CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins |
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Authors: | Christopher G Langendorf Matthew T O'Brien Kevin R W Ngoei Luke M McAloon Urmi Dhagat Ashfaqul Hoque Naomi X Y Ling Toby A Dite Sandra Galic Kim Loh Michael W Parker Jonathan S Oakhill Bruce E Kemp John W Scott |
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Institution: | 1.St Vincent''s Institute and Department of Medicine, University of Melbourne, Fitzroy, Australia;2.Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia;3.Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia;4.The Florey Institute of Neuroscience and Mental Health, Parkville, Australia |
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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. |
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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 |
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