Apoptosis and survival - Role of CDK5 in neuronal death and survival

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 [10], [11]. 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].

References:

1. Dhavan R, Tsai LH
   A decade of CDK5. Nature reviews. Molecular cell biology 2001 Oct;2(10):749-59
2. Li BS, Ma W, Jaffe H, Zheng Y, Takahashi S, Zhang L, Kulkarni AB, Pant HC
   Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. The Journal of biological chemistry 2003 Sep 12;278(37):35702-9
3. Datta SR, Brunet A, Greenberg ME
   Cellular survival: a play in three Akts. Genes & development 1999 Nov 15;13(22):2905-27
4. Martelli AM, Faenza I, Billi AM, Manzoli L, Evangelisti C, Fala F, Cocco L
   Intranuclear 3'-phosphoinositide metabolism and Akt signaling: new mechanisms for tumorigenesis and protection against apoptosis? Cellular signalling 2006 Aug;18(8):1101-7
5. Li BS, Zhang L, Takahashi S, Ma W, Jaffe H, Kulkarni AB, Pant HC
   Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3. The EMBO journal 2002 Feb 1;21(3):324-33
6. Wada T, Joza N, Cheng HY, Sasaki T, Kozieradzki I, Bachmaier K, Katada T, Schreiber M, Wagner EF, Nishina H, Penninger JM
   MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nature cell biology 2004 Mar;6(3):215-26
7. Konishi Y, Lehtinen M, Donovan N, Bonni A
   Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Molecular cell 2002 May;9(5):1005-16
8. Pathan N, Aime-Sempe C, Kitada S, Haldar S, Reed JC
   Microtubule-targeting drugs induce Bcl-2 phosphorylation and association with Pin1. Neoplasia (New York, N.Y.) 2001 Jan-Feb;3(1):70-9
9. Zheng YL, Li BS, Kanungo J, Kesavapany S, Amin N, Grant P, Pant HC
   Cdk5 Modulation of mitogen-activated protein kinase signaling regulates neuronal survival. Molecular biology of the cell 2007 Feb;18(2):404-13
10. Lee JH, Kim KT
    Regulation of cyclin-dependent kinase 5 and p53 by ERK1/2 pathway in the DNA damage-induced neuronal death. Journal of cellular physiology 2007 Mar;210(3):784-97
11. Basu A, Tu H
    Activation of ERK during DNA damage-induced apoptosis involves protein kinase Cdelta. Biochemical and biophysical research communications 2005 Sep 9;334(4):1068-73
12. Cheung ZH, Ip NY
    Cdk5: mediator of neuronal death and survival. Neuroscience letters 2004 May 6;361(1-3):47-51