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A decade of CDK5

Abstract

Since it was identified a decade ago, cyclin-dependent kinase 5 (CDK5) has emerged as a crucial regulator of neuronal migration in the developing central nervous system. CDK5 phosphorylates a diverse list of substrates, implicating it in the regulation of a range of cellular processes ? from adhesion and motility, to synaptic plasticity and drug addiction. Recent evidence indicates that deregulation of this kinase is involved in the pathology of neurodegenerative diseases.

Key Points

  • Cyclin-dependent kinase 5 (CDK5) is a member of the cyclin-dependent kinase (CDK) family. Monomeric CDK5 displays no enzymatic activity, and requires association with a regulatory partner for activation. Two activators of CDK5 ? called p35 and p39 ? have been identified.

  • Association with its activators, p35 or p39, is necessary and sufficient for maximal activation of CDK5. CDK5 activity is dictated by the temporal and spatial expression and intracellular localization of p35 and p39. Transcriptional and post-translational events also regulate CDK5.

  • The best demonstrated role for CDK5 is in regulating the cytoarchitecture of the central nervous system. To date, about two dozen proteins with diverse functions have been identified as CDK5 substrates, and the kinase has been implicated in the regulation of actin dynamics, microtubule stability and transport, cadherin-mediated adhesion, axon guidance, secretion, membrane transport and dopamine signalling. Several groups have recently demonstrated active C5 in non-neuronal tissues, and proposed a role for CDK5 in myogenesis, haematopoietic cell differentiation, spermatogenesis, insulin secretion, and lens differentiation.

  • Treatment of neurons with neurotoxic insults causes calpain-mediated cleavage of p35 to p25 (a 208-residue carboxy-terminal fragment of p35). Although p25 can bind and activate CDK5, it lacks a myristoylation signal, and is more stable than p35. The generation of p25 therefore causes prolonged activation and mislocalization of CDK5, and hyperphosphorylation of substrates like Tau. Introduction of p25 into neurons produces drastic effects, including neurite retraction, microtubule collapse and apoptosis.

  • In the human brain, elevated levels of p25 correlate with Alzheimer's disease. Increased p25 levels and Cdk5-associated kinase activity are also seen in the spinal cord of transgenic mice expressing a mutant superoxide dismutase that was identified in patients with familial amyotrophic lateral sclerosis (ALS). Production of p25 may therefore be a common neurotoxic factor in the pathology of several neurodegenerative diseases.

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Figure 1: Regulation of CDK5.
Figure 2: Regulation of CDK5 and CDK2 by phosphorylation.
Figure 3: Corticogenesis in wild-type and Cdk5−/− mice.
Figure 4: Cellular processes regulated by Cdk5.
Figure 5: Cleavage of p35 to p25 is neurotoxic.

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Author information

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Authors

Corresponding author

Correspondence to Li-Huei Tsai.

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DATABASE

Interpro:

cyclins

 Locuslink:

α-actinin

Amphiphysin

BDNF

c-Abl

N-cadherin

calpain

β-catenin

CDC2

CDK2

CDK5

EGR1

Mrf4

MYT1

Neuregulin

NFH

NFM

N-cadherin

Nudel

p21

p27

p35

p39

PAK1

synapsin 1

superoxide dismutase

Tau

 Mouse Genome Informatics:

Munc18

protein phosphatase inhibitor-1

 OMIM

Alzheimer's disease

Amytrophic lateral sclerosis

 SGD:

CAK

Cdc28

Pcl1

Pcl2

Pcl6

Pcl9

Pho4

Pho5

Pho80

Pho85

Rvs167

Wee1

 Swiss-Prot:

Cables

MAP1B

NGF

Glossary

CYTOARCHITECTURE

Cellular organization of a tissue.

ORTHOLOGUES

Genes in different species that are homologous because they are derived from a common ancestral gene.

MYOGENESIS

Differentiation and development of muscle.

LAMELLIPODIA

Thin, sheet-like extensions of the cytoplasm, temporarily put forward by some eukaryotic cells (such as fibroblasts) when moving.

FILOPODIA

Fine, thread-like extensions of the cytoplasm of eukaryotic cells.

PULSE?CHASE EXPERIMENTS

A radioactive small molecule is added to a cell for a brief period (the pulse), during which it is incorporated into macromolecules. The fate of the newly synthesized radioactive macromolecule is examined when the radioactive small molecule is removed and replaced by an excess of the same molecule, but unlabelled (the chase).

UBIQUITIN?PROTEASOME PATHWAY

A small protein, ubiquitin, becomes covalently linked to a cellular protein, which is then targeted for degradation by a multiprotein complex of proteolytic enzymes (called the proteasome).

FASCICULATION

Bundling of nerve fibres.

CALLOSAL AXON

An axon of the corpus callosum.

CORPUS CALLOSUM

A wide tract of fibres that connects the two cerebral hemispheres, and is involved in the transfer of information from one hemisphere to the other.

AFFERENT

A sensory nerve that brings impulses towards the central nervous system.

CHROMATOLYTIC CHANGES

Following injury of axons, several changes occur in the cell body of a neuron. It swells and could even double in size. The nucleus swells and moves to an eccentric position, usually opposite the axon hillock. The rough endoplasmic reticulum breaks apart and moves to the periphery of the swollen cell body.

MICROTUBULE NUCLEATION

Microtubules are assembled by polymerization of α- and β- tubulin dimers. The addition of nuclei in the form of microtubule fragments to a solution of α- and β-tubulin dimers greatly accelerates the polymerization rate and is called microtubule nucleation.

ADHERENS JUNCTION

Cell?cell adhesive junctions that are linked to cytoskeletal filaments of the microfilament type.

RETROGRADE MOTOR

A motor protein that moves cargo in axons of neurons towards the cell body of neurons.

ANTEROGRADE TRANSPORT

Transport of cargo in axons of neurons away from the cell body.

SNARE

Soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins are a family of membrane-tethered coiled-coil proteins that regulate fusion reactions and target specificity in the vacuolar system.

NEOSTRIATUM

The input nuclei for the basal ganglia, which participates in the control of movement and receives input mainly from the cerebral cortex.

PERIKARYAL

The cell body containing the nucleus in nerve cells.

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Dhavan, R., Tsai, LH. A decade of CDK5. Nat Rev Mol Cell Biol 2, 749–759 (2001). https://doi.org/10.1038/35096019

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