CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins
Journal article
Langendorf, Christopher G., O'Brien, Matthew T., Ngoei, Kevin R. W., McAloon, Luke M., Dhagat, Urmi, Hoque, Ashfaqul, Ling, Naomi X. Y., Dite, Toby A., Galic, Sandra, Loh, Kim, Parker, Michael W., Oakhill, Jonathan S., Kemp, Bruce E. and Scott, John W.. (2020). CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins. Journal of Biological Chemistry. 295(48), pp. 16239-16250. https://doi.org/10.1074/jbc.RA120.013756
Authors | Langendorf, Christopher G., O'Brien, Matthew T., Ngoei, Kevin R. W., McAloon, Luke M., Dhagat, Urmi, Hoque, Ashfaqul, Ling, Naomi X. Y., Dite, Toby A., Galic, Sandra, Loh, Kim, Parker, Michael W., Oakhill, Jonathan S., Kemp, Bruce E. and Scott, John W. |
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Abstract | The calcium-calmodulin–dependent protein kinase kinase-2 (CaMKK2) is a key regulator of cellular and whole-body energy metabolism. It is known to be activated by increases in intracellular Ca2+, but the mechanisms by which it is inactivated are less clear. CaMKK2 inhibition protects against prostate cancer, hepatocellular carcinoma, and metabolic derangements induced by a high-fat diet; therefore, elucidating the intracellular mechanisms that inactivate CaMKK2 has important therapeutic implications. Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. PKA-dependent phosphorylation of Ser495 directly impairs calcium-calmodulin activation, whereas phosphorylation of Ser100 and Ser511 mediate recruitment of 14-3-3 adaptor proteins that hold CaMKK2 in the inactivated state by preventing dephosphorylation of phospho-Ser495. We also report the crystal structure of 14-3-3ζ bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser511) and noncanonical (Ser100) 14-3-3 consensus sites on CaMKK2 cooperate to bind 14-3-3 proteins. Our findings provide detailed molecular insights into how cAMP-PKA signaling inactivates CaMKK2 and reveals a pathway to inhibit CaMKK2 with potential for treating human diseases. |
Keywords | Ca2+-calmodulin–dependent protein kinase kinase-2 (CaMKK2); calmodulin (CaM); cyclic AMP (cAMP); protein kinase A (PKA); inhibition mechanism; adaptor protein; 14-3-3; Ca2+-calmodulin–dependent protein kinase (CaMK); 14-3-3 protein; Ca2+; calmodulin; CaMKK2; cAMP; PKA |
Year | 2020 |
Journal | Journal of Biological Chemistry |
Journal citation | 295 (48), pp. 16239-16250 |
Publisher | American Society for Biochemistry and Molecular Biology, Inc. |
ISSN | 1083-351X |
Digital Object Identifier (DOI) | https://doi.org/10.1074/jbc.RA120.013756 |
Scopus EID | 2-s2.0-85092271158 |
Open access | Published as ‘gold’ (paid) open access |
Research or scholarly | Research |
Page range | 16239-16250 |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 04 Jan 2021 |
Publication process dates | |
Deposited | 19 May 2021 |
https://acuresearchbank.acu.edu.au/item/8w18y/camkk2-is-inactivated-by-camp-pka-signaling-and-14-3-3-adaptor-proteins
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Publisher's version
OA_Langendorf_2020_CaMKK2_is_inactivated_by_cAMP_PKA.pdf | |
License: CC BY 4.0 | |
File access level: Open |
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