Neurotrophins, such as NGF and BDNF, induce sustained activation of Rap1 small G protein and ERK, which are essential for neurite outgrowth. We show involvement of a GDP/GTP exchange factor (GEF) for Rap1, PDZ-GEF1, in these processes. PDZ-GEF1 is activated by GTP-Rap1 via a positive feedback mechanism. Upon NGF binding, the TrkA neurotrophin receptor is internalized from the cell surface, passes through early endosomes, and arrives in late endosomes. A tetrameric complex forms between PDZ-GEF1, synaptic scaffolding molecule and ankyrin repeat-rich membrane spanning protein which interacts directly with the TrkA receptor. At late endosomes, the complex induces sustained activation of Rap1 and ERK, resulting in neurite outgrowth. In cultured rat hippocampal neurons, PDZ-GEF1 is recruited to late endosomes in a BDNF-dependent manner involved in BDNF-induced neurite outgrowth. Thus, the interaction of PDZ-GEF1 with an internalized neurotrophin receptor transported to late endosomes induces sustained activation of both Rap1 and ERK and neurite outgrowth.
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27 August 2007
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August 27 2007
Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes, leading to sustained activation of Rap1 and ERK and neurite outgrowth
Shu Hisata,
Shu Hisata
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
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Toshiaki Sakisaka,
Toshiaki Sakisaka
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
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Takeshi Baba,
Takeshi Baba
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
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Tomohiro Yamada,
Tomohiro Yamada
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
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Kazuhiro Aoki,
Kazuhiro Aoki
2Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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Michiyuki Matsuda,
Michiyuki Matsuda
2Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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Yoshimi Takai
Yoshimi Takai
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
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Shu Hisata
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
Toshiaki Sakisaka
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
Takeshi Baba
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
Tomohiro Yamada
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
Kazuhiro Aoki
2Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
Michiyuki Matsuda
2Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
Yoshimi Takai
1Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
Correspondence to Yoshimi Takai: [email protected]
Abbreviations used in this paper: ARMS, ankyrin repeat-rich membrane spanning; BDNF, brain-derived neurotrophic factor; GEF, GDP/GTP exchange factor; PDZ-GEF, PDZ domain-containing GEF; S-SCAM, synaptic scaffolding molecule.
Received:
October 17 2006
Accepted:
July 25 2007
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2007
J Cell Biol (2007) 178 (5): 843–860.
Article history
Received:
October 17 2006
Accepted:
July 25 2007
Citation
Shu Hisata, Toshiaki Sakisaka, Takeshi Baba, Tomohiro Yamada, Kazuhiro Aoki, Michiyuki Matsuda, Yoshimi Takai; Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes, leading to sustained activation of Rap1 and ERK and neurite outgrowth . J Cell Biol 27 August 2007; 178 (5): 843–860. doi: https://doi.org/10.1083/jcb.200610073
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