A kinase of many talents: non-neuronal functions of CDK5 in development and disease

Abstract

The cyclin-dependent kinase 5 (CDK5) represents an unusual member of the family of cyclin-dependent kinases, which is activated upon binding to non-cyclin p35 and p39 proteins. The role of CDK5 in the nervous system has been very well established. In addition, there is growing evidence that CDK5 is also active in non-neuronal tissues, where it has been postulated to affect a variety of functions such as the immune response, angiogenesis, myogenesis, melanogenesis and regulation of insulin levels. Moreover, high levels of CDK5 have been observed in different tumour types, and CDK5 was proposed to play various roles in the tumorigenic process. In this review, we discuss these various CDK5 functions in normal physiology and disease, and highlight the therapeutic potential of targeting CDK5.

Keywords: CDK5; cancer; cyclin-dependent kinases; development; non-neuronal functions.

Figure 1.

Proposed physiological functions of Cdk5. (a) A summary of non-neuronal functions of Cdk5. (b) Cdk5 phosphorylates actin modulator coronin 1a and regulates actin polymerization to promote T-cell survival and motility. In T cells, Cdk5-driven phosphorylation of Sin3a, a component of HDAC1 repressor complex, promotes IL-2 production by impeding the transcriptional repression of the IL-2 gene. In addition, Cdk5 phosphorylates vimentin leading to cytoskeletal rearrangements, thereby facilitating the secretion of cytokines by neutrophils. In response to stimulation by lipopolysaccharides, Cdk5 inhibits the activation of mitogen-activated protein kinases (MAPKs) and subsequent secretion of IL-10 by macrophages. (c) Cdk5 and angiogenesis: Cdk5 is activated by proangiogenic factors, such as VEGF and FGF, and regulates angiogenesis by affecting Rac-mediated actin remodelling and endothelial migration. In addition, Cdk5 can directly phosphorylate VEGF and regulate VEGF levels; inhibition of Cdk5 activity decreases VEGF levels. Furthermore, the phosphorylation of presenilin, a γ-secretase subunit, by Cdk5 increases the cleavage of Notch1 to NICD and promotes Notch signalling and angiogenesis.

Figure 2.

Proposed functions of CDK5 in cancer cells. (a) A summary of different CDK5 functions in cancer cells. (b) CDK5 and cell cycle regulation: CDK5 has been shown to phosphorylate RB1, STAT3, AR, FAK, AKT, p21^Cip1 and each of these events has been linked to stimulation of cell cycle progression and proliferation by CDK5. (c) CDK5 and migration and invasion: in pancreatic ductal adenocarcinoma, K-Ras promotes the cleavage of p35 to p25, resulting in CDK5 hyper-activation. This, in turn, promotes migration and invasion through RalA-GTP. Likewise, in breast cancer cells, TGF-β1 promotes the cleavage of p35 to p25 and activates CDK5, resulting in EMT. In addition, CDK5 may promote migration of cancer cells by directly phosphorylating talin, FAK, PIPKIγ90, or GTPase PIKE-A, or actin regulatory protein caldesmon.