Pathway maps

Apoptosis and survival_Role of CDK5 in neuronal death and survival
Apoptosis and survival_Role of CDK5 in neuronal death and survival

Object List (links open in MetaCore):

MEK1(MAP2K1), PI3K reg class IA (p85), JNK3(MAPK10), Bcl-2, PDK (PDPK1), Apaf-1, AKT, Erk (MAPK1/3), ErbB3, TrkA, c-Jun, CDK5R1 (p35), PI3K cat class IA, ErbB2, Caspase-3, PtdIns(4,5)P2, NGF, PtdIns(3,4,5)P3, Caspase-9, Cytochrome c, PKC-delta, p53, SOS, Neuregulin 1, Shc, Bax, H-Ras, BAD, NGFR(TNFRSF16), CDK1 (p34), c-Raf-1,, CDK5, EGR1


Role of CDK5 in neuronal death and survival

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) ) [1].

CDK5R1(p35)/ CDK5 may stimulate cell survival (inhibit cell apoptosis) via Epidermal growth factor receptor family of receptor tyrosine kinases ( ErbB ). In this case, Neuregulin-1- stimulated ErbB2 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 ) [2]. Active AKT phosphorylates and down-regulates the molecules involved in cell death (e.g. Caspase-9 and/or BCL2-antagonist of cell death ( BAD )) [3], [4].

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 [5]. 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 ) [6], which in turn may activate BAD [7] and/or inhibit B-cell CLL/lymphoma 2 ( Bcl-2 ) [8].

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 [9].

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 [10]. 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 )/ Shc/ Sos/ H-Ras/ c-Raf-1/ MEK1/ Erk pathway [11], [10]. 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 ) [10]. BAX stimulates cell apoptosis via caspases cascade [12].


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