Development - Regulation of CDK5 in CNS

Regulation of CDK5 in CNS

Cyclin-dependent kinase 5 (CDK5) belongs to the small family of serine/threonine cyclin-dependent kinases (CDK).

The best known role for CDK5 is in regulating the cytoarchitecture of the central nervous system (CNS). There is also an evidence that links CDK5 activity to regulation of the cytoskeleton, axon guidance, membrane transport, synaptic function, dopamine signaling and drug addiction [1]. CDK5 activity in CNS is stimulated by neuronspecific activator of CDK5, the Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1(p35)) [2].

There are two basic pathways to regulate CDK5: regulation of the CDK5 gene transcription and regulation of the CDK5R1(p35) gene transcription. Chronic stimulation of the Dopamine D1A receptor by the Dopamine and drugs of abuse, such as Cocaine, leads to change in gene expression of CDK5 via FBJ murine osteosarcoma viral oncogene homolog B (FosB) [3]. It is possible, that this signaling cascade also includes Dopamine D1A receptor, a specific guanine nucleotide binding protein GNAS complex locus (G-protein alpha-s), Adenylate cyclase type V that raised Cyclic adenosine monophosphate (cAMP) levels, cAMP-dependent protein kinase (PKA), and cAMP responsive element binding protein 1 (CREB1) [4]. CREB1 in turn recruits CREB-binding protein (CBP) that activates FBJ murine osteosarcoma viral oncogene homolog B (FosB) [5].

It has been shown that Nerve growth factor (NGF) and Brain-derived neurotrophic factor (BDNF) can activate the CDK5R1(p35) gene transcription via mitogen-activated protein kinases (ERKs) pathway [6], [7]. NGF- and BDNF-signaling mediated by neurotrophic tyrosine kinase receptor type 1 and type 2 (TrkA and TrkB). Both Trk receptors lead to activation by phosphorylation of the SHC transforming protein 1 (Shc). After its own phosphorylation, Shc recruits the adaptor protein Growth factor receptor-bound protein 2 (Grb2) bound to son of sevenless homolog (SOS), an exchange factor for v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras). The presence of activated H-Ras stimulates v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ mitogen-activated protein kinase kinase (MEKs)/ ERKs signaling [8]. Activation of ERKs leads to phosphorylation of EGR1, which induces transcription of CDK5R1(p35) [7].

References:

1. Dhavan R, Tsai LH
   A decade of CDK5. Nature reviews. Molecular cell biology 2001 Oct;2(10):749-59
2. Paglini G, Cáceres A
   The role of the Cdk5--p35 kinase in neuronal development. European journal of biochemistry / FEBS 2001 Mar;268(6):1528-33
3. Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL, Yan Z, Sagawa ZK, Ouimet CC, Nairn AC, Nestler EJ, Greengard P
   Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 2001 Mar 15;410(6826):376-80
4. Bibb JA
   Role of Cdk5 in neuronal signaling, plasticity, and drug abuse. Neuro-Signals 2003 Sep-Oct;12(4-5):191-9
5. Levine AA, Guan Z, Barco A, Xu S, Kandel ER, Schwartz JH
   CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proceedings of the National Academy of Sciences of the United States of America 2005 Dec 27;102(52):19186-91
6. Tokuoka H, Saito T, Yorifuji H, Wei F, Kishimoto T, Hisanaga S
   Brain-derived neurotrophic factor-induced phosphorylation of neurofilament-H subunit in primary cultures of embryo rat cortical neurons. Journal of cell science 2000 Mar;113 ( Pt 6):1059-68
7. Harada T, Morooka T, Ogawa S, Nishida E
   ERK induces p35, a neuron-specific activator of Cdk5, through induction of Egr1. Nature cell biology 2001 May;3(5):453-9
8. Huang EJ, Reichardt LF
   Trk receptors: roles in neuronal signal transduction. Annual review of biochemistry 2003;72:609-42