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. 2020 Nov 2;15(2):283–290. doi: 10.1007/s12079-020-00592-1

A complete map of the Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) signaling pathway

Mohd Altaf Najar 1, D A B Rex 1, Prashant Kumar Modi 1, Nupur Agarwal 1, Shobha Dagamajalu 1, Gayathree Karthikkeyan 1, Manavalan Vijayakumar 2, Aditi Chatterjee 1,3, Uma Sankar 4, T S Keshava Prasad 1,✉
PMCID: PMC7990983  PMID: 33136287

Abstract

Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is a serine/threonine-protein kinase belonging to the Ca2+/calmodulin-dependent protein kinase subfamily. CAMKK2 has an autocatalytic site, which gets exposed when Ca2+/calmodulin (CAM) binds to it. This results in autophosphorylation and complete activation of CAMKK2. The three major known downstream targets of CAMKK2 are 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPKα), calcium/calmodulin-dependent protein kinase 1 (CAMK1) and calcium/calmodulin-dependent protein kinase 4 (CAMK4). Activation of these targets by CAMKK2 is important for the maintenance of different cellular and physiological processes within the cell. CAMKK2 is found to be important in neuronal development, bone remodeling, adipogenesis, and systemic glucose homeostasis, osteoclastgensis and postnatal myogensis. CAMKK2 is reported to be involved in pathologies like Duchenne muscular dystrophy, inflammation, osteoporosis and bone remodeling and is also reported to be overexpressed in prostate cancer, hepatic cancer, ovarian and gastric cancer. CAMKK2 is involved in increased cell proliferation and migration through CAMKK2/AMPK pathway in prostate cancer and activation of AKT in ovarian cancer. Although CAMKK2 is a molecule of great importance, a public resource of the CAMKK2 signaling pathway is currently lacking. Therefore, we carried out detailed data mining and documentation of the signaling events associated with CAMKK2 from published literature and developed an integrated reaction map of CAMKK2 signaling. This resulted in the cataloging of 285 reactions belonging to the CAMKK2 signaling pathway, which includes 33 protein–protein interactions, 74 post-translational modifications, 7 protein translocation events, and 22 activation/inhibition events. Besides, 124 gene regulation events and 25 activator/inhibitors involved in CAMKK2 activation were also cataloged. The CAMKK2 signaling pathway map data is made freely accessible through WikiPathway database (https://www.wikipathways.org/index.php/Pathway:WP4874). We expect that data on a signaling map of CAMKK2 will provide the scientific community with an improved platform to facilitate further molecular as well as biomedical investigations on CAMKK2 and its utility in the development of biomarkers and therapeutic targets.

Electronic supplementary material

The online version of this article (10.1007/s12079-020-00592-1) contains supplementary material, which is available to authorized users.

Keywords: CAMKK2, Adenocarcinoma, Tumorigenesis, Calcium signaling pathway, Molecular association, Signaling module

Introduction

CAMKK2 a serine/threonine kinase belonging to a calcium-triggered signaling cascade involved in several cellular processes. CaMKK2 isoforms 1, 2 and 3 are catalytically active and isoforms 4,5 and 6 lack the calmodulin-binding domain and are found to be inactive.CAMKK2 phosphorylates and activates calcium/calmodulin-dependent protein kinase 1 (CAMK1) and calcium/calmodulin-dependent protein kinase 4(CAMK4) (Hsu et al. 2001). CAMKK2 also phosphorylates 5′-AMP-activated protein kinase (AMPK) trimer consisting of the catalytic subunit alpha-1 (PRKAA1), and regulatory subunits beta-1(PRKAB1), andgamma-1 (PRKAG1). CAMKK2 is expressed strongly in the brain and influences signaling cascades involved with learning and memory, neuronal differentiation and migration, neurite outgrowth, and synapse formation (Cao et al. 2011). CAMKK2 plays an important role in cellular metabolism, by mediating the downstream effects of hormones, metabolites, inflammatory agents, and neuroendocrine signals. The Ca2+/CaM complex involved in the amplification of Ca2+ signals through activation of a tightly regulated set of protein kinases such as AMPK, and Acetyl-CoA carboxylase 2 (ACC), which have a role in cellular metabolism (Dong et al. 2014; Shen et al. 2007).

CAMKK2 is highly expressed in the arcuate nucleus (ARC) of the hypothalamus and plays a fundamental role in whole-body energy homeostasis (Anderson et al. 2008). CAMKK2 is required during spatial memory formation and for Cyclic AMP-responsive element-binding protein 1(CREB) up-regulation and activation but not for contextual fear (Ho et al. 2000; Peters et al. 2003). A downstream target of CAMKK2, CAMK4, is necessary for contextual long-term memory (LTM) (Mizuno et al. 2007). Since CAMK4 is activated after Long-term potentiation (LTP) at hippocampal CA1 (first region in the hippocampal circuit) synapses (Minichiello et al. 2002), and CAMKK2 is indispensable during hippocampal memory formation (Mizuno et al. 2007). Likely, CAMK4 acts downstream of CAMKK2 during spatial learning to establish late CA1 LTP. In addition to learning and memory, metabolic syndrome, and cerebral ischemia, both CAMKK2 and CAMK4 are associated with impaired energy utilization and deregulated Ca2+ signaling (Pivovarova and Andrews 2010). It is not surprising that metabolic syndrome is amajor risk factor for stroke, which also includes cognitive decline as a persistent pathology (Tatemichi et al. 1994). CAMKK2 and CAMK4 null mice show aggravated brain injuries and behavioral deficits following middle cerebral artery occlusion (MCAO) (Liu et al. 2014; McCullough et al. 2013). Phosphorylation of CAMK4 leads to its nuclear translocation and subsequent phosphorylation of histone deacetylase 4 (HDAC4), which is exported from the nucleus, allowing the transcription of CREB, a neuronal survival factor (Liu et al. 2014; McCullough et al. 2013). Similarly, both CAMKK2 and CAMK4 are instrumental for the proliferation and survival of cerebellar granule cell neurons, by the phosphorylation of CREB (Kokubo et al. 2009). CAMKK2 plays an important role in glucose metabolism in liver hepatocytes, which constitute the parenchymal cells of the liver, are essential for its metabolic capacity, and express CAMKK2. Acute deletion of hepatic CAMKK2 is sufficient to lower blood glucose and improve glucose tolerance in fed and fasted mice (Anderson et al. 2012). Primary hepatocytes (PH) isolated from CAMKK2-null mice produced less glucose, which was accompanied by reduced expression of the gluconeogenic genes glucose-6-phosphatase (G6PC) and phosphoenol pyruvate carboxykinase (PEPCK), owing to the cell-autonomous role of CAMKK2 in phosphorylating hepatic HDAC5 (Anderson et al. 2012). In vitro studies have confirmed that CAMKK2 ablation increased both lipogenesis and lipid oxidation, concomitant with a decrease in glucose utilization in the liver, both of which are consistent with a switch from glucose to fat metabolism (Anderson et al. 2012). Thus, the contribution of Ca2+/CaM signaling through CAMKK2 in regulating energy homeostasis not only involves hypothalamic in control of appetite (Anderson et al. 2008).

CAMKK2 regulates fatty acid metabolism and adipocyte differentiation during fasting or exercise, triacylglycerols (TAGs) are hydrolyzed into glycerol and free fatty acids (FFAs), which are then transported to the liver for use during gluconeogenesis. Adipocytes, therefore, largely function to balance lipid storage and release, to coincide with the feeding to fasting transition (Rosen and Spiegelman 2006). Disrupted Ca2+ signaling accompanying obesity is also associated with attenuated differentiation of pre-adipocyte progenitors (Rosen and Spiegelman 2006).CAMKK2-null mice display increased adiposity when fed standard chow due to increases in both size and number of adipocytes (Lin et al. 2011). The CAMKK2 expression is suppressed once pre-adipocytes differentiate into mature adipocytes, while in vitro ablation or pharmacological inhibition of CAMKK2 increased adipogenesis (Lin et al. 2011). CAMKK2 reportedly regulates AMPK action in response to glucagon, which then phosphorylates Acetyl-CoA carboxylase 1 (ACC1) in adipocytes. Glucagon-induced phosphorylation of ACC1 attenuates its activity during fatty acid synthesis (Peng et al. 2012).

CAMKK2 is found to be dysregulated in many cancers, its expression is markedly upregulated in hepatocellular carcinoma (HCC) compared to matched normal tissue and similarly in several human and murine hepatic cancer cell lines (Lin et al. 2015). The survival of HCC patients also inversely correlates with high CAMKK2 expression. Consistent with these findings, knockdown or pharmacological inhibition of CAMKK2 greatly reduces colony formation and proliferation of liver cancer cells. An upregulation of CAMKK2 in prostate cancer (Fu et al. 2015) and gastric cancer (Subbannayya et al. 2015) has been reported. Its inhibition greatly reduced the cancer phenotypes in both cases. The important roles played by CAMKK2 in multiple biological processes are increasingly being appreciated. However, a basic depiction of the signaling pathway associated with CAMKK2 is still lacking. To fill this gap, we carried out detailed data mining and curation of the signaling events induced by CAMKK2 from published literature and developed an integrated network map of CAMKK2 signaling (Fig. 1).

Fig. 1.

Fig. 1

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An illustrated view of CAMKK2 signaling. The pathway map of CAMKK2 signaling represents the activation of CAMKK2 and the downstream signaling events triggered by the activation. These induced signaling events include protein–protein interactions, post-translational modifications, transport, activation/inhibition, gene regulation events and activators and inhibitors. These events have been represented by various color codes, as shown in the legend. The details of post-translational events, including sites and residues, have also been provided in the map

Materials and methods

Annotation of CAMKK2 signaling events

The literature searches were carried out in PubMed using key terms “CAMKK2” OR “CAMKKB” OR “Calcium calmodulin kinase 2” AND “Signaling” OR “Pathway” NOT ‘Review’. After going through the abstract of these articles, only those articles which describe molecular reactions induced by CAMKK2 were selected for further curation. Further, CAMKK2-induced molecular reactions were categorized into enzyme-catalyzed events, site-specific post-translational modification (PTMs) events, protein–protein interactions (PPIs), and activation/inhibition with respect to their activity and gene regulation events. Manual curation of these events was carried out as per previously described NetPath annotation criteria (Kandasamy et al. 2010) for a series of signaling pathways such as IL-33 (Pinto et al. 2018), RANKL/RANK (Raju et al. 2011a), prolactin (Radhakrishnan et al. 2012), IL-10 (Verma et al. 2016), and oncostatin M (Dey et al. 2013). PathBuilder, a manual curation software for NetPath, was used for manual documentation of signaling events (Kandasamy et al. 2009). The data of diverse molecular reaction events induced by CAMKK2 gathered from the manual curation were then used to generate the CAMKK2 signaling pathway map using ‘PathVisio’ (van Iersel et al. 2008). The curated signaling events underwent two rounds of internal reviews and one round of external review by a Pathway Authority (US, one of the authors). Each molecular reaction is hyperlinked to the PubMed identifier of the articles, where it was described.

Visualization of the signaling pathway

PathVisio (version 3.3.0) was used for the pictorial representation of the pathway reactions (van Iersel et al. 2008). The arrangement of reactions in the pathway map was made based on literature-derived information as per NetPath criteria (Kandasamy et al. 2009, 2010; Raju et al. 2011b) and implemented in WikiPathways (https://www.wikipathways.org/index.php/WikiPathways). The reactions activated by CAMKK2 were arranged in topological order, binding of calmodulin with CAMKK2 changes its topology and activates CAMKK2 exposed its autocatalytic site, which then activates the downstream substrates. Besides, proteins that are translocated by the activation of CAMKK2 were depicted in the pathway along with their translocation. We also listed the genes, which are transcriptionally regulated and their functions, as done in our previous manuscript on the signaling pathway of IL-18 (Rex et al. 2020).

Results and discussion

Curation of CAMKK2 mediated signaling events

To generate CAMKK2-mediated signaling pathway map, a total of 964 research articles published until Dec 30, 2019, were screened from the PubMed database. CAMKK2-mediated signaling events in the presence or absence of the different molecules which regulates the intracellular calcium (Ca2+) and results in the activation/inhibition of CAMKK2 were documented. A total of 81 research articles were found to contain potential CAMKK2 signaling events. From the manually screened articles, a total of 285 reactions mediated by 229 molecules were curated (Supplementary Data S1–S6). We cataloged 74 post-translational modification events, 22 activation/inhibition events, 33 protein–protein interactions, 7 protein translocation events, 124 gene regulation events induced by CAMKK2 signaling. Besides, we also curated 25 activators/inhibitors of CAMKK2.

Summary of CAMKK2-mediated signaling pathway

CAMKK2 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 (Tokumitsu et al. 1997). The most well-characterized substrates of CAMKK2 are CAMK1,CAMK4, and AMPKα. CAMKK2 phosphorylates CAMK4, CAMK1, and AMPKα on activation loop Thr and Ser residues (Thr-200, Thr-177, and Ser-172 respectively), which increases their kinase activities. CAMKK2 was reported in neuroblastoma as phosphorylating MAPK1 through the CAMK1/CAMKK2 pathway (Schmitt et al. 2004). CAMKK2 was also found to be involved in fatty acid metabolism by activating acetyl CoA carboxylase (ACC) through the CAMKK2/AMPK pathway (Dong et al. 2014; Shen et al. 2007). Endothelial nitric oxide synthase (eNOS) activation by intercellular adhesion molecule 1 (ICAM-1) through the AMPK/CAMKK2 pathway has been reported (Martinelli et al. 2009). CAMMK2 was found to be involved in the regulation of autophagy by regulating phosphorylation of the mechanistic target of rapamycin kinase (mTOR) (Yang et al. 2017). Glyceollin (a phytoalexin found in the soybean) was known to activate insulin receptor substrate 1 (IRS1) through the CAMKK2/AMPK pathway, which increased the glucose uptake in myotubes (Yoon et al. 2013). CAMKK2 activation is also known to increase the gluconeogenesis by phosphorylating CAMP responsive element binding protein 1 (CREB1) via activation of AMPK (Jeong et al. 2014). GTPase-activating protein (GIT1), a protein once activated results in increased cell adhesion and migration, was also found to be activated via the CAMKK2/AMPK pathway (Saneyoshi et al. 2008). CAMKK2 activation by quercetin (a plant flavonoid) increased glucose transport, which increased the expression and translocation of GLUT4 towards the plasma membrane (Dhanya et al. 2017). Activation of CAMKK2 was also known to result in the translocation ofclaudin1 (CLDN1), claudin 4 (CLDN4), tight junction protein 1 (ZO-1), and hematopoietic progenitor cell antigen (CD34) via activation of AMPK-alpha (Abbott et al. 2009; Wang et al. 2016).

The activation and deactivation reactions of CAMKK2 by certain small molecules have also been reported. Estrogen has been reported to activate CAMKK2 by increasing the cytosolic calcium concentration in primary human aortic endothelial cells (HAECs) (Yang and Wang 2015). Betulinic acid was also found to be involved in the CAMKK2 activation (Jin et al. 2016). Eugenol was known to activate CAMKK2 in HePG2 cells (Jo et al. 2014). It was also found that polyunsaturated fatty acids decrease the activity of CAMKK2 by decreasing the phosphorylation of CAMKK2 in HEP3B cells (Kang et al. 2018). Oxytocin, a peptide hormone, was found to activate CAMKK2 in C2C12 myoblasts (Lee et al. 2008).

Association of CAMKK2 signaling in human diseases

The cellular homeostasis depends on the regulation of energy intake and its expenditure in response to the stimuli from the peripheral environment (Williams and Sankar 2019). AMPK, a heterotrimeric kinase, is known to act as a key factor in the modulation of energy during nutrient intake, glucose homeostasis, and energy expenditure. Ca2+, a universal second messenger, is known to be detected by its receptor calmodulin (CAM) resulting in the amplification of downstream molecules such as metabolites, inflammatory agents and hormones as a part of the Ca2+/CaM-dependent protein kinase (CAMK) signaling cascade (Carafoli 2002; Marcelo et al. 2016; Racioppi and Means 2012). The CAMKK2 pathway was also found to be involved in the regulation of various physiological processes such as hepatic gluconeogenesis, lymphocyte activation, macroautophagy, adipocyte differentiation, and hypothalamic feeding behavior. Genetic studies have demonstrated the involvement of CAMKK2 in disorders such as pulmonary nontuberculous mycobacterial (NTM) infections as it plays an important role in the killing of phagocytosed bacteria and macrophage dysfunction (Gaff et al. 2018; Goullee et al. 2016; Halstrom et al. 2017).

Overexpression of CAMKK2 has been observed in the various physiological and pathological condition such as homeostatic osteoclastogenesis, postnatal myogenesis, neuron development, muscle regeneration, adipogenesis inhibition, gastric adenocarcinoma, Duchenne muscular dystrophy (Cary et al. 2013; Lin et al. 2011; Racioppi 2013; Racioppi and Means 2012; Subbannayya et al. 2015; Ye et al. 2016). Several studies have also demonstrated its role in hepatocellular carcinoma, inflammation, and bone remodeling (Anderson et al. 2012; Lin et al. 2015). Histone deacetylase 5 (HDAC5), responsible for the gluconeogenic enzyme expression,is known to be activated by CAMKK2 in hepatocytes. Reduced expression of CAMKK2 was reported to result in increased lipogenesis, fatty acid oxidation, and decreased gluconeogenesis (Anderson et al. 2012; Lin et al. 2015). The pharmacological treatments for non-alcoholic fatty liver disease (NAFLD) and hepatic steatosis target CAMKK2 (York et al. 2017). Expression of osteoblasts (OBs) and osteoclasts (OCs) occur via the CAMKK2/CAMK4 pathway (Cary et al. 2013). CAMKK2 inhibition was also found to be protective of age-related osteoporosis. Studies have even suggested CAMKK2 as the potential molecular target for the treatment of bone fractures and the strengthening of bones (Pritchard et al. 2015; Williams et al. 2018). The central hub of signaling, cellular metabolism, and proliferation in prostate cancer (PCa) occurs via the CAMKK2/AMPK pathway. The Inhibition of CAMKK2 protein has been found to reverse cell growth and invasion of prostate cancer (Dadwal et al. 2018; MacDonald et al. 2018). The emerging hypothesis from these studies indicates CaMKK2 as a key effector in PCa cells, responsible for the cell cycle stabilization, glycolysis, and cell migration or invasion via AMPK signaling cascade. In vivo studies with clinical samples have also identified CAMKK2 to be enriched in PCa (Massie et al. 2011; Shima et al. 2012). In ovarian cancer, CAMKK2 was found to activate AKT, by phosphorylating it (Gocher et al. 2017). Higher expression of CAMKK2 in patients diagnosed with ovarian cancer (Carden et al. 2012) has also been reported. CAMKK2 was found to regulate the expression of chemokines and the set of genes involved in the immune activity in breast cancer thus decreasing the immuno-suppressive inhibition tumor growth. (Racioppi et al. 2019). Additionally, the upregulation of CAMKK2 has been observed in gastric cancer and is depicted to be the potential therapeutic target for gastric adenocarcinoma (Subbannayya et al. 2015). CAMKK2 is known to act as a regulator via AMPK during myoblast differentiation, muscle regeneration, and myogenesis (Williamson et al. 2009). CAMKK2 inhibition helps in the depletion of preadipocytes and protects from obesity (Lin et al. 2011; Williams and Sankar 2019). CAMKK2 was found to be responsible for the regulation of glucose metabolism in the liver. Its involvement in the production of insulin by pancreatic β cells and whole-body glucose regulation made CAMKK2 as a candidate therapeutic target for diabetes/hyperglycemia. CAMKK2 is known to act via CAMKK2/AMPK signaling and liver kinase B1 (LKB1) for glucose suppression (Anderson et al. 2012; Foretz et al. 2010; Viollet et al. 2012). CAMKK2 is also known to be involved in inflammatory events, as it mediates the release of BM-derived macrophages (BMMs) in response to integrin signaling/toll-like receptor4 (TLR4). Inhibition of CAMKK2 leads to the decrease in M1 macrophage in the visceral adipose tissue, thus helping in protection from obesity-induced inflammation (Racioppi et al. 2012).

Conclusions

CAMKK2 is a vital molecule, which takes part in cellular metabolism, and development by activating the different signaling modules involved in different cellular physiologies. Furthermore, its dysregulation is reported in different pathologies like Duchenne muscular dystrophy, inflammation and osteoporosis. CAMKK2 overexpression is reported in different cancers and is involved in increase in cancer cell proliferation by activating different signaling modules. Despite its biomedical significance, the signaling data related to CAMKK2 was scattered in the literature. The signaling map of CAMKK2 generated in this effort will provide as a platform for the acceleration of research investigations on CAMKK2 and associated molecules either as candidate biomarkers or therapeutic targets. The signaling data has been made available in multiple community exchange formats to ensure easy integration of data with multiple public repositories worldwide.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12079_2020_592_MOESM1_ESM.xlsx (75.7KB, xlsx)

Supplementary Table 1 A compendium of curated reactions for the CAMKK2 signalling pathway (XLSX 75 kb)

Acknowledgements

We thank Karnataka Biotechnology and Information Technology Services (KBITS), Government of Karnataka, for the support of the Center for Systems Biology and Molecular Medicine at Yenepoya (Deemed to be University) under the Biotechnology Skill Enhancement Programme in Multiomics Technology (BiSEP GO ITD 02 MDA 2017). MAN is a recipient of a Senior Research Fellowship from the University Grants Commission (UGC), Government of India. RDAB is a recipient of a Senior Research Fellowship from the Indian Council of Medical Research (ICMR), Government of India. GK has been a recipient of a Senior Research Fellowship from the Council of Scientific & Industrial Research (CSIR) Government of India and is currently a recipient of KSTePs DST-Ph.D. Fellowship from the Department of Science and Technology-Karnataka Science and Technology Promotion Society, Government of Karnataka (2020–2021).

Abbreviations

CAMKK2

Calcium/calmodulin-dependent protein kinase kinase 2

AMPKα

5′-adenosine monophosphate-activated protein kinase

ACC

Acetyl-CoA carboxylase 2

LTM

Long-term memory

LTP

Long-term potentiation

Compliance with ethical standards

Conflict of interest

The authors report no conflict of interest.

Contributor Information

Mohd Altaf Najar, Email: altaf@yenepoya.edu.in.

D. A. B. Rex, Email: rexprem@yenepoya.edu.in

Prashant Kumar Modi, Email: prashantmodi@yenepoya.edu.in.

Nupur Agarwal, Email: nupur@yenepoya.edu.in.

Shobha Dagamajalu, Email: shobhabiotech82@gmail.com.

Gayathree Karthikkeyan, Email: gayathreekarthikkeyan@yenepoya.edu.in.

Manavalan Vijayakumar, Email: vicechancellor@yenepoya.edu.in.

Aditi Chatterjee, Email: aditixchatterjee@gmail.com.

Uma Sankar, Email: usankar@iupui.edu.

T. S. Keshava Prasad, Email: keshav@yenepoya.edu.in.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

12079_2020_592_MOESM1_ESM.xlsx (75.7KB, xlsx)

Supplementary Table 1 A compendium of curated reactions for the CAMKK2 signalling pathway (XLSX 75 kb)

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