JNK phosphorylates synaptotagmin-4 and enhances Ca2+-evoked release.
Ca2+ influx induced by membrane depolarization triggers the exocytosis of secretory vesicles in various cell types such as endocrine cells and neurons. Peptidyl growth factors enhance Ca2+-evoked release, an effect that may underlie important adaptive responses such as the long-term potentiation of synaptic transmission induced by growth factors. Here, we show that activation of the c-Jun N-terminal kinase (JNK) plays an essential role in nerve growth factor (NGF) enhancement of Ca2+-evoked release in PC12 neuroendocrine cells. Moreover, JNK associated with phosphorylated synaptotagmin-4 (Syt 4), a key mediator of NGF enhancement of Ca2+-evoked release in this system. NGF treatment led to phosphorylation of endogenous Syt 4 at Ser135 and translocation of Syt 4 from immature to mature secretory vesicles in a JNK-dependent manner. Furthermore, mutation of Ser135 abrogated enhancement of Ca2+-evoked release by Syt 4. These results provide a molecular basis for the effect of growth factors on Ca2+-mediated secretion.
Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Yasunori
Y
Mori
Maiko
M
Higuchi
Yusuke
Y
Hirabayashi
Mitsunori
M
Fukuda
Yukiko
Y
Gotoh
D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000502:physiology*; D002522:Chlorocebus aethiops; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D020932:Nerve Growth Factor / Q000502:physiology; D009490:Neurosecretory Systems / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D050857:Synaptotagmins / Q000378:metabolism*
D007527:Isoenzymes; D050857:Synaptotagmins; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D002118:Calcium