Distinct signaling pathways of precursor BDNF and mature BDNF in cultured cerebellar granule neurons.
Recent studies have focused on a distinctive contrast between bioactivities of precursor brain-derived neurotrophic factor (proBDNF) and mature BDNF (matBDNF). In this study, using a proteolytic cleavage-resistant proBDNF mutant (CR-proBDNF), signaling mechanisms underlying the proapoptotic effect of proBDNF and antiapoptotic effect of matBDNF on the low potassium (LK)-inducing cell death of cultured cerebellar granule neurons (CGNs) were analyzed. A time course study demonstrated that unlike matBDNF, CR-proBDNF failed to induce TrkB phosphorylation for up to 360 min. CR-proBDNF did not activate ERK-1, ERK-2 and Akt, which are involved in TrkB-induced cell survival signaling, while matBDNF activated these kinases. On the other hand treatment of CGNs with CR-proBDNF led to a rapid activation of Rac-GTPase and phosphorylation of JNK which are involved in p75(NTR)-induced apoptosis. In addition, a JNK-specific inhibitor, SP600125, inhibited the CR-proBDNF-induced apoptosis but did not affect the antiapoptotic effect of matBDNF. CR-proBDNF treatment led to an earlier appearance of active caspase-3. In contrast, matBDNF dramatically postponed the appearance of active caspase-3. Not like other signaling molecules, activation of caspase-3 was conversely regulated by both CR-proBDNF and matBDNF. These results thus suggest that in CGNs proBDNF elicits apoptosis via activation of p75(NTR), Rac-GTPase, JNK, and caspase-3, while matBDNF signals cell survival via activation of TrkB, ERKs and Akt, and deactivation of caspase-3.
Koshimizu
Hisatsugu
H
Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology, Ikeda 563-8577, Japan.
Hazama
Shunsuke
S
Hara
Tomoko
T
Ogura
Akihiko
A
Kojima
Masami
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D053148:Caspase 3 / Q000502:physiology; D016923:Cell Death; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D011498:Protein Precursors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C426674:brain-derived neurotrophic factor precursor; D020813:Receptor, trkB; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D020744:rac GTP-Binding Proteins; D011188:Potassium