. (2011, background): “In some cell types, Thr 172 can also be phosphorylated by the Ca2+/calmodulin-dependent protein kinase CaMKKb, providing a Ca2+-activated pathway to switch on AMPK (Hawley et al. 2005; Hurley et al. 2005; Woods et al. 2005).”
• AMPK in Health and Disease. (2009, background): “Since the constitutively active AMPK fragment 1 (1-312) is not activated by the PT1 compound, it is proposed that PT1 acts by reversing the autoinhibition of the AIS (313-335).”