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The Journal of Neuroscience, August 1, 2001, 21(15):5406-5416
Nerve Growth Factor Activates Persistent Rap1 Signaling in
Endosomes
Chengbiao
Wu,
Chun-Fai
Lai, and
William C.
Mobley
Departments of Neurology and Neurological Sciences and of
Pediatrics and the Program in Neuroscience, Stanford University School
of Medicine, Stanford, California 94305
We investigated a role for endogenous Rap1, a small monomeric
GTP-binding protein of the Ras family, in nerve growth factor (NGF)
signaling in PC12 cells. Although both epidermal growth factor (EGF)
and NGF caused transient activation of Ras, only NGF induced the
activation of Rap1. Moreover, Rap1 activation was sustained for hours,
an effect that matched the sustained activation of the
mitogen-activated protein kinase (MAPK) pathway. To investigate the
molecular basis for Rap1 activation, we examined complexes containing
C3G, a guanine nucleotide exchange factor for Rap1, and CrkL, an
adapter protein known to influence Rap1 signaling. NGF induced the
formation of a long-lived complex containing C3G/CrkL/Shp2/Gab2/TrkA.
Linking the complex to Rap1 activation, we coprecipitated
activated TrkA and activated MAPK with activated Rap1 in NGF-treated
cells. Confocal microscopy and subcellular fractionation showed that
activated Rap1 and the other proteins of the signaling complex were
present in endosomes. Pretreatment of PC12 cells with brefeldin A
(BFA), which disrupts the Golgi and endosomal compartments, had little
effect on Ras activation but strongly inhibited NGF-induced Rap1
activation and continuing MAPK activation. We propose that endosomes
are a site from which NGF induces the prolonged activation of Rap1 and MAPK.
Key words:
PC12; NGF; TrkA; Gab2; Rap1; endosome
Copyright © 2001 Society for Neuroscience 0270-6474/01/21155406-11$05.00/0
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