Unveiling the Role of CaMK Family in Cancer

Introduction

Ca²⁺ serves as a crucial second messenger in cells, playing a vital role in various signaling pathways. Changes in intracellular Ca²⁺ levels regulate key biological processes such as gene transcription, exocytosis, the cell cycle, migration, and apoptosis. Disruptions in normal Ca²⁺ signaling are now recognized as contributors to tumorigenesis, influencing each hallmark of cancer. Ca²⁺ signals, in the form of spikes or oscillations, are tightly regulated and decoded by downstream effectors like calmodulin (CaM). The binding of Ca²⁺ alters CaM's conformation, enhancing its affinity for numerous CaM-binding proteins, including multifunctional CaM kinases (CaMKK, CaMKI, CaMKII, and CaMKIV). These kinases, with widespread expression, control various cancer-related functions across different cancer types, highlighting their potential as targets for anti-cancer therapeutic intervention.

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Calcium/Calmodulin-Stimulated Protein Kinase (CaMK) Family

CaMKK

CaMKK, a Ca²⁺/calmodulin-stimulated protein kinase, is encoded by CAMKK1 and CAMKK2 genes, producing CaMKKα and CaMKKβ. While primarily expressed in the brain, it is also found in peripheral tissues. CaMKK phosphorylates CaMKI, CaMKIV, AMPK, and PKB/Akt, forming the Ca²⁺/CaM-dependent kinase cascade implicated in various cellular processes. CaMKKα and CaMKKβ, though similar in structure, differ in biochemical properties. CaMKKβ exhibits autonomous activity regulated by phosphorylation, making it responsive to stimuli of longer duration. Ca²⁺/CaM binding to CaMKKα modulates phosphorylation, affecting its activity and interaction.

Fig. 1 Schematic representing the domain structure of CaMKK (Brzozowski J. S., Skelding K. A. 2019).

CaMKI

CaMKI, a Ca²⁺/calmodulin-stimulated protein kinase I family, comprises four members (CaMKIα, CaMKIβ/Pnck, CaMKIγ/CLICK3, and CaMKIδ/CKLiK). Ubiquitously expressed, they are abundant in various brain regions, influencing functions like long-term potentiation, synapsin control, and bone resorption. All isoforms share a common structure, with Ca²⁺/CaM binding relieving autoinhibition and allowing phosphorylation by CaMKK, crucial for maximal activity. CaMKIδ, once phosphorylated, enters a 'primed' state, responding more readily to Ca²⁺ signals than other CaMKI enzymes.

CaMKII

CaMKII, encoded by CAMK2A, CAMK2B, CAMK2G, and CAMK2D, consists of α, β, γ, and δ isoforms. Highly expressed in neurons, it regulates neurotransmitter functions, neurite extension, and synaptic plasticity. Additionally, CaMKII is involved in non-neuronal processes like fertilization, vascular tone, cardiac function, apoptosis, and cell proliferation. Structurally, CaMKII has N-terminal catalytic and regulatory domains, with a unique C-terminal association domain forming a multimeric structure.

CaMKIV

CaMKIV, encoded by CAMK4, has isoforms CaMKIVα and CaMKIVβ. Primarily expressed in the brain, CaMKIV is also found in immune cells, testes, and ovaries. Enriched in cerebellar granule cells, it regulates homeostatic plasticity, neurite outgrowth, fear memory, immune responses, CREB regulation, and cell proliferation. CaMKIVβ differs by 28 amino acids at the N-terminus. Structurally, CaMKIV has a catalytic domain, an autoregulatory domain with an autoinhibitory region overlapping the CaM-binding region. Activation requires Ca²⁺/CaM, phosphorylation at T200 by CaMKK, and autophosphorylation at S12 and S13 for Ca²⁺/CaM independent activity. Phosphorylation at S336 inhibits CaMKIV by preventing CaM binding.

The Role of CaMK Family in Cancer

The Role of CaMKK in Cancer

The CaMK family members play crucial roles in cancer due to their involvement in Ca²⁺ signaling. Overexpression or aberrant activation of CaMKKβ is observed in various cancers, including gastric tumors, hepatocellular carcinoma, high-grade gliomas, and ovarian, and prostate cancer. CaMKKβ correlates with poor patient survival in hepatic cancer and glioma. It regulates cancer cell proliferation, migration, and invasion, making it a potential prognostic marker and anti-cancer target across different cancer types.

The Role of CaMKI in Cancer

Various CaMKI isoforms are overexpressed in different cancer subtypes. In endometrial carcinomas, CaMKI is more expressed in stages III and IV, correlating with PCNA labeling, clinical stage, histological grade, and invasion, suggesting a role in progression. CaMKI isoforms, like CaMKIγ/PNCK, are overexpressed in breast and renal cell carcinoma, with PNCK predicting poor survival in clear cell renal carcinoma. CaMKI regulates cellular processes in breast cancer and AML, controlling G1 progression and impacting cell proliferation, migration, and survival, making it a potential anti-cancer target for these cancers.

The Role of CaMKII in Cancer

Tumor cells exhibit a distinct spectrum of CaMKII isozymes compared to normal tissues. CaMKII is overexpressed in various cancers, such as endometrial, colon, breast, lung, and gastric cancers. Specific isoforms, like CaMKIIγ, are associated with chemoresistance in melanoma and AML. Single-nucleotide polymorphisms in CAMK2D are linked to poor survival in lung cancer. Enhanced autophosphorylation at T286 is observed in multiple cancers, correlating with metastatic disease. CaMKII isoforms control cellular functions, influencing proliferation, migration, and invasion in diverse cancer types. CaMKII emerges as a potential prognostic biomarker and anti-cancer target across various cancers.

The Role of CaMKIV in Cancer

CaMKIV, typically restricted in normal tissues, is overexpressed in various cancers like hepatocellular carcinoma, small cell lung cancer, and endometrial carcinoma. Its elevated expression correlates with clinical stage, myometrial invasion, and clinical outcome in endometrial carcinoma. High CAMK4 expression is linked to worse overall survival in AML patients and endometrial carcinoma. CaMKIV, expressed in immune cells, regulates hematopoietic stem cell homeostasis and influences cell proliferation. Modulating CaMKIV expression inhibits AML and hepatic cancer cell proliferation, but its effects may vary within the same cancer subtype.

In conclusion, the CaMK family, especially CaMKII, emerges as promising anti-cancer targets due to their overexpression in various cancer types compared to normal tissue. They play a crucial role in modulating cancer cell proliferation, survival, invasion, and migration.

Reference

1. Brzozowski J. S., Skelding K. A. The multi-functional calcium/calmodulin stimulated protein kinase (CaMK) family: emerging targets for anti-cancer therapeutic intervention. Pharmaceuticals. 2019, 12(1): 8.