Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes, leading to sustained activation of Rap1 and ERK and neurite outgrowth.
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.
Hisata
Shu
S
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan.
Sakisaka
Toshiaki
T
Baba
Takeshi
T
Yamada
Tomohiro
T
Aoki
Kazuhiro
K
Matsuda
Michiyuki
M
Takai
Yoshimi
Y
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000235:genetics / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D020932:Nerve Growth Factor / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism* / Q000648:ultrastructure; D016716:PC12 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D020735:Guanine Nucleotide-Releasing Factor 2; C418610:Kidins220 protein, rat; C114103:Magi2 protein, rat; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C403525:RAPGEF2 protein, human; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D006160:Guanosine Triphosphate; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases; D051528:Guanylate Kinases; D020827:rap1 GTP-Binding Proteins