CAMKK2 pathway (WP4874)

Homo sapiens

CaMKK2 is a 66–68-kDa serine kinase, consists of unique N- and C-terminal domains and a central Ser/Thr-directed kinase domain that is followed by a regulatory domain composed of overlapping autoinhibitory and CaM-binding regions (PMID:9335539). CAMKK2 is activated once calmodulin (CALM1) binds with CAAMKK2. The most well-characterized substrates of CaMKK2 are CaMKI, CaMKIV and AMPKα. CaMKK2 phosphorylates CaMKIV, CaMKI and AMPKα on activation loop Thr residues (Thr-200, Thr-177 and Thr-172, respectively), which increases their kinase activities (PMID:9822657). CaMKK2 is present in many areas of the brain, including the olfactory bulb, hippocampus, dentate gyrus, amygdala, hypothalamus, and cerebellum (PMID:9822657, 12654522). The creation of this pathway is described in [ Najar et al].


Dr. T. S. Keshava Prasad , Denise Slenter , Rex D A B , Egon Willighagen , Kristina Hanspers , Friederike Ehrhart , and Eric Weitz


last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.


Homo sapiens



Disease Ontology


Pathway Ontology

calcium/calcium-mediated signaling pathway


Label Type Compact URI Comment
Caulerpin Metabolite chebi:80923
Isorhamnetin Metabolite chebi:6052
Ramipril Metabolite chebi:8774
Homocysteine sulfinic acid Metabolite chebi:137439
Apigenin Metabolite chebi:18388
Eugenol Metabolite chebi:4917
Glyceollin Metabolite chebi:16470
Quercetin Metabolite chebi:16243
Oxytocin Metabolite chebi:7872
Bupivacaine Metabolite chebi:31322
Betulinic acid Metabolite chebi:3087
MAF GeneProduct ncbigene:4094
VCAM1 GeneProduct ncbigene:7412
FIS1 GeneProduct ncbigene:51024
DRP1 GeneProduct ncbigene:10059
HMOX1 GeneProduct ncbigene:3162
CALM1 GeneProduct ncbigene:801
MAP1LC3A GeneProduct ncbigene:84557
NFATC2 GeneProduct ncbigene:4773
STIM1 GeneProduct ncbigene:6786
RPTOR GeneProduct ncbigene:57521
MTOR GeneProduct ncbigene:2475
CAMK1 GeneProduct ncbigene:8536
ARHGEF7 GeneProduct ncbigene:8874
EP300 GeneProduct ncbigene:2033
SMC1 GeneProduct ncbigene:8243
WFS1 GeneProduct ncbigene:7466
MAPK1 GeneProduct ncbigene:5594
CAMK4 GeneProduct ncbigene:814
RELA GeneProduct ncbigene:5970
VCAM1 GeneProduct ncbigene:7412
NOS1 GeneProduct ncbigene:4842
GIT1 GeneProduct ncbigene:28964
SQSTM1 GeneProduct ncbigene:8878
PAK1 GeneProduct ncbiprotein:5058
CREB1 GeneProduct ncbigene:1385
CHRM3 GeneProduct ncbigene:1131
ICAM1 GeneProduct ncbigene:3383
GDH1 GeneProduct ncbigene:854557
CAMKK2 GeneProduct ncbigene:10645
RAC1 GeneProduct ncbigene:5879
HDCA4 GeneProduct ncbigene:9759
HMOX1 GeneProduct ncbigene:3162
CREB1 GeneProduct ncbigene:1385
TSC1 GeneProduct ncbigene:7248
SIRT1 GeneProduct ncbigene:23411
PRKAA2 GeneProduct ncbiprotein:NP_006243.2
MAPK3 GeneProduct ncbigene:5595
NRF2 GeneProduct ncbigene:4780
ACACA Protein ncbiprotein:NP_942131.1
FOXO3A Protein ncbiprotein:NP_001446.1
Adropin Protein interpro:IPR034461
NOS3 Protein ncbiprotein:NP_000594.2
MAPK14 Protein ncbiprotein:NP_001306.1
EIF4EBP1 Protein ncbiprotein:NP_004086.1
IRS-1 Protein ncbiprotein:NP_005535.1
TBC1D4 Protein ncbiprotein:NP_001273587.1
Protein Protein ncbigene:5894
AKT Protein ncbiprotein:NP_001014431.1
TSC2 Protein ncbiprotein:NP_000539.2
PRKCA Protein ncbiprotein:NP_002728.1


  1. Components of a calmodulin-dependent protein kinase cascade. Molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase beta. Anderson KA, Means RL, Huang QH, Kemp BE, Goldstein EG, Selbert MA, et al. J Biol Chem. 1998 Nov 27;273(48):31880–9. PubMed Europe PMC Scholia
  2. A comparison between 1,25-dihydroxy-22-oxavitamin D(3) and 1,25-dihydroxyvitamin D(3) regarding suppression of parathyroid hormone secretion and calcaemic action. Hirata M, Endo K, Katsumata K, Ichikawa F, Kubodera N, Fukagawa M. Nephrol Dial Transplant. 2002;17 Suppl 10:41–5. PubMed Europe PMC Scholia
  3. Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation. Schmitt JM, Guire ES, Saneyoshi T, Soderling TR. J Neurosci. 2005 Feb 2;25(5):1281–90. PubMed Europe PMC Scholia
  4. The involvement of AMP-activated protein kinases in the anti-inflammatory effect of nicotine in vivo and in vitro. Cheng PY, Lee YM, Law KK, Lin CW, Yen MH. Biochem Pharmacol. 2007 Dec 15;74(12):1758–65. PubMed Europe PMC Scholia
  5. Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex. Saneyoshi T, Wayman G, Fortin D, Davare M, Hoshi N, Nozaki N, et al. Neuron. 2008 Jan 10;57(1):94–107. PubMed Europe PMC Scholia
  6. Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses. Kwon HB, Castillo PE. Neuron. 2008 Jan 10;57(1):108–20. PubMed Europe PMC Scholia
  7. Oxytocin stimulates glucose uptake in skeletal muscle cells through the calcium-CaMKK-AMPK pathway. Lee ES, Uhm KO, Lee YM, Kwon J, Park SH, Soo KH. Regul Pept. 2008 Nov 29;151(1–3):71–4. PubMed Europe PMC Scholia
  8. ICAM-1-mediated endothelial nitric oxide synthase activation via calcium and AMP-activated protein kinase is required for transendothelial lymphocyte migration. Martinelli R, Gegg M, Longbottom R, Adamson P, Turowski P, Greenwood J. Mol Biol Cell. 2009 Feb;20(3):995–1005. PubMed Europe PMC Scholia
  9. Regulation of renal epithelial tight junctions by the von Hippel-Lindau tumor suppressor gene involves occludin and claudin 1 and is independent of E-cadherin. Harten SK, Shukla D, Barod R, Hergovich A, Balda MS, Matter K, et al. Mol Biol Cell. 2009 Feb;20(3):1089–101. PubMed Europe PMC Scholia
  10. CaMKK is an upstream signal of AMP-activated protein kinase in regulation of substrate metabolism in contracting skeletal muscle. Abbott MJ, Edelman AM, Turcotte LP. Am J Physiol Regul Integr Comp Physiol. 2009 Dec;297(6):R1724-32. PubMed Europe PMC Scholia
  11. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, et al. Nature. 2010 Apr 29;464(7293):1313–9. PubMed Europe PMC Scholia
  12. The glutamate agonist homocysteine sulfinic acid stimulates glucose uptake through the calcium-dependent AMPK-p38 MAPK-protein kinase C zeta pathway in skeletal muscle cells. Kim JH, Lee JO, Lee SK, Moon JW, You GY, Kim SJ, et al. J Biol Chem. 2011 Mar 4;286(9):7567–76. PubMed Europe PMC Scholia
  13. Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes. Tong X, Smith KA, Pelling JC. Mol Carcinog. 2012 Mar;51(3):268–79. PubMed Europe PMC Scholia
  14. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, et al. EMBO J. 2011 May 20;30(13):2719–33. PubMed Europe PMC Scholia
  15. Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-β (CaMKK-β). Ghislat G, Patron M, Rizzuto R, Knecht E. J Biol Chem. 2012 Nov 9;287(46):38625–36. PubMed Europe PMC Scholia
  16. Nanosecond pulsed electric fields activate AMP-activated protein kinase: implications for calcium-mediated activation of cellular signaling. Morotomi-Yano K, Akiyama H, Yano K ichi. Biochem Biophys Res Commun. 2012 Nov 23;428(3):371–5. PubMed Europe PMC Scholia
  17. Glyceollin improves endoplasmic reticulum stress-induced insulin resistance through CaMKK-AMPK pathway in L6 myotubes. Yoon EK, Jeong YT, Li X, Song-Cui, Park DC, Kim YH, et al. J Nutr Biochem. 2013 Jun;24(6):1053–61. PubMed Europe PMC Scholia
  18. Laminar shear stress upregulates endothelial Ca²⁺-activated K⁺ channels KCa2.3 and KCa3.1 via a Ca²⁺/calmodulin-dependent protein kinase kinase/Akt/p300 cascade. Takai J, Santu A, Zheng H, Koh SD, Ohta M, Filimban LM, et al. Am J Physiol Heart Circ Physiol. 2013 Aug 15;305(4):H484-93. PubMed Europe PMC Scholia
  19. Stimulation of glucose uptake by theasinensins through the AMP-activated protein kinase pathway in rat skeletal muscle cells. Qiu J, Maekawa K, Kitamura Y, Miyata Y, Tanaka K, Tanaka T, et al. Biochem Pharmacol. 2014 Jan 15;87(2):344–51. PubMed Europe PMC Scholia
  20. Ramipril protects the endothelium from high glucose-induced dysfunction through CaMKKβ/AMPK and heme oxygenase-1 activation. Tian S, Ge X, Wu K, Yang H, Liu Y. J Pharmacol Exp Ther. 2014 Jul;350(1):5–13. PubMed Europe PMC Scholia
  21. Enhanced expression of WD repeat-containing protein 35 via CaMKK/AMPK activation in bupivacaine-treated Neuro2a cells. Huang L, Kondo F, Gosho M, Feng GG, Harato M, Xia Z yuan, et al. PLoS One. 2014 May 23;9(5):e98185. PubMed Europe PMC Scholia
  22. AMPK activation by isorhamnetin protects hepatocytes against oxidative stress and mitochondrial dysfunction. Dong GZ, Lee JH, Ki SH, Yang JH, Cho IJ, Kang SH, et al. Eur J Pharmacol. 2014 Oct 5;740:634–40. PubMed Europe PMC Scholia
  23. Eugenol ameliorates hepatic steatosis and fibrosis by down-regulating SREBP1 gene expression via AMPK-mTOR-p70S6K signaling pathway. Jo HK, Kim GW, Jeong KJ, Kim DY, Chung SH. Biol Pharm Bull. 2014;37(8):1341–51. PubMed Europe PMC Scholia
  24. Alpha Lipoic Acid Modulated High Glucose-Induced Rat Mesangial Cell Dysfunction via mTOR/p70S6K/4E-BP1 Pathway. Lv C, Wu C, Zhou YH, Shao Y, Wang G, Wang QY. Int J Endocrinol. 2014;2014:658589. PubMed Europe PMC Scholia
  25. Estrogen Activates AMP-Activated Protein Kinase in Human Endothelial Cells via ERβ/Ca(2+)/Calmodulin-Dependent Protein Kinase Kinase β Pathway. Yang S, Wang J. Cell Biochem Biophys. 2015 Jul;72(3):701–7. PubMed Europe PMC Scholia
  26. Autocrine Activation of CHRM3 Promotes Prostate Cancer Growth and Castration Resistance via CaM/CaMKK-Mediated Phosphorylation of Akt. Wang N, Yao M, Xu J, Quan Y, Zhang K, Yang R, et al. Clin Cancer Res. 2015 Oct 15;21(20):4676–85. PubMed Europe PMC Scholia
  27. Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling. Sinha RA, Singh BK, Zhou J, Wu Y, Farah BL, Ohba K, et al. Autophagy. 2015;11(8):1341–57. PubMed Europe PMC Scholia
  28. AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells. Kim N, Lee JO, Lee HJ, Lee YW, Kim HI, Kim SJ, et al. J Endocrinol. 2016 Feb;228(2):105–14. PubMed Europe PMC Scholia
  29. Betulinic Acid Increases eNOS Phosphorylation and NO Synthesis via the Calcium-Signaling Pathway. Jin SW, Choi CY, Hwang YP, Kim HG, Kim SJ, Chung YC, et al. J Agric Food Chem. 2016 Feb 3;64(4):785–91. PubMed Europe PMC Scholia
  30. Clopidogrel Protects Endothelium by Hindering TNFα-Induced VCAM-1 Expression through CaMKKβ/AMPK/Nrf2 Pathway. Yang H, Zhao P, Tian S. J Diabetes Res. 2016;2016:9128050. PubMed Europe PMC Scholia
  31. The Ca(2+)/Calmodulin/CaMKK2 Axis: Nature’s Metabolic CaMshaft. Marcelo KL, Means AR, York B. Trends Endocrinol Metab. 2016 Oct;27(10):706–18. PubMed Europe PMC Scholia
  32. Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1α axis. Sallé-Lefort S, Miard S, Nolin MA, Boivin L, Paré MÈ, Debigaré R, et al. Int J Oncol. 2016 Oct;49(4):1731–6. PubMed Europe PMC Scholia
  33. Metabolic reprogramming and AMPKα1 pathway activation by caulerpin in colorectal cancer cells. Yu H, Zhang H, Dong M, Wu Z, Shen Z, Xie Y, et al. Int J Oncol. 2017 Jan;50(1):161–72. PubMed Europe PMC Scholia
  34. Adropin Is a Key Mediator of Hypoxia Induced Anti-Dipsogenic Effects via TRPV4-CamKK-AMPK Signaling in the Circumventricular Organs of Rats. Yang F, Zhou L, Qian X, Wang D, He WJ, Tang ZW, et al. Front Mol Neurosci. 2017 Apr 20;10:105. PubMed Europe PMC Scholia
  35. WSF-P-1, a novel AMPK activator, promotes adiponectin multimerization in 3T3-L1 adipocytes. Wang Y, Zhang Y, Wang Y, Peng H, Rui J, Zhang Z, et al. Biosci Biotechnol Biochem. 2017 Aug;81(8):1529–35. PubMed Europe PMC Scholia
  36. Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells. Huang Q, Cao H, Zhan L, Sun X, Wang G, Li J, et al. Cancer Lett. 2017 Sep 10;403:108–18. PubMed Europe PMC Scholia
  37. Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer. Takasawa K, Takasawa A, Osanai M, Aoyama T, Ono Y, Kono T, et al. Cancer Lett. 2017 Sep 10;403:66–73. PubMed Europe PMC Scholia
  38. Akt activation by Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in ovarian cancer cells. Gocher AM, Azabdaftari G, Euscher LM, Dai S, Karacosta LG, Franke TF, et al. J Biol Chem. 2017 Aug 25;292(34):14188–204. PubMed Europe PMC Scholia
  39. Quercetin, a Lead Compound against Type 2 Diabetes Ameliorates Glucose Uptake via AMPK Pathway in Skeletal Muscle Cell Line. Dhanya R, Arya AD, Nisha P, Jayamurthy P. Front Pharmacol. 2017 Jun 8;8:336. PubMed Europe PMC Scholia
  40. Hydrogen Sulphide Treatment Increases Insulin Sensitivity and Improves Oxidant Metabolism through the CaMKKbeta-AMPK Pathway in PA-Induced IR C2C12 Cells. Chen X, Zhao X, Lan F, Zhou T, Cai H, Sun H, et al. Sci Rep. 2017 Oct 16;7(1):13248. PubMed Europe PMC Scholia
  41. Omega-3 polyunsaturated fatty acids protect human hepatoma cells from developing steatosis through FFA4 (GPR120). Kang S, Huang J, Lee BK, Jung YS, Im E, Koh JM, et al. Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Feb;1863(2):105–16. PubMed Europe PMC Scholia
  42. Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival. Vara-Ciruelos D, Dandapani M, Gray A, Egbani EO, Evans AM, Hardie DG. Mol Cancer Res. 2018 Feb;16(2):345–57. PubMed Europe PMC Scholia
  43. The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer. Jin L, Chun J, Pan C, Kumar A, Zhang G, Ha Y, et al. Mol Cell. 2018 Jan 4;69(1):87-99.e7. PubMed Europe PMC Scholia
  44. GLUT12 promotes prostate cancer cell growth and is regulated by androgens and CaMKK2 signaling. White MA, Tsouko E, Lin C, Rajapakshe K, Spencer JM, Wilkenfeld SR, et al. Endocr Relat Cancer. 2018 Apr;25(4):453–69. PubMed Europe PMC Scholia