Camkk2, also known as calcium/calmodulin-dependent protein kinase kinase 2, is a serine/threonine-protein kinase. It is involved in maintaining various physiological and cellular processes within the cell, regulating energy homeostasis and cell growth. CaMKK2 regulates glucose metabolism by activating downstream kinases like AMP-activated protein kinase (AMPK) and other calcium/calmodulin-dependent protein kinases. It bridges the gap between Ca2+ signaling and energy-sensing, and its deregulation is associated with multiple human metabolic diseases including obesity, cancer, and neurological disorders [3,4].

In mice, hepatocyte-specific knockout of Cdo1, which tethers Camkk2 to AMPK, decreases basal metabolic rate and impairs the effect of exercise against non-alcoholic fatty liver disease (NAFLD), suggesting that the Cdo1-Camkk2-AMPK axis is crucial for exercise-mediated protection against NAFLD [1]. Genetic deletion of Camkk2 in mice causes bipolar-like behaviors similar to those in patients, and these behaviors are ameliorated by lithium, indicating that Camkk2 could be a new treatment target for bipolar disorder [2]. In glioblastoma, host CaMKK2 reduces survival and promotes immune checkpoint blockade (ICB) resistance, with CaMKK2 promoting exhaustion in CD8+ T cells and affecting the expansion and tumor penetrance of effector CD4+ T cells [5].

In conclusion, Camkk2 is a key regulator in multiple biological processes, playing a significant role in diseases such as NAFLD, bipolar disorder, and glioblastoma. The use of gene knockout mouse models has been instrumental in uncovering its functions in these disease areas, providing insights into potential therapeutic strategies targeting Camkk2.

References:

1. Chen, Min, Zhu, Jie-Ying, Mu, Wang-Jing, Li, Ruo-Ying, Guo, Liang. 2023. Cdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice. In Nature communications, 14, 8391. doi:10.1038/s41467-023-44242-7. https://pubmed.ncbi.nlm.nih.gov/38110408/

2. Kaiser, Jacqueline, Nay, Kevin, Horne, Christopher R, Gundlach, Andrew L, Scott, John W. 2023. CaMKK2 as an emerging treatment target for bipolar disorder. In Molecular psychiatry, 28, 4500-4511. doi:10.1038/s41380-023-02260-3. https://pubmed.ncbi.nlm.nih.gov/37730845/

3. Kennedy, Grace, Gibson, Olivia, T O'Hare, Dáire, Mills, Ian G, Evergren, Emma. . The role of CaMKK2 in Golgi-associated vesicle trafficking. In Biochemical Society transactions, 51, 331-342. doi:10.1042/BST20220833. https://pubmed.ncbi.nlm.nih.gov/36815702/

4. McAloon, Luke M, Muller, Abbey G, Nay, Kevin, Febbraio, Mark A, Scott, John W. . CaMKK2: bridging the gap between Ca2+ signaling and energy-sensing. In Essays in biochemistry, 68, 309-320. doi:10.1042/EBC20240011. https://pubmed.ncbi.nlm.nih.gov/39268917/

5. Tomaszewski, William H, Waibl-Polania, Jessica, Chakraborty, Molly, Gunn, Michael D, Sampson, John H. 2022. Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma. In Nature communications, 13, 6483. doi:10.1038/s41467-022-34175-y. https://pubmed.ncbi.nlm.nih.gov/36309495/