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  • The EMBO Journal (2008) 27, 76 - 87
  • doi:10.1038/sj.emboj.7601935

Published online: 29 November 2007

JNK phosphorylates synaptotagmin-4 and enhances Ca2+-evoked release

Yasunori Mori1, Maiko Higuchi1, Yusuke Hirabayashi1, Mitsunori Fukuda2 and Yukiko Gotoh1

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
  2. Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan

Correspondence to:

Yukiko Gotoh, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Tel.: +81 3 5841 8473; Fax: +81 3 5841 8472; E-mail: ygotoh@iam.u-tokyo.ac.jp

Maiko Higuchi, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Tel.: +81 3 5841 8473; Fax: +81 3 5841 8472; E-mail: mhiguchi@iam.u-tokyo.ac.jp

Received 27 April 2007; Accepted 6 November 2007

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.

  • Keywords:

    • JNK,
    • NGF,
    • PC12 cells,
    • secretion,
    • synaptotagmin-4