CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins.

Autor:	Langendorf CG; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., O'Brien MT; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., Ngoei KRW; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., McAloon LM; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., Dhagat U; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia., Hoque A; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., Ling NXY; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., Dite TA; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., Galic S; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., Loh K; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia., Parker MW; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia., Oakhill JS; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia., Kemp BE; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia., Scott JW; St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia; Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, Parkville, Australia. Electronic address: jscott@svi.edu.au.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2020 Nov 27; Vol. 295 (48), pp. 16239-16250. Date of Electronic Publication: 2020 Sep 09.
DOI:	10.1074/jbc.RA120.013756
Abstrakt:	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 Ca 2+ , 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 Ser 495 directly impairs calcium-calmodulin activation, whereas phosphorylation of Ser 100 and Ser 511 mediate recruitment of 14-3-3 adaptor proteins that hold CaMKK2 in the inactivated state by preventing dephosphorylation of phospho-Ser 495 We also report the crystal structure of 14-3-3ζ bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser 511 ) and noncanonical (Ser 100 ) 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. Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article. (© 2020 Langendorf et al.)
Databáze:	MEDLINE
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