Post-translational modifications of CDK5 and their biological roles in cancer

Abstract

Post-translational modifications (PTMs) of Cyclin-dependent kinase 5 (CDK5) have emerged as important regulatory mechanisms that modulate cancer development in patients. Though CDK5 is an atypical member of the cyclin-dependent kinase family, its aberrant expression links to cell proliferation, DNA damage response, apoptosis, migration and angiogenesis in cancer. Current studies suggested that, new PTMs on CDK5, including S-nitrosylation, sumoylation, and acetylation, serve as molecular switches to control the kinase activity of CDK5 in the cell. However, a majority of these modifications and their biological significance in cancer remain uncharacterized. In this review, we discussed the role of PTMs on CDK5-mediated signaling cascade, and their possible mechanisms of action in malignant tumors, as well as the challenges and future perspectives in this field. On the basis of the newly identified regulatory signaling pathways of CDK5 related to PTMs, researchers have investigated the cancer therapeutic potential of chemical compounds, small-molecule inhibitors, and competitive peptides by targeting CDK5 and its PTMs. Results of these preclinical studies demonstrated that targeting PTMs of CDK5 yields promising antitumor effects and that clinical translation of these therapeutic strategies is warranted.

Keywords: CDK5; Cancer; Posttranslational modifications.

Fig. 1

The structure and amino acid sequence of CDK5 and its expression in cancers. a The interaction between CDK5 and p25 (yellow). CDK5 structurally contains an ATP binding domain, activators binding domain, hinge region, PSSALRE helix and T-loop. The N lobe mainly contains 5 β-sheets and C lobe includes 4 α-helices. b CDK5 amino acid sequence contains β-bridge, bend, turn, β-strand and a-helix sequence. The PTM sites are labelled with colors: phosphorylation, red; acetylation, blue; S-nitrosylation, yellow. c The genomic alterations including mutation, amplification and deletion of CDK5 as well as p35 and p39 were analyzed in clinical samples from cBioPortal (www.cbioportal.org)

Fig. 2

The mechanism of CDK5 activation. The expression of p35 can be transcriptionally regulated by upstream regulators N-Myc, Menin, EGR1 and miR-505. Myristoylation on Gly2 of p35 determines its affinity to cell membrane, which signals for proteasomal degradation. Activated CDK5 phosphorylates p35 on Ser8 to sustain its cytoplasmic localization. When the cell faces with the death signal, the N-methyl-D-aspartate (NMDA) receptor on the cell membrane can be activated, enhancing the uptake of calcium for calpain activation. Calpain has proteolytic activity to cleave p35 into p25 fragment, a more stable protein than p35. This cleavage leads to the translocation of CDK5/p25 complex into the nucleus and prolongs the activation time of CDK5, which induces the pathological signal pathway of cell death

Fig. 3

PTM events in CDK5-mediated biological function in cancer progression. a PTM events in CDK5-mediated cell proliferation and DNA damage repair. (1) In cancer cells, CDK5 mediates cell proliferation through activating E2F-CDK2 pathway. (2) CDK5 induces c-Myc Ser62 phosphorylation for abolishing Bridging integrator 1 (BIN1)/c-Myc interaction, promoting cell cycle progression. (3) During DNA damage, CDK5 can be up-regulated or phosphorylated by EGFR, inducing the phosphorylation of Ser727 on STAT3, the activated STAT3 promotes the expression of Eme1 gene to initiate DNA damage repair. (4) In response to radiation, ATM can be phosphorylated by CDK5 at Ser794 and undergoes autophosphorylation at Ser1981 for activation, which signals for p53 and H2AX pathways to initiate DNA damage repair. b The mechanism of CDK5 in apoptosis, cell migration and angiogenesis. CDK5 is activated upon EGF stimulation, which regulates downstream proteins phosphorylation, including Girdin, STMN1, CRMP-2, Talin and FAK to promote cell movement and migration. K-Ras^G12D promotes the production of p25 to enhance the activity of CDK5, which results in the activation of Ral (Ras-Like) pathway and morphological changes conducive to cell migration. In addition, CDK5 regulates angiogenesis through directly controlling the HIF1α target gene, VEGF and its receptor expression

Fig. 4

S-nitrosylation and acetylation of CDK5 in cell. The interaction between NOS1 and CDK5 promotes the formation of SNO-CDK5, and then SNO-CDK5 may transfer NO group to DRP1 by transnitrosation, resulting in excessive mitochondrial division and subsequently mitochondrial dysfunction. SNO-CDK5 phosphorylates NOS1 on S292 and S298, creating a negative-feedback loop by suppressing NOS1 activity. In addition, NO is able to negatively regulate the activity of CDK5 by inducing p35 S-nitrosation at C92 for controlling the development of neuronal cells. In nucleus, the acetylation of CDK5 at K33 and K56 mediated by SIRT1 and GCN5 leads to the loss of ATP binding and the impairment of kinase activity, which regulates multiple cellular processes, including neurite outgrowth and cell damage. The activated CDK5 can in turn phosphorylate SIRT1 at S47 that contributes to cell senescence