Role of CDK5 in neuronal death and
Cyclin-dependent kinase 5 (CDK5) is a member of the small
serine/threonine cyclin-dependent kinase (CDK) family.
The best known role of CDK5 is its regulatoin of the
cytoskeleton architecture of the central nervous system (CNS). There is also some
evidence that links CDK5 activity to regulation of the
cytoskeleton, axon guidance, membrane transport, synaptic function, dopamine signaling
and drug addiction through it neuronspecific activator, cyclin-dependent kinase 5
regulatory subunit 1 (CDK5R1(p35)) .
CDK5R1(p35)/ CDK5 may stimulate cell survival (inhibit
cell apoptosis) via Epidermal growth factor receptor family of receptor tyrosine kinases
(ErbB). In this case,
and ErbB3 are activated by CDK5R1(p35)/
CDK5 phosphorylation in their proline-directed Ser/Thr residues in the
C-terminal tail domain. This, in turn, activates Phosphoinositide-3-kinase
(PI3K), which induces 3-phosphoinositide dependent protein
kinase-1 (PDK1)-dependent activation of v-akt murine thymoma
viral oncogene (AKT) . Active
AKT phosphorylates and down-regulates the molecules involved
in cell death (e.g. Caspase-9 and/or BCL2-antagonist of cell
death (BAD)) , .
In addition, CDK5R1(p35)/ CDK5 may depress cell
apoptosis via direct phosphorylation of c-Jun N-terminal kinase 3 (JNK
3) on Thr131. It inhibits its kinase activity and leads to reduction of
c-Jun phosphorylation . It is unknown, that
exactly pathway leads from c-Jun to apoptosis in this case.
It is possible, that c-Jun acts via Cell division cycle 2,
G1 to S and G2 to M (CDK1) , which in turn
may activate BAD  and/or inhibit B-cell
CLL/lymphoma 2 (Bcl-2) .
Moreover, CDK5R1(p35)/ CDK5 may repress Nerve growth
factor (NGF) signaling. It is unknown whether
NGF activates cell apoptosis via Src homology 2 domain
containing transforming protein 1 (Shc)/ Son of sevenless
homologies (Sos)/ v-Ha-ras Harvey rat sarcoma viral
oncogene homolog (H-Ras)/ v-raf-1 murine leukemia viral
oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein
kinase kinase 1 (MEK1)/ Mitogen activated protein kinases
(Erk) pathway. In normally functioning neurons,
CDK5R1(p35)/ CDK5 inhibits
MEK1 activity, thus repressing
NGF/ Erk-dependent apoptosis
On the other hand, it was shown, that CDK5R1(p35)/ CDK5
may activate cell apoptosis.
For example, CDK5 is activated
and plays an important role in neuronal death induced by DNA damage . The pathway leading to CDK5 activation at DNA
damage is not known. It is possible, that signal from damaged DNA is transited via
Protein kinase C, delta (PKC-delta)/
MEK1/ Erk pathway , . DNA damage-stimulated Erk may
phosphorylate Early growth response 1 (EGR1), which in turn
activates transcription of CDK5R1(p35). Then
CDK5R1(p35)/ CDK5 phosphorylates
p53 tumor suppressor, which activates transcription of
BCL2-associated X protein (BAX) .
BAX stimulates cell apoptosis via caspases cascade .
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