CAMKK2 explained

Calcium/calmodulin-dependent protein kinase kinase 2 is an enzyme that in humans is encoded by the CAMKK2 gene.^{[1] [2]}

Function

The product of this gene belongs to the serine/threonine-specific protein kinase family, and to the Ca⁺⁺/calmodulin-dependent protein kinase subfamily. This protein plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4,^[2] which increases their catalytic activity.^[3] CaMK1 and CaMK4 are phosphorylated at the Thr 177 and Thr 196 resides respectively.^{[4] [5]}

CaMKK2 regulates production of the appetite stimulating hormone neuropeptide Y and functions as an AMPK kinase in the hypothalamus.^[6] It also has an important role in the development of hyperalgesia and tolerance to opioid analgesic drugs, through reduction in downstream signalling pathways and mu opioid receptor downregulation.^{[7] [8] [9]} Inhibition of CaMKK2 in mice reduces appetite and promotes weight loss.^[6]

CaMKK2 has several functions in different brain regions. In the hippocampus, the CaMKK2/CaMK1 cascade is necessary for memory formation through the regulation of learning-induced structural changes in the neuronal cytoskeleton.^{[10] [11]} Morphological changes in dendritic spines in the hippocampus - which are necessary for initiating and maintaining the synaptic plasticity in CA1 pyramidal neurons - are the main structural basis for the formation of memories.^[12]

The CaMKK2/CaMKIV/CREB cascade is involved in the postnatal development of the cerebellum. CaMKK2 deletion impairs development of Cerebellar Granule Cells -the most abundant cells in the cerebellum- by inhibiting the ability of Granule Cell Precursors (GCPs) to stop proliferating in the external granule layer (EGL) and migrate to the internal granule layer.^{[13] [14] [15]} This phenotype is also tied to reduced BDNF expression and decreased CREB phosphorylation. Thus, the CaMKK2/CaMKIV/CREB cascade is required for BDNF (Brain Derived Neurotrophic Factor) production in the post-natal cerebellum in order to complete an important step of CGC development. Neuronal CaMKK2's regulation of BDNF was recently implicated in progression of Glioblastoma.^[16]

In the hypothalamus, CaMKK2 is involved in centrally mediating energy homeostasis by forming a signaling complex with AMPKα/β and Ca2+/CaM. Genetic ablation of CaMKK2 decreases AMPK^[17] activity in hypothalamus and down regulates NPY and AgRP gene expression in NPY Neurons, which has been shown to protect mice from diet-induced obesity, hyperglycemia, and insulin resistance. Additionally, CaMKK2 is involved in the genetic regulation of genes necessary for optimal sympathetic activity in the medial hypothalamus, and therefore bone mass accrual, which can be said to be negatively associated to sympathetic tone.^[18]

Isoforms

Seven transcript variants encoding six distinct isoforms have been identified for this gene. Additional splice variants have been described but their full-length nature has not been determined. The identified isoforms exhibit a distinct ability to undergo autophosphorylation and to phosphorylate the downstream kinases.^{[2] [19]}

Further reading

• Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T . Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones . DNA Research . 9 . 3 . 99–106 . June 2002 . 12168954 . 10.1093/dnares/9.3.99 . free .
• Anderson KA, Means RL, Huang QH, Kemp BE, Goldstein EG, Selbert MA, Edelman AM, Fremeau RT, Means AR . 6 . Components of a calmodulin-dependent protein kinase cascade. Molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase beta . The Journal of Biological Chemistry . 273 . 48 . 31880–9 . November 1998 . 9822657 . 10.1074/jbc.273.48.31880 . free .
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 6 . Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 5 . 5 . 277–86 . October 1998 . 9872452 . 10.1093/dnares/5.5.277 . free .
• Hsu LS, Chen GD, Lee LS, Chi CW, Cheng JF, Chen JY . Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity . The Journal of Biological Chemistry . 276 . 33 . 31113–23 . August 2001 . 11395482 . 10.1074/jbc.M011720200 . free .
• Imai S, Okayama N, Shimizu M, Itoh M . Increased intracellular calcium activates serum and glucocorticoid-inducible kinase 1 (SGK1) through a calmodulin-calcium calmodulin dependent kinase kinase pathway in Chinese hamster ovary cells . Life Sciences . 72 . 20 . 2199–209 . April 2003 . 12628440 . 10.1016/S0024-3205(03)00092-4 .
• Ishikawa Y, Tokumitsu H, Inuzuka H, Murata-Hori M, Hosoya H, Kobayashi R . Identification and characterization of novel components of a Ca2+/calmodulin-dependent protein kinase cascade in HeLa cells . FEBS Letters . 550 . 1–3 . 57–63 . August 2003 . 12935886 . 10.1016/S0014-5793(03)00817-2 . 22116744 . free .
• Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG . 6 . Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase . Cell Metabolism . 2 . 1 . 9–19 . July 2005 . 16054095 . 10.1016/j.cmet.2005.05.009 . free .
• Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D . 6 . Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells . Cell Metabolism . 2 . 1 . 21–33 . July 2005 . 16054096 . 10.1016/j.cmet.2005.06.005 . free .
• Novak G, Seeman P, Tallerico T . Increased expression of calcium/calmodulin-dependent protein kinase IIbeta in frontal cortex in schizophrenia and depression . Synapse . 59 . 1 . 61–8 . January 2006 . 16247765 . 10.1002/syn.20211 . 24010912 .
• Stahmann N, Woods A, Carling D, Heller R . Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta . Molecular and Cellular Biology . 26 . 16 . 5933–45 . August 2006 . 16880506 . 1592798 . 10.1128/MCB.00383-06 .
• Erhardt A, Lucae S, Unschuld PG, Ising M, Kern N, Salyakina D, Lieb R, Uhr M, Binder EB, Keck ME, Müller-Myhsok B, Holsboer F . 6 . Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders . Journal of Affective Disorders . 101 . 1–3 . 159–68 . August 2007 . 17197037 . 10.1016/j.jad.2006.11.016 .

Notes and References

1. Hsu LS, Tsou AP, Chi CW, Lee CH, Chen JY . Cloning, expression and chromosomal localization of human Ca2+/calmodulin-dependent protein kinase kinase . Journal of Biomedical Science . 5 . 2 . 141–9 . Sep 1998 . 9662074 . 10.1159/000025324 . 90281764 .
2. Web site: Entrez Gene: CAMKK2 calcium/calmodulin-dependent protein kinase kinase 2, beta.
3. Web site: CAMK1 - Calcium/calmodulin-dependent protein kinase type 1 - Homo sapiens (Human) - CAMK1 gene & protein. 2021-05-15. www.uniprot.org. en.
4. Soderling TR . The Ca-calmodulin-dependent protein kinase cascade . Trends in Biochemical Sciences . 24 . 6 . 232–6 . June 1999 . 10366852 . 10.1016/s0968-0004(99)01383-3 .
5. Selbert MA, Anderson KA, Huang QH, Goldstein EG, Means AR, Edelman AM . Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation . The Journal of Biological Chemistry . 270 . 29 . 17616–21 . July 1995 . 7615569 . 10.1074/jbc.270.29.17616 . free .
6. Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, Witters LA, Kemp BE, Means AR . 6 . Hypothalamic CaMKK2 contributes to the regulation of energy balance . Cell Metabolism . 7 . 5 . 377–88 . May 2008 . 18460329 . 10.1016/j.cmet.2008.02.011 . free .
7. Sánchez-Blázquez P, Rodríguez-Muñoz M, Montero C, de la Torre-Madrid E, Garzón J . Calcium/calmodulin-dependent protein kinase II supports morphine antinociceptive tolerance by phosphorylation of glycosylated phosducin-like protein . Neuropharmacology . 54 . 2 . 319–30 . February 2008 . 18006024 . 10.1016/j.neuropharm.2007.10.002 . free . 23956064 . 10261/63344 .
8. Chen Y, Jiang Y, Yue W, Zhou Y, Lu L, Ma L . Chronic, but not acute morphine treatment, up-regulates alpha-Ca2+/calmodulin dependent protein kinase II gene expression in rat brain . Neurochemical Research . 33 . 10 . 2092–8 . October 2008 . 18408996 . 10.1007/s11064-008-9690-0 . 1686579 .
9. Chen Y, Yang C, Wang ZJ . Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia . The Journal of Neuroscience . 30 . 1 . 38–46 . January 2010 . 20053885 . 2821163 . 10.1523/JNEUROSCI.4346-09.2010 .
10. Wayman GA, Lee YS, Tokumitsu H, Silva AJ, Silva A, Soderling TR . Calmodulin-kinases: modulators of neuronal development and plasticity . Neuron . 59 . 6 . 914–31 . September 2008 . 18817731 . 2664743 . 10.1016/j.neuron.2008.08.021 .
11. Racioppi L, Means AR . Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology . The Journal of Biological Chemistry . 287 . 38 . 31658–65 . September 2012 . 22778263 . 3442500 . 10.1074/jbc.R112.356485 . free .
12. Morgado-Bernal I . Learning and memory consolidation: linking molecular and behavioral data . Neuroscience . 176 . 12–9 . March 2011 . 21215299 . 10.1016/j.neuroscience.2010.12.056 . 34665819 .
13. Hatten ME, Heintz N . Mechanisms of neural patterning and specification in the developing cerebellum . Annual Review of Neuroscience . 18 . 385–408 . 1995 . 7605067 . 10.1146/annurev.ne.18.030195.002125 .
14. Wang VY, Zoghbi HY . Genetic regulation of cerebellar development . Nature Reviews. Neuroscience . 2 . 7 . 484–91 . July 2001 . 11433373 . 10.1038/35081558 . 20373774 .
15. Kokubo M, Nishio M, Ribar TJ, Anderson KA, West AE, Means AR . BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV . The Journal of Neuroscience . 29 . 28 . 8901–13 . July 2009 . 19605628 . 2763571 . 10.1523/JNEUROSCI.0040-09.2009 .
16. Tomaszewski WH, Waibl-Polania J, Chakraborty M, Perera J, Ratiu J, Miggelbrink A, McDonnell DP, Khasraw M, Ashley DM, Fecci PE, Racioppi L, Sanchez-Perez L, Gunn MD, Sampson JH . 6 . Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma . Nature Communications . 13 . 1 . 6483 . October 2022 . 36309495 . 10.1038/s41467-022-34175-y . free . 9617949 . 2022NatCo..13.6483T .
17. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ . 6 . AMP-activated protein kinase plays a role in the control of food intake . The Journal of Biological Chemistry . 279 . 13 . 12005–8 . March 2004 . 14742438 . 10.1074/jbc.C300557200 . free . 10044/1/631 . free .
18. Oury F, Yadav VK, Wang Y, Zhou B, Liu XS, Guo XE, Tecott LH, Schutz G, Means AR, Karsenty G . 6 . CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons . Genes & Development . 24 . 20 . 2330–42 . October 2010 . 20952540 . 2956211 . 10.1101/gad.1977210 .
19. Hsu LS, Chen GD, Lee LS, Chi CW, Cheng JF, Chen JY . Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity . The Journal of Biological Chemistry . 276 . 33 . 31113–23 . August 2001 . 11395482 . 10.1074/jbc.M011720200 . free .