Late Endosomal Traffic of the EGFR Ensures Spatial and Temporal Fidelity of MAPK Signaling

N. Taub,* D. Teis, ${dagger}$ ${ddagger}$ H. L. Ebner, ${sect}$ M. W. Hess, ${sect}$ and L. A. Huber*

^*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 regulatedby assembling distinct scaffold complexes at the plasma membraneand on endosomes. Thus, spatial resolution might be criticalto determine signaling specificity. Therefore, we investigatedif EGFR traffic through the endosomal system provides spatialinformation for MAPK signaling. To mis-localize late endosomesto the cell periphery we used the dynein subunit p50, dynamitin.The peripheral translocation of late endosomes resulted in aprolonged EGFR activation on late endosomes and a slow downin EGFR degradation. Continuous EGFR signaling from late endosomescaused sustained ERK and p38 signaling and resulted in hyperactivationof nuclear targets, such as Elk-1. In contrast, clustering lateendosomes in the perinuclear region by expression of dominantactive Rab7 delayed the entry of the EGFR into late endosomeswhich caused a delay in EGFR degradation and a sustained MAPKsignaling. Surprisingly, the activation of nuclear targets wasreduced. Thus, we conclude that appropriate trafficking of theactivated EGFR through endosomes controls the spatial and temporalregulation of MAPK signaling.

Address correspondence to: L. A. Huber (Lukas.A.Huber{at}i-med.ac.at)