The Multi-Functional Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Intervention

Joshua S Brzozowski, Kathryn A Skelding, Joshua S Brzozowski, Kathryn A Skelding

Abstract

The importance of Ca2+ signalling in key events of cancer cell function and tumour progression, such as proliferation, migration, invasion and survival, has recently begun to be appreciated. Many cellular Ca2+-stimulated signalling cascades utilise the intermediate, calmodulin (CaM). The Ca2+/CaM complex binds and activates a variety of enzymes, including members of the multifunctional Ca2+/calmodulin-stimulated protein kinase (CaMK) family. These enzymes control a broad range of cancer-related functions in a multitude of tumour types. Herein, we explore the cancer-related functions of these kinases and discuss their potential as targets for therapeutic intervention.

Keywords: CaMKI; CaMKII; CaMKIV; CaMKK; anti-cancer drugs.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representing the domain structure of CaMKK. There are two CaMKK isoforms—CaMKKα and CaMKKβ. CaMKK consists of a unique N-terminal domain (grey), a catalytic domain (red) which contains an ATP binding region, and a regulatory domain (blue) containing overlapping autoinhibitory and calmodulin (CaM) binding regions. Phosphorylation sites are indicated by green balls, with protein kinase A (PKA) phosphorylation sites indicated with red arrows.
Figure 2
Figure 2
Schematic representing the domain structure of the CaMKI family. There are four CaMKI isoforms—CaMKIα, CaMKIβ, CaMKIγ, and CaMKIδ, with each isoform sharing a similar structure. CaMKI consists of a unique N-terminal domain (grey), adjacent to a catalytic domain (red) which contains an ATP binding region, and a regulatory domain (blue) containing overlapping autoinhibitory and calmodulin (CaM) binding regions. Phosphorylation sites are indicated by green balls.
Figure 3
Figure 3
Schematic representing the domain structure of the CaMKII family. There are four CaMKII isoforms—CaMKIIα, CaMKIIβ, CaMKIIγ, and CaMKIIδ, with each isoform sharing a similar structure. CaMKII consists of a unique N-terminal domain (grey), adjacent to a catalytic domain (red) which contains an ATP binding region, and a regulatory domain (blue) containing overlapping autoinhibitory and calmodulin (CaM) binding regions. Phosphorylation sites are indicated by green balls. All isoforms also contain a C-terminal association domain (brown), which is involved in the formation of CaMKII multimers.
Figure 4
Figure 4
Schematic representing the domain structure of the CaMKIV family. The two CaMKIV isoforms—CaMKIVα and CaMKIIβ differ only at their N-terminus. CaMKIV consists of a unique N-terminal domain (grey), adjacent to a catalytic domain (red) which contains an ATP binding region, and a regulatory domain (blue) containing overlapping autoinhibitory and calmodulin (CaM) binding regions. Phosphorylation sites are indicated (green balls).
Figure 5
Figure 5
Structures of STO-609, KN-62, KN-93, berbamine dihydrochloride and bbd24.

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