CDK5

Official Full Name

cyclin dependent kinase 5

Organism

Homo sapiens

GeneID

1020

Background

This gene encodes a proline-directed serine/threonine kinase that is a member of the cyclin-dependent kinase family of proteins. Unlike other members of the family, the protein encoded by this gene does not directly control cell cycle regulation. Instead the protein, which is predominantly expressed at high levels in mammalian postmitotic central nervous system neurons, functions in diverse processes such as synaptic plasticity and neuronal migration through phosphorylation of proteins required for cytoskeletal organization, endocytosis and exocytosis, and apoptosis. In humans, an allelic variant of the gene that results in undetectable levels of the protein has been associated with lethal autosomal recessive lissencephaly-7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

Synonyms

LIS7; PSSALRE;

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Detailed Information

Cyclin dependent kinases (Cdks) are a large family of serine/threonine kinases. Their main function is to regulate cell cycle and transcription, but they are highly deregulated in the majority of tumors. Cyclin dependent kinase 5 (Cdk5) is a member of Cdk family with the catalytic site that binds to ATP sandwiched between N- and C-terminal lobes. The unique feature of widely distributed Cdk5 is that it is activated primarily by the noncyclin proteins, p35, p39 and their respective truncated products p25 and p29. Recent reports also showed that CDK5 is activated by unusual cyclins such as cyclin I (CCNI) and cyclin I-like (CCNI2), which have no known role in the activation of other CDKs.

Functions of CDK5 in Physiology and Pathology

CDK5 has long been considered a neuron-specific kinase because it was first discovered and characterized in the brain, where many of its functions have been well studied. In the nervous system, CDK5 performs important roles not only as a regulator of normal activities but also as a promoter of the pathogenesis of common neurological diseases. Physiologically, CDK5 plays significant roles in brain development during embryogenesis and, after birth, it drives synaptic plasticity, neuronal migration and provides protections for neurons under stress, such as ischemia and exposure to neurotoxin. The role of CDK5 in cell cycle progression has also been recently confirmed. When deregulated, it becomes the major mediator of many CNS disorders, including but not limited to ischemic stroke, Parkinson's disease, Alzheimer's disease and multiple sclerosis.

Figure 1. Biological roles of CDK5. (Lenjisa J L, et al., 2017)

In addition, CDK5 is also found to be involved in many biological processes of extraneuronal activities, such as gene expression, cell migration, apoptosis, etc.; and pathological processes including diabetes, senescence, cancer, inflammation and immune dysfunction. Most importantly, aberrant expression of CDK5 and its activators has been observed in various solid and hematological malignancies, but not in normal tissues. Thus, targeting CDK5 allows the discovery of new drugs that may circumvent the drawbacks of the current therapies including the lack of efficacy, the emergence of drug resistance and toxic effects to healthy tissues. Beyond cancer, CDK5 has been demonstrated to play a role in the pathophysiology of common cancer-related co-morbidities such as pain and diabetes and neurodegenerative disorders. Therefore, the discovery of CDK5-targeted anticancer drug could result in the development of effective treatments for multiple diseases.

Current Strategies for Cdk5 Targeting

Because of the biological and clinically relevant importance of CDK5's function in multiple cell types, CDK5 presents an attractive therapeutic target for treating a variety of conditions such as diabetes, neurodegeneration, and cancer. From pan-Cdk inhibitors to pathway-specific blocking peptides, there are more and more Cdk5-targeting drugs.

Small Molecules Inhibitors

Inhibition of kinase activity using pan-Cdk small molecules inhibitors is the most common strategy on hand to target Cdk5 in preclinical studies. Several pan-CDK inhibitors are being evaluated in clinical trials. For example, dinaciclib inhibited CDK1, CDK2, CDK5 and CDK9 with almost equivalent potency of single-digit nanomolar range, and showed significant antitumor effect. At present, dinaciclib is being evaluated in patients with advanced malignancies, as a single or combination therapy.

A Peptide for the Disruption of Cdk5/Activator Binding

A peptide extracted from p35/p25 that selectively blocks Cdk5/p25 interactions has been used to rescue the Cdk5/p25-induced pathological phenotypes. A peptide that disrupts Cdk5/p35 binding would be a useful tool to target Cdk5 in tumor cells or animal models since both holoenzymes, Cdk5/p35 and Cdk5/p25, appear to be tumorigenic. Nevertheless, the anticancer effect of this peptide remains to be determined.

Small Interfering Peptides: Targeting Cdk5/Substrate Interactions

An alternative method for preventing Cdk5-induced pathogenesis consists in using short peptides to selectively block Cdk5-dependent phosphorylation of aberrant substrate within a given pathogenic pathway. These approximately 20-amino acid peptides, designed based on the Cdk5 phosphorylation site on the substrate, were successful in selectively preventing Cdk5 phosphorylation of Rb, N-methyl-D-aspartate receptor subunit, and phosphodiesterase 4 (PDE4) to impair molecular processes leading to cancer progression, loss of cognition, or depression, respectively.

References:

Lenjisa J L, et al. CDK5 in oncology: recent advances and future prospects. Future medicinal chemistry, 2017, 9(16): 1939-1962.
Pozo K, Bibb J A. The emerging role of Cdk5 in cancer. Trends in cancer, 2016, 2(10): 606-618.
Cortés N, et al. CDK5: a unique CDK and its multiple roles in the nervous system. Journal of Alzheimer's Disease, 2019, 68(3): 843-855.
Liu W, et al. Cdk5 links with DNA damage response and cancer. Molecular cancer, 2017, 16(1): 1-9.
Shupp A, et al. Biological functions of CDK5 and potential CDK5 targeted clinical treatments. Oncotarget, 2017, 8(10): 17373.
Sharma S, Sicinski P. A kinase of many talents: non-neuronal functions of CDK5 in development and disease. Open biology, 2020, 10(1): 190287.

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