CAMKK2

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, which increases their catalytic activity.{{Cite web|title=CAMK1 - Calcium/calmodulin-dependent protein kinase type 1 - Homo sapiens (Human) - CAMK1 gene & protein|url=https://www.uniprot.org/uniprot/Q14012|access-date=2021-05-15|website=www.uniprot.org|language=en}} CaMK1 and CaMK4 are phosphorylated at the Thr 177 and Thr 196 residues respectively.{{cite journal | vauthors = Soderling TR | title = The Ca-calmodulin-dependent protein kinase cascade | journal = Trends in Biochemical Sciences | volume = 24 | issue = 6 | pages = 232–6 | date = June 1999 | pmid = 10366852 | doi = 10.1016/s0968-0004(99)01383-3 }}{{cite journal | vauthors = Selbert MA, Anderson KA, Huang QH, Goldstein EG, Means AR, Edelman AM | title = 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 | journal = The Journal of Biological Chemistry | volume = 270 | issue = 29 | pages = 17616–21 | date = July 1995 | pmid = 7615569 | doi = 10.1074/jbc.270.29.17616 | doi-access = free }}

CaMKK2 regulates production of the appetite stimulating hormone neuropeptide Y and functions as an AMPK kinase in the hypothalamus.{{cite journal | vauthors = Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, Witters LA, Kemp BE, Means AR | display-authors = 6 | title = Hypothalamic CaMKK2 contributes to the regulation of energy balance | journal = Cell Metabolism | volume = 7 | issue = 5 | pages = 377–88 | date = May 2008 | pmid = 18460329 | doi = 10.1016/j.cmet.2008.02.011 | doi-access = free }} 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.{{cite journal | vauthors = Sánchez-Blázquez P, Rodríguez-Muñoz M, Montero C, de la Torre-Madrid E, Garzón J | title = Calcium/calmodulin-dependent protein kinase II supports morphine antinociceptive tolerance by phosphorylation of glycosylated phosducin-like protein | journal = Neuropharmacology | volume = 54 | issue = 2 | pages = 319–30 | date = February 2008 | pmid = 18006024 | doi = 10.1016/j.neuropharm.2007.10.002 | hdl-access = free | s2cid = 23956064 | hdl = 10261/63344 }}{{cite journal | vauthors = Chen Y, Jiang Y, Yue W, Zhou Y, Lu L, Ma L | title = Chronic, but not acute morphine treatment, up-regulates alpha-Ca2+/calmodulin dependent protein kinase II gene expression in rat brain | journal = Neurochemical Research | volume = 33 | issue = 10 | pages = 2092–8 | date = October 2008 | pmid = 18408996 | doi = 10.1007/s11064-008-9690-0 | s2cid = 1686579 }}{{cite journal | vauthors = Chen Y, Yang C, Wang ZJ | title = Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia | journal = The Journal of Neuroscience | volume = 30 | issue = 1 | pages = 38–46 | date = January 2010 | pmid = 20053885 | pmc = 2821163 | doi = 10.1523/JNEUROSCI.4346-09.2010 }} Inhibition of CaMKK2 in mice reduces appetite and promotes weight loss.

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.{{cite journal | vauthors = Wayman GA, Lee YS, Tokumitsu H, Silva AJ, Silva A, Soderling TR | title = Calmodulin-kinases: modulators of neuronal development and plasticity | journal = Neuron | volume = 59 | issue = 6 | pages = 914–31 | date = September 2008 | pmid = 18817731 | pmc = 2664743 | doi = 10.1016/j.neuron.2008.08.021 }}{{cite journal | vauthors = Racioppi L, Means AR | title = Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology | journal = The Journal of Biological Chemistry | volume = 287 | issue = 38 | pages = 31658–65 | date = September 2012 | pmid = 22778263 | pmc = 3442500 | doi = 10.1074/jbc.R112.356485 | doi-access = free }} 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.{{cite journal | vauthors = Morgado-Bernal I | title = Learning and memory consolidation: linking molecular and behavioral data | journal = Neuroscience | volume = 176 | pages = 12–9 | date = March 2011 | pmid = 21215299 | doi = 10.1016/j.neuroscience.2010.12.056 | s2cid = 34665819 }}

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.{{cite journal | vauthors = Hatten ME, Heintz N | title = Mechanisms of neural patterning and specification in the developing cerebellum | journal = Annual Review of Neuroscience | volume = 18 | pages = 385–408 | date = 1995 | pmid = 7605067 | doi = 10.1146/annurev.ne.18.030195.002125 }}{{cite journal | vauthors = Wang VY, Zoghbi HY | title = Genetic regulation of cerebellar development | journal = Nature Reviews. Neuroscience | volume = 2 | issue = 7 | pages = 484–91 | date = July 2001 | pmid = 11433373 | doi = 10.1038/35081558 | s2cid = 20373774 }}{{cite journal | vauthors = Kokubo M, Nishio M, Ribar TJ, Anderson KA, West AE, Means AR | title = BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV | journal = The Journal of Neuroscience | volume = 29 | issue = 28 | pages = 8901–13 | date = July 2009 | pmid = 19605628 | pmc = 2763571 | doi = 10.1523/JNEUROSCI.0040-09.2009 }} 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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma | journal = Nature Communications | volume = 13 | issue = 1 | pages = 6483 | date = October 2022 | pmid = 36309495 | doi = 10.1038/s41467-022-34175-y | doi-access = free | pmc = 9617949 | bibcode = 2022NatCo..13.6483T }}

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{{cite journal | vauthors = Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ | display-authors = 6 | title = AMP-activated protein kinase plays a role in the control of food intake | journal = The Journal of Biological Chemistry | volume = 279 | issue = 13 | pages = 12005–8 | date = March 2004 | pmid = 14742438 | doi = 10.1074/jbc.C300557200 | doi-access = free | hdl = 10044/1/631 | hdl-access = free }} 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.{{cite journal | vauthors = Oury F, Yadav VK, Wang Y, Zhou B, Liu XS, Guo XE, Tecott LH, Schutz G, Means AR, Karsenty G | display-authors = 6 | title = CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons | journal = Genes & Development | volume = 24 | issue = 20 | pages = 2330–42 | date = October 2010 | pmid = 20952540 | pmc = 2956211 | doi = 10.1101/gad.1977210 }}

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.{{cite journal | vauthors = Hsu LS, Chen GD, Lee LS, Chi CW, Cheng JF, Chen JY | title = Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 33 | pages = 31113–23 | date = August 2001 | pmid = 11395482 | doi = 10.1074/jbc.M011720200 | doi-access = free }}

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• {{UCSC gene info|CAMKK2}}

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