CDK5 Signaling

Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases which regulate post-mitotic processes such as neuronal activity, neuronal migration during development, and neurite outgrowth. Activation of CDK5 requires its association with a regulatory subunit p35/CDK5R1. p35 is a short-lived protein, and its phosphorylation by CDK5 targets it for ubiquitin-mediated proteolysis. Calpain1 also directly cleaves p35 to release a 25 kD protein product, which causes prolonged activation and mislocalization of CDK5 and hyperphosphorylation of Tau (a neuron-specific MAP), leading to the formation of paired helical filaments and apoptosis. Post-translational modifications, such as phosphorylation by c-Abl (through an Abl-binding adaptor protein called Cables), regulate CDK5 kinase activity. Engagement of the integrin receptors by laminin stimulates transcription of p35. NGF and BDNF bind to receptors induce the ERK-mediated expression of p35, which requires the transcription factor EGR1. Phosphorylation of Tau by CDK5 reduces the binding of Tau to microtubules, inhibits the ability of Tau to promote microtubule assembly, and decreases microtubule nucleation activity. One target of CDK5 is MEK1. Phosphorylation of MEK1 by CDK5 represses MEK1 activity and blocks downstream cellular responses. The activation of p35 by MAPK pathways followed by deactivation of MAPK signaling by the CDK5/p35 complex completes the loop of a feedback circuit to terminate MAPK signaling. CDK5 induces PAK1 hyperphosphorylation in a Rac-dependent manner, which results in downregulation of PAK1 kinase activity.The p35-CDK5 complex associates with β-catenin and N-Cadherin, and inhibition of CDK5 activity causes an increase in N-Cadherin-mediated aggregation of neurons. Conversely, active CDK5 dissociates β-Ctnn from N-Cadherin, which is accompanied by a loss of adhesion. β-Ctnn is a substrate of CDK5, and phosphorylation by CDK5 regulates its association with the cadherins. CDK5-mediated phosphorylation of Synapsin-1, MUNC18, Amphiphysin-1, and the α-subunit (1A) of P/Q-type -dependent Ca2+ channels plays a role in synaptic vesicle trafficking and neurotransmitter release. CDK5 is also involved in postsynaptic transmission, and modulates dopaminergic signaling through dopamine receptors (DRD) in the neostriatal region of the brain. DRD stimulates adenlyate cyclase (AC) activity and activates cAMP-dependent protein kinases, which regulate neuronal growth and development. The transcription factor δ-FosB promotes CDK5 expression in response to chronic cocaine and electroconvulsive seizure treatments, implicating the dopaminergic signaling pathway. The role of CDK5 in dopamine responses occurs through phosphorylation of DARPP32. Depending on its phosphorylation state, DARPP32 inhibits either the phosphatase PP1 or the kinase PKA. Phosphorylation of DARPP32 by PKA on Thr34 makes it a potent inhibitor of PP1, and potentiates dopamine-induced phosphorylation of PKA substrates. In contrast, phosphorylation of DARPP32 at Thr75 by CDK5 renders it an inhibitor of PKA. PP1 is also phosphorylated by both PKA and CDK5 with antagonistic consequences. CDK5 activity has also been implicated in the mGluR-mediated enhancement of voltage-dependent Ca2+ currents.CDK5 also has been implicated in the pathological degeneration of neurons. Dysregulation of CDK5 causes the hyperphosphorylation of Tau, thereby contributing to neurofibrillary tangle formation, which is the hallmark of Alzheimer's Disease. CDK5 phosphorylates NUDEL, a novel LIS1-interacting protein in the growth cone. The inhibition of CDK5 activity alters NUDEL localization and its association with the dynein complex, resulting in the alteration of neuronal migration.