The Role of CDK5 in Tumours and Tumour Microenvironments

Abstract

Cyclin-dependent kinase 5 (CDK5), which belongs to the protein kinase family, regulates neuronal function but is also associated with cancer development and has been proposed as a target for cancer treatment. Indeed, CDK5 has roles in cell proliferation, apoptosis, angiogenesis, inflammation, and immune response. Aberrant CDK5 activation triggers tumour progression in numerous types of cancer. In this review, we summarise the role of CDK5 in cancer and neurons and CDK5 inhibitors. We expect that our review helps researchers to develop CDK5 inhibitors as treatments for refractory cancer.

Keywords: CDK5; cancer; microtubule; neuron; tumour microenvironments.

Figure 1

The mechanism of Cdk5 activation. The mechanism of Cdk5 activation. CDK5 alone is an inert catalyst subunit. CDK5 is activated by the p35 CDK5 activator and moves to the membrane as p35 binds to the membrane through myristoylation of the N-terminal region. p35 is a short-lived protein that is broken down by proteasomes. When cells are stressed or met with death signal, calpain is activated and cuts p35 into p25 C-terminal fragments. The deletion of p10 prolongs the half-life of p25. CDK5/p25 can be separate from the membrane and phosphorylate additional proteins. (modified from Kimura et al. [46]).

Figure 2

Schematic of kinase pathway phosphorylating EPRS Ser886 and Ser999. IFN-γ–activated CDK5 phosphorylate EPRS, leading to the formation of the GAIT complex. This inhibits inflammatory mRNA translation. Abbreviations- interferon-gamma (IFNγ), glutamyl-prolyl tRNA synthetase (EPRS), IFN-γ–activated inhibitor of translation (GAIT), tRNA multisynthetase complex (MSC). (modified from Arif et al. [85]).

Figure 3

A summary of the various cyclin-dependent kinase 5 (CDK5)-mediated biological processes. CDK5 plays important roles not only in the central nervous system but also in different biological processes. Functions in the central nervous system include synaptic function, axon guidance, cell adhesion, and neurodegenerative diseases. Functions outside of the central nervous system include androgen production, cell cycle, cancer cell proliferation/apoptosis, and tumour metastasis. Abbreviations- microtubule-associated proteins 1B (MAP1B), focal adhesion kinase (FAK), doublecortin (DCX), p21 activated kinase 1 (Pak-1), Wiskott-Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE-1), Eph receptor A4 (EphA4), transforming growth factor-β1′ (TGF-β1), retinoblastoma (Rb), E2F transcription factor 1 (E2F1). (modified from Shupp et al. [19]).

Figure 4

Impacts of CDK5 on the hallmarks of cancer: Uncontrolled proliferative signalling, Overcome growth suppressors, escaping antitumor immune system evasion, replicative immortality, tumour promoting inflammation, invasion and metastasis, inducing angiogenesis, genomic instability and mutation, resisting programmed cell death, metabolic reprogramming. Through the effect on the target protein, CDK5 is conducive to tumour development and metastasis. Abbreviations: phorbol-12-myristate-13-acetate-induced protein 1 (Noxa), Signal transducer and activator of transcription 3 (STAT3), androgen receptor (AR), retinoblastoma (Rb), bridging integrator 1 (BIN1), programmed cell death ligand 1 (PD-L1), focal adhesion kinase (FAK), targeting protein for Xklp2 (TPX2), hypoxia-inducible factor-1α (HIF-1α), ataxia-telangiectasia mutated (ATM). (Line 516–525). This figure is adapted and modified from Lenjisa et al., and Stecca et al. [134,135].

Figure 5

Structures of CDK5 inhibitors: roscovitine, flavopiridol, dinaciclib, olomoucine, purvalanol A, indurubin-3′, 20-223, AT7519.