cyclin-dependent kinase-5 [CDK5] activator (CDK5R1, tau protein kinase 2 regulatory subunit)

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Function

p35 is a neuron specific activator of CDK5
the complex p35/CDK5 is required for neurite outgrowth & cortical lamination
activator of TPKII
proteolytic cleavage yields 23-25 kD fragment that allows constitutive activity of CDK5
heterodimer composed of CDK5 & CDK5R (p25) & macromolecular complex composed of at least CDK5, CDK5R (p35) & CDK5RAP1 or CDK5RAP2 or CDK5RAP3
only the heterodimer shows kinase activity (putative)
interacts with RASGRF2
p35 form is proteolytically cleaved by calpain, giving rise to the p25 form
p35 has a 5-10 fold shorter half-life compared to p25
conversion results in deregulation of the CDK5 kinase: p25/CDK5 kinase displays an increased & altered tau phosphorylation in comparison to the p35/CDK5 kinase in vivo

probably myristoylated; gly-2-Ala mutant is absent of the cell periphery, suggesting that a proper myristoylation signal is essential for the proper distribution of p35
belongs to the cyclin-dependent kinase 5 activator family
structure marginally similar to cyclins

cyclin-dependent kinase 5 activator 1, p35: cell membrane, lipid-anchor, cytoplasmic side; in the primary cortical neurons, p35 is present in the peripheries & nerve terminals
cyclin-dependent kinase 5 activator 1, p25: nucleus, cytoplasm, perinuclear region conversion of p35 to p25 relocalizes the protein from cell periphery to the cytoplasm, in nuclear & perinuclear regions; in the primary cortical neurons, p25 is primarily concentrated in the cell soma & is largely absent from neurites

brain & neuron specific

cleavage of p35 to p25 may be involved in the pathogenesis of Alzheimer disease
p25 form accumulates in neurons in the brain of patients with Alzheimer disease, but not in normal brain
this accumulation correlates with an increase in CDK5 kinase activity
application of amyloid beta peptide A-beta(1-42) induced the conversion of p35 to p25 in primary cortical neurons
expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration & apoptosis

↑ Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E. p35 is a neural-specific regulatory subunit of cyclin- dependent kinase 5. Nature. 1994 Sep 29;371(6496):419-23. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8090221
↑ Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001 Apr;81(2):741-66. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11274343
↑ UniProt http://www.uniprot.org/uniprot/Q15078.html