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

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Journal of Cell Communication and Signaling Aims and scope

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.

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Fig. 1

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

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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).

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Authors and Affiliations

  1. Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, 575018, India

    Mohd Altaf Najar, D. A. B. Rex, Prashant Kumar Modi, Nupur Agarwal, Shobha Dagamajalu, Gayathree Karthikkeyan, Aditi Chatterjee & T. S. Keshava Prasad

  2. Department of Surgical Oncology, Yenepoya Medical College and Hospital, Yenepoya (Deemed to be University), Mangalore, 575018, India

    Manavalan Vijayakumar

  3. Institute of Bioinformatics, International Technology Park, Bangalore, Karnataka, 560066, India

    Aditi Chatterjee

  4. Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, 635 Barnhill Drive, MS-5055, Indianapolis, IN, 46202, USA

    Uma Sankar

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  1. Mohd Altaf Najar
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  2. D. A. B. Rex
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  10. T. S. Keshava Prasad
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Correspondence to T. S. Keshava Prasad.

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Najar, M.A., Rex, D.A.B., Modi, P.K. et al. A complete map of the Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) signaling pathway. J. Cell Commun. Signal. 15, 283–290 (2021). https://doi.org/10.1007/s12079-020-00592-1

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