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A more recent version of this article appeared on December 1, 2007
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Submitted on February 2, 2007
Revised on August 27, 2007
Accepted on September 7, 2007
*Division of Cell Biology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria; Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, CA 92093-0651; Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853; Division of Histology and Embryology, Innsbruck Medical University, A-6020 Innsbruck, Austria
Monitoring Editor: Jean Gruenberg
MAPK signaling is regulated by assembling distinct scaffold complexes at the plasma membrane and on endosomes. Thus, spatial resolution might be critical to determine signaling specificity. Therefore, we investigated if EGFR traffic through the endosomal system provides spatial information for MAPK signaling. To mis-localize late endosomes to the cell periphery we used the dynein subunit p50, dynamitin. The peripheral translocation of late endosomes resulted in a prolonged EGFR activation on late endosomes and a slow down in EGFR degradation. Continuous EGFR signaling from late endosomes caused sustained ERK and p38 signaling and resulted in hyperactivation of nuclear targets, such as Elk-1. In contrast, clustering late endosomes in the perinuclear region by expression of dominant active Rab7 delayed the entry of the EGFR into late endosomes which caused a delay in EGFR degradation and a sustained MAPK signaling. Surprisingly, the activation of nuclear targets was reduced. Thus, we conclude that appropriate trafficking of the activated EGFR through endosomes controls the spatial and temporal regulation of MAPK signaling.
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