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
. CDK5 activity in CNS is stimulated by
neuronspecific activator of CDK5, the
Cyclin-dependent kinase 5 regulatory subunit 1
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)
. 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) . CREB1
in turn recruits CREB-binding protein (CBP) that activates
FBJ murine osteosarcoma viral oncogene homolog B (FosB)
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 , .
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 . Activation of ERKs leads to
phosphorylation of EGR1, which
induces transcription of CDK5R1(p35) .
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