CDK5R1

Function

p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-BMAL1 heterodimer in association with altered stability and subcellular distribution.

Post-translational modifications

The p35 form is proteolytically cleaved by calpain, giving rise to the p25 form. P35 has a 5 to 10 fold shorter half-life compared to p25. The conversion results in deregulation of the CDK5 kinase: p25/CDK5 kinase displays an increased and altered tau phosphorylation in comparison to the p35/CDK5 kinase in vivo (By similarity).

Myristoylated. A proper myristoylation signal is essential for the proper distribution of p35.

Ubiquitinated, leading to its degradation: degradation of p35 by proteasome results in down-regulation of CDK5 activity (PubMed:12393264). During this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation (PubMed:12393264). Ubiquitinated by the CRL2(FEM1B) complex, which recognizes the -Gly-Leu-Asp-Arg C-degron at the C-terminus, leading to its degradation (PubMed:33398168, PubMed:33398170).

Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-mediated proteolysis.

Sequence Similarities

Belongs to the cyclin-dependent kinase 5 activator family.

Tissue Specificity

Brain and neuron specific.

Cellular localization

• Cyclin-dependent kinase 5 activator 1, p35
• Cell membrane
• Lipid-anchor
• Cytoplasmic side
• Cell projection
• Neuron projection
• In the primary cortical neurons, p35 is present in the peripheries and nerve terminals.
• Cyclin-dependent kinase 5 activator 1, p25
• Nucleus
• Cytoplasm
• Perinuclear region
• Perikaryon
• The conversion of p35 to p25 relocalizes the protein from the cell periphery to the cytoplasm, in nuclear and perinuclear regions (PubMed:18507738). In the primary cortical neurons, p25 is primarily concentrated in the cell soma and is largely absent from neurites (PubMed:18507738).

Alternative names

CDK5R, NCK5A, CDK5R1, Cyclin-dependent kinase 5 activator 1, CDK5 activator 1, Cyclin-dependent kinase 5 regulatory subunit 1, TPKII regulatory subunit

Database links

swissprot:Q15078 omim:603460 swissprot:Q00535 entrezGene:8851