CaMKK2: Bridging the Gap Between Ca2+ Signaling and Energy-Sensing

Authors

Luke M McAloon
Abbey G Muller
Kevin Nay
Eudora L Lu
Benoit Smeuninx
Anthony R Means
Mark A Febbraio
John W Scott

Publication Date

11-18-2024

Journal

Essays in Biochemistry

DOI

10.1042/EBC20240011

PMID

39268917

PMCID

PMC11576191

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Calcium-Calmodulin-Dependent Protein Kinase Kinase, Humans, Calcium Signaling, Energy Metabolism, Animals, Calcium, Neoplasms, AMP-Activated Protein Kinases, AMPK, calcium signaling, calmodulin, CaMKK2, energy-sensing

Abstract

Calcium (Ca2+) ions are ubiquitous and indispensable signaling messengers that regulate virtually every cell function. The unique ability of Ca2+ to regulate so many different processes yet cause stimulus specific changes in cell function requires sensing and decoding of Ca2+ signals. Ca2+-sensing proteins, such as calmodulin, decode Ca2+ signals by binding and modifying the function of a diverse range of effector proteins. These effectors include the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme, which is the core component of a signaling cascade that plays a key role in important physiological and pathophysiological processes, including brain function and cancer. In addition to its role as a Ca2+ signal decoder, CaMKK2 also serves as an important junction point that connects Ca2+ signaling with energy metabolism. By activating the metabolic regulator AMP-activated protein kinase (AMPK), CaMKK2 integrates Ca2+ signals with cellular energy status, enabling the synchronization of cellular activities regulated by Ca2+ with energy availability. Here, we review the structure, regulation, and function of CaMKK2 and discuss its potential as a treatment target for neurological disorders, metabolic disease, and cancer.