Calcium/calmodulin-dependent protein kinase kinase 2 mediates pleiotropic effects of epidermal growth factor in cancer cells

Dai, Shuhang; Venturini, Elisa; Yadav, Saveg; Lin, Xin; Clapp, Dylan; Steckiewicz, Martin; Gocher-Demske, Angela M; Hardie, D. Grahame; Edelman, Arthur M.

doi:10.1016/j.bbamcr.2022.119252

Cited by 6 publications

(11 citation statements)

References 50 publications

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“…The activation of the EGFR also results in the activation of CaM-dependent kinase kinase 2 (CaMKK2) by the Ca 2+ /CaM complex, formed upon a transient increase in the cytosolic Ca 2+ concentration induced by the ligand-dependent activation of the receptor [ 88 ]. The translocation of active CaMKK2 to the nucleus results in the expression of different EGFR target genes (e.g., phosphofructokinase, urokinase) by a mechanism not yet fully understood [ 88 ].…”

Section: Erbb Receptor Signaling and Cam-dependent Protein Kinasesmentioning

confidence: 99%

Regulation of ErbB Receptors by the Ca2+ Sensor Protein Calmodulin in Cancer

Villalobo

2023

Biomedicines

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Overexpression and mutations of the epidermal growth factor receptor (EGFR/ErbB1/HER1) and other tyrosine kinase receptors of the ErbB family (ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4) play an essential role in enhancing the proliferation, the migratory capacity and invasiveness of many tumor cells, leading to cancer progression and increased malignancy. To understand these cellular processes in detail is essential to understand at a molecular level the signaling pathways and regulatory mechanisms controlling these receptors. In this regard, calmodulin (CaM) is a Ca2+-sensor protein that directly interacts with and regulates ErbB receptors, as well as some CaM-dependent kinases that also regulate these receptors, particularly EGFR and ErbB2, adding an additional layer of CaM-dependent regulation to this system. In this short review, an update of recent advances in this area is presented, covering the direct action of Ca2+/CaM on the four ErbB family members mostly in tumor cells and the indirect action of Ca2+/CaM on the receptors via CaM-regulated kinases. It is expected that further understanding of the CaM-dependent mechanisms regulating the ErbB receptors in future studies could identify new therapeutic targets in these systems that could help to control or delay cancer progression.

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Section: Erbb Receptor Signaling and Cam-dependent Protein Kinasesmentioning

confidence: 99%

Regulation of ErbB Receptors by the Ca2+ Sensor Protein Calmodulin in Cancer

Villalobo

2023

Biomedicines

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“…Although we achieved a robust knockdown of CAMKK2 or PDPK1 when singly transfecting HeLa, A431, A549, N87 and LNCaP cell, we have not tested this dual sequential knockdown approach on additional cell lines nor additional gene targets. 8 …”

Section: Limitationsmentioning

confidence: 99%

Distinguishing parallel from series circuits with a double knockdown procedure in human cell lines

Gocher-Demske¹,

Dai²,

Edelman³

2022

STAR Protocols

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“…Its localisation is predominantly cytosolic as determined by immunocytochemistry and biochemical fractionation experiments [ 15–17 ]. However, it has also been shown to localise to the nucleus and facilitate transcriptional regulation in prostate and ovarian epithelial cells [ 8 , 18 ]. In ovarian cancer cells, this translocation is induced by epidermal growth factor (EGF) stimulation [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, it has also been shown to localise to the nucleus and facilitate transcriptional regulation in prostate and ovarian epithelial cells [ 8 , 18 ]. In ovarian cancer cells, this translocation is induced by epidermal growth factor (EGF) stimulation [ 8 ]. In addition to its cytosolic localisation, an experiment using subcellular fractionation of endothelial cells showed a prominent association of CaMKK2 with the endoplasmic reticulum (ER) and mitochondria [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…CaMKK2 is known to be significantly overexpressed in many cancers, including prostate, glioblastoma, liver and ovarian cancer [ 2 , 8 , 18 , 95 , 96 ]. Given the significant literature on the role of AMPK and CAMKIV activities on metabolic regulation, and their established status as CaMKK2 substrates, many of the biological effects of CaMKK2 on cancer have been attributed to this relationship.…”

Section: Introductionmentioning

confidence: 99%

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The role of CaMKK2 in Golgi-associated vesicle trafficking

Kennedy

Gibson

O'Hare

et al. 2023

Biochemical Society Transactions

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Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a serine/threonine-protein kinase, that is involved in maintaining various physiological and cellular processes within the cell that regulate energy homeostasis and cell growth. CaMKK2 regulates glucose metabolism by the activation of downstream kinases, AMP-activated protein kinase (AMPK) and other calcium/calmodulin-dependent protein kinases. Consequently, its deregulation has a role in multiple human metabolic diseases including obesity and cancer. Despite the importance of CaMKK2, its signalling pathways and pathological mechanisms are not completely understood. Recent work has been aimed at broadening our understanding of the biological functions of CaMKK2. These studies have uncovered new interaction partners that have led to the description of new functions that include lipogenesis and Golgi vesicle trafficking. Here, we review recent insights into the role of CaMKK2 in membrane trafficking mechanisms and discuss the functional implications in a cellular context and for disease.

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Calcium/calmodulin-dependent protein kinase kinase 2 mediates pleiotropic effects of epidermal growth factor in cancer cells

Cited by 6 publications

References 50 publications

Regulation of ErbB Receptors by the Ca2+ Sensor Protein Calmodulin in Cancer

Regulation of ErbB Receptors by the Ca2+ Sensor Protein Calmodulin in Cancer

Distinguishing parallel from series circuits with a double knockdown procedure in human cell lines

The role of CaMKK2 in Golgi-associated vesicle trafficking

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