Cell Cycle 6(11): 1332-1335

Pin1 in Neuronal Apoptosis

Department of Pathology; Harvard Medical School; Boston, Massachusetts USA

^{Correspondence to: Azad Bonni; Department of Pathology; Harvard Medical, School; 77 Avenue Louis Pasteur; Boston, Massachusetts 02115 USA; Tel.: 617.432.4104; Fax: 617.432.4101; Email:}ude.dravrah.smh@innob_daza

Abstract

While the role of the prolyl isomerase Pin1 in dividing cells has long been recognized, Pin1’s function in postmitotic neurons is poorly understood. We have identified a novel mechanism by which Pin1 mediates activation of the mitochondrial cell death machinery specifically in neurons. This perspective presents a sophisticated signaling pathway that triggers neuronal apoptosis upon JNK-mediated phosphorylation of the BH3-only protein BIM_EL at serine 65. Pin1 is enriched at the mitochondria in neurons together with BIM_EL and components of a neuron-specific JNK signaling complex and functions as a molecular switch that couples the phosphorylation of BIM_EL by JNK to apoptosis specifically in neurons. We discuss how these findings relate to our understanding of the development of the nervous system and the pathogenesis of neurologic disorders.

Keywords: cell death, neuron, Pin1, BIM, JNK

Abstract

ABBREVIATIONS

BAD	BCL-2 associated death agonist
BCL-2	B-cell leukemia/lymphoma 2
BIM	BCL-2-interacting mediator of cell death
JIP3	JNK-interacting protein 3
JNK	c-Jun N-terminal kinase

ABBREVIATIONS

References

1. Lu KP, Liou YC, Zhou XZPinning down proline-directed phosphorylation signaling. Trends Cell Biol. 2002;12:164–172.[PubMed][Google Scholar]
2. Yaffe MB, Schutkowski M, Shen M, Zhou XZ, Stukenberg PT, Rahfeld JU, Xu J, Kuang J, Kirschner MW, Fischer G, Cantley LC, Lu KPSequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism. Science. 1997;278:1957–1960.[PubMed][Google Scholar]
3. Lu KP, Hanes SD, Hunter TA human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature. 1996;380:544–547.[PubMed][Google Scholar]
4. Lu KPPinning down cell signaling, cancer and Alzheimer’s disease. Trends Biochem Sci. 2004;29:200–209.[PubMed][Google Scholar]
5. Wulf G, Finn G, Suizu F, Lu KPPhosphorylation-specific prolyl isomerization: Is there an underlying theme? Nat Cell Biol. 2005;7:435–441.[PubMed][Google Scholar]
6. Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer GCell death by mitotic catastrophe: A molecular definition. Oncogene. 2004;23:2825–2837.[PubMed][Google Scholar]
7. Lu PJ, Zhou XZ, Liou YC, Noel JP, Lu KPCritical role of WW domain phosphorylation in regulating phosphoserine binding activity and Pin1 function. J Biol Chem. 2002;277:2381–2384.[PubMed][Google Scholar]
8. Bao L, Kimzey A, Sauter G, Sowadski JM, Lu KP, Wang DGPrevalent overexpression of prolyl isomerase Pin1 in human cancers. Am J Pathol. 2004;164:1727–1737.[Google Scholar]
9. Fukuchi M, Fukai Y, Kimura H, Sohda M, Miyazaki T, Nakajima M, Masuda N, Tsukada K, Kato H, Kuwano HProlyl isomerase Pin1 expression predicts prognosis in patients with esophageal squamous cell carcinoma and correlates with cyclinD1 expression. Int J Oncol. 2006;29:329–334.[PubMed][Google Scholar]
10. Kuramochi J, Arai T, Ikeda S, Kumagai J, Uetake H, Sugihara KHigh Pin1 expression is associated with tumor progression in colorectal cancer. J Surg Oncol. 2006;94:155–160.[PubMed][Google Scholar]
11. Becker EB, Bonni APin1 mediates neural-specific activation of the mitochondrial apoptotic machinery. Neuron. 2006;49:655–662.[PubMed][Google Scholar]
12. Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KPThe prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature. 1999;399:784–788.[PubMed][Google Scholar]
13. Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, Uchida T, Bronson R, Bing G, Li X, Hunter T, Lu KPRole of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature. 2003;424:556–561.[PubMed][Google Scholar]
14. Levi-Montalcini RThe nerve growth factor 35 years later. Science. 1987;237:1154–1162.[PubMed][Google Scholar]
15. Oppenheim RWCell death during development of the nervous system. Annu Rev Neurosci. 1991;14:453–501.[PubMed][Google Scholar]
16. Cleveland DW, Rothstein JDFrom Charcot to Lou Gehrig: Deciphering selective motor neuron death in ALS. Nat Rev Neurosci. 2001;2:806–819.[PubMed][Google Scholar]
17. Mattson MPApoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol. 2000;1:120–129.[PubMed][Google Scholar]
18. Yuan J, Yankner BAApoptosis in the nervous system. Nature. 2000;407:802–809.[PubMed][Google Scholar]
19. Putcha GV, Johnson EM., Jr Men are but worms: Neuronal cell death in C. elegans and vertebrates. Cell Death Differ. 2004;11:38–48.[PubMed]
20. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 1999;13:1899–1911.[PubMed]
21. Huang DC, Strasser ABH3-Only proteins-essential initiators of apoptotic cell death. Cell. 2000;103:839–842.[PubMed][Google Scholar]
22. Becker EB, Howell J, Kodama Y, Barker PA, Bonni ACharacterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis. J Neurosci. 2004;24:8762–8770.[Google Scholar]
23. Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A, Johnson EMInduction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron. 2001;29:615–628.[PubMed][Google Scholar]
24. Whitfield J, Neame SJ, Paquet L, Bernard O, Ham JDominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron. 2001;29:629–643.[PubMed][Google Scholar]
25. Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM, Greene LABim is elevated in Alzheimer’s disease neurons and is required for beta-amyloid-induced neuronal apoptosis. J Neurosci. 2007;27:893–900.[Google Scholar]
26. Engidawork E, Gulesserian T, Seidl R, Cairns N, Lubec GExpression of apoptosis related proteins in brains of patients with Alzheimer’s disease. Neurosci Lett. 2001;303:79–82.[PubMed][Google Scholar]
27. Ness JM, Harvey CA, Strasser A, Bouillet P, Klocke BJ, Roth KASelective involvement of BH3-only Bcl-2 family members Bim and Bad in neonatal hypoxia-ischemia. Brain Res. 2006;1099:150–159.[PubMed][Google Scholar]
28. Harper SJ, LoGrasso PSignalling for survival and death in neurones: The role of stress-activated kinases, JNK and p38. Cell Signal. 2001;13:299–310.[PubMed][Google Scholar]
29. Ham J, Eilers A, Whitfield J, Neame SJ, Shah Bc-Jun and the transcriptional control of neuronal apoptosis. Biochem Pharmacol. 2000;60:1015–1021.[PubMed][Google Scholar]
30. Mielke K, Herdegen TJNK and p38 stresskinases-degenerative effectors of signal-transduction-cascades in the nervous system. Prog Neurobiol. 2000;61:45–60.[PubMed][Google Scholar]
31. Harris CA, Johnson EMBH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons. J Biol Chem. 2001;276:37754–37760.[PubMed][Google Scholar]
32. Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S, Youle RJ, LaMarche A, Maroney AC, Johnson EMJNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron. 2003;38:899–914.[PubMed][Google Scholar]
33. Ley R, Ewings KE, Hadfield K, Howes E, Balmanno K, Cook SJExtracellular signal-regulated kinases 1/2 are serum-stimulated “Bim(EL) kinases” that bind to the BH3-only protein Bim(EL) causing its phosphorylation and turnover. J Biol Chem. 2004;279:8837–8847.[PubMed][Google Scholar]
34. Luciano F, Jacquel A, Colosetti P, Herrant M, Cagnol S, Pages G, Auberger PPhosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. Oncogene. 2003;22:6785–6793.[PubMed][Google Scholar]
35. Reginato MJ, Mills KR, Becker EB, Lynch DK, Bonni A, Muthuswamy SK, Brugge JSBim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes. Mol Cell Biol. 2005;25:4591–4601.[Google Scholar]
36. van Drogen F, Sangfelt O, Malyukova A, Matskova L, Yeh E, Means AR, Reed SIUbiquitylation of cyclin E requires the sequential function of SCF complexes containing distinct hCdc4 isoforms. Mol Cell. 2006;23:37–48.[PubMed][Google Scholar]
37. Harada H, Quearry B, Ruiz-Vela A, Korsmeyer SJSurvival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc Natl Acad Sci USA. 2004;101:15313–15317.[Google Scholar]
38. Deverman BE, Cook BL, Manson SR, Niederhoff RA, Langer EM, Rosova I, Kulans LA, Fu X, Weinberg JS, Heinecke JW, Roth KA, Weintraub SJBcl-xL deamidation is a critical switch in the regulation of the response to DNA damage. Cell. 2002;111:51–62.[PubMed][Google Scholar]
39. Srivastava RK, Mi QS, Hardwick JM, Longo DLDeletion of the loop region of Bcl-2 completely blocks paclitaxel-induced apoptosis. Proc Natl Acad Sci USA. 1999;96:3775–3780.[Google Scholar]
40. Yamamoto K, Ichijo H, Korsmeyer SJBCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol. 1999;19:8469–8478.[Google Scholar]
41. Morrison DK, Davis RJRegulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol. 2003;19:91–118.[PubMed][Google Scholar]
42. Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto KIJSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Mol Cell Biol. 1999;19:7539–7548.[Google Scholar]
43. Kelkar N, Delmotte MH, Weston CR, Barrett T, Sheppard BJ, Flavell RA, Davis RJMorphogenesis of the telencephalic commissure requires scaffold protein JNK-interacting protein 3 (JIP3) Proc Natl Acad Sci USA. 2003;100:9843–9848.[Google Scholar]
44. Becker EB, Bonni ACell cycle regulation of neuronal apoptosis in development and disease. Prog Neurobiol. 2004;72:1–25.[PubMed][Google Scholar]
45. Konishi Y, Lehtinen M, Donovan N, Bonni ACdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol Cell. 2002;9:1005–1016.[PubMed][Google Scholar]
46. Donovan N, Becker EB, Konishi Y, Bonni AJNK phosphorylation and activation of BAD couples the stress-activated signaling pathway to the cell death machinery. J Biol Chem. 2002;277:40944–40949.[PubMed][Google Scholar]
47. Berndtsson M, Konishi Y, Bonni A, Hagg M, Shoshan M, Linder S, Havelka AMPhosphorylation of BAD at Ser-128 during mitosis and paclitaxel-induced apoptosis. FEBS Lett. 2005;579:3090–3094.[PubMed][Google Scholar]
48. Hashimoto A, Hirose K, Iino MBAD detects coincidence of G₂/M phase and growth factor deprivation to regulate apoptosis. J Biol Chem. 2005;280:26225–26232.[PubMed][Google Scholar]
49. Becker EB, Bonni ABeyond proliferation-cell cycle control of neuronal survival and differentiation in the developing mammalian brain. Semin Cell Dev Biol. 2005;16:439–448.[PubMed][Google Scholar]
50. McClellan KA, Slack RSNovel functions for cell cycle genes in nervous system development. Cell Cycle. 2006;5:1506–1513.[PubMed][Google Scholar]
51. Johnson GL, Nakamura KThe c-jun kinase/stress-activated pathway: Regulation, function and role in human disease. Biochim Biophys Acta. 2007[Google Scholar]