CAMKK2 Gene

Name	calcium/calmodulin-dependent protein kinase kinase 2, beta
Description	The product of this gene belongs to the Serine/Threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. The major isoform of this gene plays a role in the calcium/calmodulin-dependent (CaM) kinase cascade by phosphorylating the downstream kinases CaMK1 and CaMK4. Protein products of this gene also phosphorylate AMP-activated protein kinase (AMPK). This gene has its strongest expression in the brain and influences signalling cascades involved with learning and memory, neuronal differentiation and migration, neurite outgrowth, and synapse formation. Alternative splicing results in multiple transcript variants encoding distinct isoforms. The identified isoforms differ in their ability to undergo autophosphorylation and to phosphorylate downstream kinases. [provided by RefSeq, Jul 2012]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CAMKK2—particularly its β‐isoform—acts as a pivotal calcium‐responsive kinase that links increases in intracellular Ca²⁺ to the activation of key metabolic regulators. By phosphorylating downstream targets such as AMP‐activated protein kinase (AMPK), CaMKI, and CaMKIV, CAMKK2 rapidly transmits Ca²⁺ signals into metabolic and survival responses.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In conditions where intracellular Ca²⁺ is elevated (for example, upon stimulation with Ca²⁺ ionophores), CAMKK2 activates AMPK independently of changes in adenine nucleotide levels, producing a rapid response to metabolic stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " This Ca²⁺‐dependent mechanism is reinforced in receptor‐mediated contexts; for instance, binding of adiponectin to its receptor (AdipoR1) promotes extracellular Ca²⁺ influx that subsequently activates CAMKK2, leading to stimulation of AMPK and SIRT1. This cascade enhances mitochondrial biogenesis and improves metabolic function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Similarly, in endothelial cells, thrombin‐induced Ca²⁺ influx activates CAMKK2 to stimulate AMPK, highlighting its role in diverse physiologic settings."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond these roles in normal metabolism, CAMKK2 also contributes to pathological adaptations. In LKB1‐deficient lung cancer cells, for example, the metabolite α‐ketoglutarate enhances CAMKK2’s capacity to promote AMPK binding, thereby supporting energy production and anoikis resistance that favor metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, thyroid hormone (T3)–induced reactive oxygen species activate CAMKK2, leading to AMPK phosphorylation that is essential for initiating mitophagy and maintaining mitochondrial quality control."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Comprehensive reviews further emphasize that CAMKK2 regulates a broad spectrum of processes—including energy balance, adiposity, glucose homeostasis, inflammation, and oncogenic signaling—by integrating Ca²⁺ signals within various cellular contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Collectively, these findings establish CAMKK2 as a key node in Ca²⁺‐dependent signaling cascades that coordinate metabolic reprogramming and cellular survival under both physiological and disease conditions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Simon A Hawley, David A Pan, Kirsty J Mustard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2005.05.009"}], "href": "https://doi.org/10.1016/j.cmet.2005.05.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16054095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16054095"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Angela Woods, Kristina Dickerson, Richard Heath, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2005.06.005"}], "href": "https://doi.org/10.1016/j.cmet.2005.06.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16054096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16054096"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Masato Iwabu, Toshimasa Yamauchi, Miki Okada-Iwabu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature08991"}], "href": "https://doi.org/10.1038/nature08991"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20357764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20357764"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nadine Stahmann, Angela Woods, David Carling, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00383-06"}], "href": "https://doi.org/10.1128/MCB.00383-06"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16880506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16880506"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lingtao Jin, Jaemoo Chun, Chaoyun Pan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2017.11.025"}], "href": "https://doi.org/10.1016/j.molcel.2017.11.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29249655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29249655"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Rohit A Sinha, Brijesh K Singh, Jin Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2015.1061849"}], "href": "https://doi.org/10.1080/15548627.2015.1061849"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26103054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26103054"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Luigi Racioppi, Anthony R Means "}, {"type": "b", "children": [{"type": "t", "text": "Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.R112.356485"}], "href": "https://doi.org/10.1074/jbc.R112.356485"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22778263"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22778263"}]}]}]}
Synonyms	CAMKKB, CAMKK
Proteins	KKCC2_HUMAN
NCBI Gene ID	10645
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CAMKK2 has 8,341 functional associations with biological entities spanning 9 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 126 datasets.

Click the + buttons to view associations for CAMKK2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CAMKK2 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CAMKK2 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of CAMKK2 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of CAMKK2 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CAMKK2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of CAMKK2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CAMKK2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving CAMKK2 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CAMKK2 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CAMKK2 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of CAMKK2 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CAMKK2 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of CAMKK2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with CAMKK2 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with CAMKK2 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with CAMKK2 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CAMKK2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CAMKK2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of CAMKK2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CAMKK2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CAMKK2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing CAMKK2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing CAMKK2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CAMKK2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with CAMKK2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of CAMKK2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CAMKK2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with CAMKK2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with CAMKK2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with CAMKK2 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of CAMKK2 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CAMKK2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with CAMKK2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CAMKK2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with CAMKK2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with CAMKK2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at CAMKK2 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CAMKK2 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CAMKK2 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing CAMKK2 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with CAMKK2 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.