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Published online
doi:10.1083/jcb.200610073
The Journal of Cell Biology, Vol. 178, No. 5, 843-860
The Rockefeller University Press, 0021-9525 $30.00
© Hisata et al.
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Article

Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes, leading to sustained activation of Rap1 and ERK and neurite outgrowth



Shu Hisata1, Toshiaki Sakisaka1, Takeshi Baba1, Tomohiro Yamada1, Kazuhiro Aoki2, Michiyuki Matsuda2, and Yoshimi Takai1

1 Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
2 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

Correspondence to Yoshimi Takai: ytakai{at}molbio.med.osaka-u.ac.jp

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.

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.


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