Importance of Ca++/CaM Dependent CaMKK2 Signaling

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(Last Updated On: April 4, 2020)
Activation of Calmodulin to activate CaMKK2 signaling pathway
The structure of calmodulin and its activation. A: modular structure of calmodulin showing ca binding site, B: binding of Ca leads to the conformational changes and activates the CaM that binds to the target protein. Image: Molecular Biology of The Cell, 6e

Calcium is a second messenger that mediates many cellular processes. It binds to calcium-binding protein calmodulin (CaM) to form a complex. Calcium-binding activates the calmodulin that serves as a calcium receptor and activates downstream signaling proteins such as CaM-dependent protein kinases (CaMK).


There are three types of CaMKs; CaMK1, CaMK2, and CaMK4. They are activated by the key threonine phosphorylation catalyzes by their respective CaM kinase kinases
(CaMKK). CaMKKs not only activate the CaMK but also activate the AMP-activated protein kinases AMPK involved in the regulation of the energy balance in the hypothalamus.

Structure-activity relationship of the CaMKK2 in CaMKK2 signaling pathway
The structure of CaMKK2 showing different domains and activation of the CaMKK2 by Ca++/CaM. Image: Racioppi and Means, 2012

CaMKK2, similar to CaMK family, contains three domains; C-terminal, N-terminal and a central catalytic domain possessing Ser/Thr kinase. The centrally located catalytic domain contains autoinhibitory and calcium-binding regions. CaMKK2 catalyzes the phosphorylation of the key threonine residues located in the activation loop of the CaMK1 and CaMK4 and enhances their kinase activity.

CamKK2 possesses kinase activity even in the absence of Ca++/CaM binding, an autonomous activity.  To confirm the presence of this activity, researchers mutated a region of the 23 amino acid located on the N-terminal to the catalytic domain of the CaMKK2 and found that mutated CaMKK2 showed increased autonomous activity without any alteration in the Ca++/CaM dependent activity.

CaMKK2 signaling pathway regulated different cellular processes
CaMKK2 signaling pathway activated by Ca++/CaM leads to the activation of different cellular processes. Image: Racioppi and Means, 2012

Calcium controls many cellular processes such as muscle contraction and neuronal signal transmission. In both cases, it acts as a second messenger involved in the downstream signaling cascade activation. In the neurons, calcium plays an important role in the synthesis and secretion of neurotransmitters and the morphology of the dendritic cells. The main signaling of the calcium involves the Ca++ dependent pathway such as Ca++/CaM dependent protein kinase signaling pathway.

It has been found that the absence of the CaMKK2 is associated with the loss of long-term nerve impulse transmission at the hippocampal CA1 synapses and also decreases activation of the cAMP response-element binding protein in the hippocampus. Proper initiation and maintenance of the synaptic plasticity in the hippocampal CA1 neurons require morphological changes in the dendritic spines because dendritic cells constitute the main structural basis of memory formation.

Study of the cultured neurons revealed that regulation of the axonal growth, cone morphology and outgrowth, spine and synapse formation requires CaMKK/CaMK1 signaling cascade induced by Ca++/CaM. It has also been found that CaMKK along with CaMK1, a p21-activated kinase interacting exchange factor (βPIX), and a G-protein linked kinase interacting protein-1 (GIT1) to form a multiprotein complex that leads to the regulation of the actin dynamics during the cytoskeleton remodeling. Thus, neuronal cytoskeleton remodeling and memory formation involve CaMKK2/CaMK1 signaling cascade.

CaMKK2/CaMK1 signaling pathway also plays an important role in cerebellum development. The neuronal cells of the cerebellum are called cerebellar granule cells. The development of cerebellar granule cells and their migration requires expression of the CaMKK2. This reveals that CaMKK2 is necessary for the development of the cerebellar granule cells. However, in this case, the CaM kinase involved in the downstream signaling mediated by the CaMKK2 is CaMK4.

Similarly, in the hypothalamic neuronal cells are called the arcuate nucleus (ARC). ARCs are involved in the regulation of electrical activity and the release of orexigenic neuropeptide-Y (NPY), and NPY/Agouti-related protein (AgRP) required for the positive regulation of the feeding behavior. While the pro-opiomelanocortin neurons secret the α-melanocyte-stimulating hormone that inhibits the feeding behavior. Therefore, AgRP inhibits the activity of the pro-opiomelanocortin neurons and serves as a modulator.

Ghrelin is a hormone produced in the intestine that acts on the hypothalamic NPY/AgRP neurons releasing them to exert a potential orexigenic effect.  Ghrelin exerts its effect when it binds the ghrelin receptor, Gq-coupled growth hormone secretagogue receptor, in the hypothalamic neuron cells. Ghrelin binds to the receptor and leads to the Ca++/CaM dependent CaMKK2 signaling pathway that leads to the expression of the NYP/AgRP genes in the hypothalamic neurons.

CaMKK2 signaling plays an important role not only in neurons but also in other tissues. As, for example, in adipose tissues and liver, it plays an important role in glucose metabolism. In adipose tissue, the formation of the adipocytes via adipogenesis is directly related to the expression of the CaMKK2 and inhibition of the CaMKK2 signaling enhances the adipogenesis.

While in the case of the liver, it has been observed that acute reduction of the hepatic CaMKK2 leads to the reduced blood sugar level in the mice fed with a regular or high-fat diet. In fact, a deletion mutation of the CaMKK2 (inactivated CaMKK2 signaling pathway) prevents the up-regulation of the key enzymes of the gluconeogenesis and the consequence is reduced blood glucose level.

In hematopoiesis and immune system, it has been observed that CaMKK2/CaMK4 regulates the survival of the activated dendritic cells and increases the strength of the antibody response induced by the vaccines. CaMK1 initiates the Toll-like receptor-4 (TLR4) signaling as well as inflammatory responses induced by the sepsis. AMPK also plays an important role together with CaMKK2 in the inflammatory responses indicating that CaMKK2 together with AMPK signaling may control the hematopoiesis and inflammatory responses.

The CaMKK2 signaling pathway is also important in some cancers. Androgen receptor (AR) plays an important role in the regulation of prostate growth while it can also be a principle target site for the therapy to prevent androgen-dependent prostate cancer. Researchers have found that androgen stimulates the CaMKK2 expression in the androgen-dependent prostate cancer cells. Androgen-induced activation of the CaMKK2 in association with the AMPK signaling pathway mediates prostate cancer cell migration and invasion.

In conclusion, CaMKK2 mediates many signaling pathways involved in the varieties of cellular responses such as hematopoiesis, immunity, and inflammation, neuronal neurotransmission, prostate cancer, etc. However, CaMKK2 undergoes several post-translational modifications that affect protein stability and activity. cAMP/PKA pathway inhibits the CaMKK2 activity while Gq-coupled receptors and Ca++.

Reference: The Journal of Biological Chemistry (Calcium/Calmodulin-dependent Protein Kinase Kinase 2: Roles in Signaling and Pathophysiology)

Article DOI: 10.1074/jbc.R112.356485

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