Serine/threonine cyclin-dependent kinase 5 (CDK5) activation is regulated by interactions with neuron-specific co-activators p35 (CDK5R1) and p39 (CDK5R2) [1,4-5,9-10]. These interactions are important for the normal physiological roles of CDK5 [1,3,6].

The p35 protein can be proteolytically cleaved by calpain (removing the terminal regulatory motif) which generates a more stable p25 protein that retains CDK5 binding. CDK5/p25 complexes hyperactive CDK5, and this dysregulation has been associated with pathological neurodegenerative changes [2,8]. For this reason modulators of CDK5/p25 complex formation and/or activity are of therapeutic interest [7].

1. Bankston AN, Li W, Zhang H, Ku L, Liu G, Papa F, Zhao L, Bibb JA, Cambi F, Tiwari-Woodruff SK et al.. (2013) p39, the primary activator for cyclin-dependent kinase 5 (Cdk5) in oligodendroglia, is essential for oligodendroglia differentiation and myelin repair. J Biol Chem, 288 (25): 18047-57. [PMID:23645679]

2. Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH. (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature, 405 (6784): 360-4. [PMID:10830966]

3. Luo F, Zhang J, Burke K, Miller RH, Yang Y. (2016) The Activators of Cyclin-Dependent Kinase 5 p35 and p39 Are Essential for Oligodendrocyte Maturation, Process Formation, and Myelination. J Neurosci, 36 (10): 3024-37. [PMID:26961956]

4. Muravenko OV, Gizatullin RZ, Protopopov AI, Kashuba VI, Zabarovsky ER, Zelenin AV. (2000) Assignment of CDK5R2 coding for the cyclin-dependent kinase 5, regulatory subunit 2 (NCK5AI protein) to human chromosome band 2q35 by fluorescent in situ hybridization. Cytogenet Cell Genet, 89 (3-4): 160-1. [PMID:10965112]

5. Ohshima T, Kozak CA, Nagle JW, Pant HC, Brady RO, Kulkarni AB. (1996) Molecular cloning and chromosomal mapping of the mouse gene encoding cyclin-dependent kinase 5 regulatory subunit p35. Genomics, 35 (2): 372-5. [PMID:8661152]

6. Ouyang L, Chen Y, Wang Y, Chen Y, Fu AKY, Fu WY, Ip NY. (2020) p39-associated Cdk5 activity regulates dendritic morphogenesis. Sci Rep, 10 (1): 18746. [PMID:33127972]

7. Pao PC, Seo J, Lee A, Kritskiy O, Patnaik D, Penney J, Raju RM, Geigenmuller U, Silva MC, Lucente DE et al.. (2023) A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes. Proc Natl Acad Sci U S A, 120 (16): e2217864120. [PMID:37043533]

8. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 402 (6762): 615-22. [PMID:10604467]

9. Saito T, Yano M, Kawai Y, Asada A, Wada M, Doi H, Hisanaga SI. (2013) Structural basis for the different stability and activity between the Cdk5 complexes with p35 and p39 activators. J Biol Chem, 288 (45): 32433-32439. [PMID:24085300]

10. Tsai LH, Delalle I, Caviness Jr VS, Chae T, Harlow E. (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature, 371 (6496): 419-23. [PMID:8090221]