CAMKK2

CAMKK2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2ZV2
Identifiers
Aliases	CAMKK2, CAMKK, CAMKKB, calcium/calmodulin-dependent protein kinase kinase 2, calcium/calmodulin dependent protein kinase kinase 2
External IDs	OMIM: 615002; MGI: 2444812; HomoloGene: 32756; GeneCards: CAMKK2; OMA:CAMKK2 - orthologs
Gene location (Human)
Chr.	Chromosome 12 (human)
End	121,298,308 bp
Gene location (Mouse)
Chr.	Chromosome 5 (mouse)
End	122,917,472 bp
RNA expression pattern
	Top expressed in
	cerebellar cortex; ; cerebellar hemisphere; ; right hemisphere of cerebellum; ; cerebellar vermis; ; paraflocculus of cerebellum; ; right frontal lobe; ; prefrontal cortex; ; dorsolateral prefrontal cortex; ; Brodmann area 9; ; orbitofrontal cortex;
	Top expressed in
	motor neuron; ; medullary collecting duct; ; barrel cortex; ; superior frontal gyrus; ; primary motor cortex; ; trigeminal ganglion; ; dorsal striatum; ; visual cortex; ; Rostral migratory stream; ; primary visual cortex;
	More reference expression data
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	transferase activity; nucleotide binding; calcium ion binding; protein kinase activity; calmodulin binding; kinase activity; protein serine/threonine kinase activity; protein tyrosine kinase activity; ATP binding; calmodulin-dependent protein kinase activity;
Cellular component	cell projection; intracellular anatomical structure; nucleus; cytoplasm; cytosol; nucleoplasm;
Biological process	phosphorylation; MAPK cascade; positive regulation of transcription, DNA-templated; protein phosphorylation; protein autophosphorylation; regulation of protein kinase activity; calcium-mediated signaling; peptidyl-tyrosine phosphorylation; positive regulation of protein phosphorylation; peptidyl-serine phosphorylation; peptidyl-threonine phosphorylation; cellular response to reactive oxygen species; positive regulation of protein kinase activity; CAMKK-AMPK signaling cascade; positive regulation of autophagy of mitochondrion;
	Sources:Amigo / QuickGO
Orthologs
	10645
	207565
	ENSG00000110931
	ENSMUSG00000029471
	Q96RR4
	Q8C078
NM_001270485; NM_001270486; NM_006549; NM_153499; NM_153500;
	NM_172214; NM_172215; NM_172216; NM_172226
	NM_001199676; NM_145358
NP_001257414; NP_001257415; NP_006540; NP_705719; NP_705720;
	NP_757363; NP_757364; NP_757365; NP_757380; NP_757365.1
	NP_001186605; NP_663333
	Wikidata
View/Edit Human	View/Edit Mouse

Calcium/calmodulin-dependent protein kinase kinase 2 is an enzyme that in humans is encoded by the CAMKK2 gene.^[5]^[6]

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,^[6] which increases their catalytic activity.^[7] CaMK1 and CaMK4 are phosphorylated at the Thr 177 and Thr 196 residues respectively.^[8]^[9]

CaMKK2 regulates production of the appetite stimulating hormone neuropeptide Y and functions as an AMPK kinase in the hypothalamus.^[10] 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.^[11]^[12]^[13] Inhibition of CaMKK2 in mice reduces appetite and promotes weight loss.^[10]

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.^[14]^[15] 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.^[16]^[15]

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.^[17]^[18]^[19] 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.^[15] Neuronal CaMKK2's regulation of BDNF was recently implicated in progression of Glioblastoma.^[20]

In the hypothalamus, CaMKK2 is involved in centrally mediating energy homeostasis by forming a signaling complex with AMPKα/β and Ca2+/CaM.^[10]^[15] Genetic ablation of CaMKK2 decreases AMPK^[21] 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.^[10] 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.^[22]^[15]

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.^[6]^[23]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000110931 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000029471 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Hsu LS, Tsou AP, Chi CW, Lee CH, Chen JY (Sep 1998). "Cloning, expression and chromosomal localization of human Ca2+/calmodulin-dependent protein kinase kinase". Journal of Biomedical Science. 5 (2): 141–9. doi:10.1159/000025324. PMID 9662074. S2CID 90281764.
^ ^a ^b ^c "Entrez Gene: CAMKK2 calcium/calmodulin-dependent protein kinase kinase 2, beta".
^ "CAMK1 - Calcium/calmodulin-dependent protein kinase type 1 - Homo sapiens (Human) - CAMK1 gene & protein". www.uniprot.org. Retrieved 2021-05-15.
^ Soderling TR (June 1999). "The Ca-calmodulin-dependent protein kinase cascade". Trends in Biochemical Sciences. 24 (6): 232–6. doi:10.1016/s0968-0004(99)01383-3. PMID 10366852.
^ Selbert MA, Anderson KA, Huang QH, Goldstein EG, Means AR, Edelman AM (July 1995). "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. doi:10.1074/jbc.270.29.17616. PMID 7615569.
^ ^a ^b ^c ^d Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, et al. (May 2008). "Hypothalamic CaMKK2 contributes to the regulation of energy balance". Cell Metabolism. 7 (5): 377–88. doi:10.1016/j.cmet.2008.02.011. PMID 18460329.
^ Sánchez-Blázquez P, Rodríguez-Muñoz M, Montero C, de la Torre-Madrid E, Garzón J (February 2008). "Calcium/calmodulin-dependent protein kinase II supports morphine antinociceptive tolerance by phosphorylation of glycosylated phosducin-like protein". Neuropharmacology. 54 (2): 319–30. doi:10.1016/j.neuropharm.2007.10.002. hdl:10261/63344. PMID 18006024. S2CID 23956064.
^ Chen Y, Jiang Y, Yue W, Zhou Y, Lu L, Ma L (October 2008). "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. doi:10.1007/s11064-008-9690-0. PMID 18408996. S2CID 1686579.
^ Chen Y, Yang C, Wang ZJ (January 2010). "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. doi:10.1523/JNEUROSCI.4346-09.2010. PMC 2821163. PMID 20053885.
^ Wayman GA, Lee YS, Tokumitsu H, Silva AJ, Silva A, Soderling TR (September 2008). "Calmodulin-kinases: modulators of neuronal development and plasticity". Neuron. 59 (6): 914–31. doi:10.1016/j.neuron.2008.08.021. PMC 2664743. PMID 18817731.
^ ^a ^b ^c ^d ^e Racioppi L, Means AR (September 2012). "Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology". The Journal of Biological Chemistry. 287 (38): 31658–65. doi:10.1074/jbc.R112.356485. PMC 3442500. PMID 22778263.
^ Morgado-Bernal I (March 2011). "Learning and memory consolidation: linking molecular and behavioral data". Neuroscience. 176: 12–9. doi:10.1016/j.neuroscience.2010.12.056. PMID 21215299. S2CID 34665819.
^ Hatten ME, Heintz N (1995). "Mechanisms of neural patterning and specification in the developing cerebellum". Annual Review of Neuroscience. 18: 385–408. doi:10.1146/annurev.ne.18.030195.002125. PMID 7605067.
^ Wang VY, Zoghbi HY (July 2001). "Genetic regulation of cerebellar development". Nature Reviews. Neuroscience. 2 (7): 484–91. doi:10.1038/35081558. PMID 11433373. S2CID 20373774.
^ Kokubo M, Nishio M, Ribar TJ, Anderson KA, West AE, Means AR (July 2009). "BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV". The Journal of Neuroscience. 29 (28): 8901–13. doi:10.1523/JNEUROSCI.0040-09.2009. PMC 2763571. PMID 19605628.
^ Tomaszewski WH, Waibl-Polania J, Chakraborty M, Perera J, Ratiu J, Miggelbrink A, et al. (October 2022). "Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma". Nature Communications. 13 (1): 6483. Bibcode:2022NatCo..13.6483T. doi:10.1038/s41467-022-34175-y. PMC 9617949. PMID 36309495.
^ Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, et al. (March 2004). "AMP-activated protein kinase plays a role in the control of food intake". The Journal of Biological Chemistry. 279 (13): 12005–8. doi:10.1074/jbc.C300557200. hdl:10044/1/631. PMID 14742438.
^ Oury F, Yadav VK, Wang Y, Zhou B, Liu XS, Guo XE, et al. (October 2010). "CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons". Genes & Development. 24 (20): 2330–42. doi:10.1101/gad.1977210. PMC 2956211. PMID 20952540.
^ Hsu LS, Chen GD, Lee LS, Chi CW, Cheng JF, Chen JY (August 2001). "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. doi:10.1074/jbc.M011720200. PMID 11395482.

External links

Human CAMKK2 genome location and CAMKK2 gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000110931 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000029471 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9662074-5] Hsu LS, Tsou AP, Chi CW, Lee CH, Chen JY (Sep 1998). "Cloning, expression and chromosomal localization of human Ca2+/calmodulin-dependent protein kinase kinase". Journal of Biomedical Science. 5 (2): 141–9. doi:10.1159/000025324. PMID 9662074. S2CID 90281764.

[entrez-6] "Entrez Gene: CAMKK2 calcium/calmodulin-dependent protein kinase kinase 2, beta".

[7] "CAMK1 - Calcium/calmodulin-dependent protein kinase type 1 - Homo sapiens (Human) - CAMK1 gene & protein". www.uniprot.org. Retrieved 2021-05-15.

[8] Soderling TR (June 1999). "The Ca-calmodulin-dependent protein kinase cascade". Trends in Biochemical Sciences. 24 (6): 232–6. doi:10.1016/s0968-0004(99)01383-3. PMID 10366852.

[9] Selbert MA, Anderson KA, Huang QH, Goldstein EG, Means AR, Edelman AM (July 1995). "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. doi:10.1074/jbc.270.29.17616. PMID 7615569.

[pmid18460329-10] Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, et al. (May 2008). "Hypothalamic CaMKK2 contributes to the regulation of energy balance". Cell Metabolism. 7 (5): 377–88. doi:10.1016/j.cmet.2008.02.011. PMID 18460329.

[pmid18006024-11] Sánchez-Blázquez P, Rodríguez-Muñoz M, Montero C, de la Torre-Madrid E, Garzón J (February 2008). "Calcium/calmodulin-dependent protein kinase II supports morphine antinociceptive tolerance by phosphorylation of glycosylated phosducin-like protein". Neuropharmacology. 54 (2): 319–30. doi:10.1016/j.neuropharm.2007.10.002. hdl:10261/63344. PMID 18006024. S2CID 23956064.

[pmid18408996-12] Chen Y, Jiang Y, Yue W, Zhou Y, Lu L, Ma L (October 2008). "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. doi:10.1007/s11064-008-9690-0. PMID 18408996. S2CID 1686579.

[pmid20053885-13] Chen Y, Yang C, Wang ZJ (January 2010). "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. doi:10.1523/JNEUROSCI.4346-09.2010. PMC 2821163. PMID 20053885.

[14] Wayman GA, Lee YS, Tokumitsu H, Silva AJ, Silva A, Soderling TR (September 2008). "Calmodulin-kinases: modulators of neuronal development and plasticity". Neuron. 59 (6): 914–31. doi:10.1016/j.neuron.2008.08.021. PMC 2664743. PMID 18817731.

[:0-15] Racioppi L, Means AR (September 2012). "Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology". The Journal of Biological Chemistry. 287 (38): 31658–65. doi:10.1074/jbc.R112.356485. PMC 3442500. PMID 22778263.

[16] Morgado-Bernal I (March 2011). "Learning and memory consolidation: linking molecular and behavioral data". Neuroscience. 176: 12–9. doi:10.1016/j.neuroscience.2010.12.056. PMID 21215299. S2CID 34665819.

[17] Hatten ME, Heintz N (1995). "Mechanisms of neural patterning and specification in the developing cerebellum". Annual Review of Neuroscience. 18: 385–408. doi:10.1146/annurev.ne.18.030195.002125. PMID 7605067.

[18] Wang VY, Zoghbi HY (July 2001). "Genetic regulation of cerebellar development". Nature Reviews. Neuroscience. 2 (7): 484–91. doi:10.1038/35081558. PMID 11433373. S2CID 20373774.

[19] Kokubo M, Nishio M, Ribar TJ, Anderson KA, West AE, Means AR (July 2009). "BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV". The Journal of Neuroscience. 29 (28): 8901–13. doi:10.1523/JNEUROSCI.0040-09.2009. PMC 2763571. PMID 19605628.

[20] Tomaszewski WH, Waibl-Polania J, Chakraborty M, Perera J, Ratiu J, Miggelbrink A, et al. (October 2022). "Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma". Nature Communications. 13 (1): 6483. Bibcode:2022NatCo..13.6483T. doi:10.1038/s41467-022-34175-y. PMC 9617949. PMID 36309495.

[21] Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, et al. (March 2004). "AMP-activated protein kinase plays a role in the control of food intake". The Journal of Biological Chemistry. 279 (13): 12005–8. doi:10.1074/jbc.C300557200. hdl:10044/1/631. PMID 14742438.

[22] Oury F, Yadav VK, Wang Y, Zhou B, Liu XS, Guo XE, et al. (October 2010). "CREB mediates brain serotonin regulation of bone mass through its expression in ventromedial hypothalamic neurons". Genes & Development. 24 (20): 2330–42. doi:10.1101/gad.1977210. PMC 2956211. PMID 20952540.

[pmid11395482-23] Hsu LS, Chen GD, Lee LS, Chi CW, Cheng JF, Chen JY (August 2001). "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. doi:10.1074/jbc.M011720200. PMID 11395482.

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CAMKK2

Function

Isoforms

References

Further reading

External links

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