PXD020133

PXD020133 is an original dataset announced via ProteomeXchange.

Title	CaMKK2 Inactivation by cAMP-PKA Signaling and 14-3-3 Adaptor Proteins
Description	The calcium-calmodulin (Ca2+-CaM) dependent protein kinase kinase-2 (CaMKK2) is activated by increases in intracellular Ca2+ and is a key regulator of cellular and wholebody energy metabolism. 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 cyclic AMP (cAMP)-dependent protein kinase (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. PKA-dependent phosphorylation of Ser495 directly impairs Ca2+-CaM 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 14-3-3z bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser511) and non-canonical (Ser100) 14-3-3 consensus sites on CaMKK2 co-operate to bind 14-3-3 proteins. Our findings provide a detailed mechanistic insight into how cAMP-PKA signaling inactivates CaMKK2 and reveals a pathway to inhibit CaMKK2 with potential for treating human diseases.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:14:43.612.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ashfaqul Hoque
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-01 03:08:05	ID requested
1	2020-11-06 06:09:25	announced
⏵ 2	2024-10-22 05:14:44	announced	2024-10-22: Updated project metadata.

10.1074/jbc.ra120.013756;

Langendorf CG, O'Brien MT, Ngoei KRW, McAloon LM, Dhagat U, Hoque A, Ling NXY, Dite TA, Galic S, Loh K, Parker MW, Oakhill JS, Kemp BE, Scott JW, CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins. J Biol Chem, 295(48):16239-16250(2020) [pubmed]

submitter keyword: cyclic AMP (cAMP),Calcium-calmodulin (Ca2+-CaM) dependent protein kinase kinase-2 (CaMKK2), protein kinase A (PKA), 14-3-3 adaptor proteins

John W Scott
contact affiliation	Protein Chemistry and Metabolism Unit St Vincent's Institute of Medical Research (SVI) 9 Princes Street Fitzroy, Victoria 3065 Australia
contact email	jscott@svi.edu.au
lab head
Ashfaqul Hoque
contact affiliation	St Vincent's Institute of Medical Research (SVI)
contact email	ahoque@svi.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/11/PXD020133

PRIDE project URI

• PRIDE
  1. PXD020133
     1. Label: PRIDE project
     2. Name: CaMKK2 Inactivation by cAMP-PKA Signaling and 14-3-3 Adaptor Proteins