Late endosomal traffic of the epidermal growth factor receptor ensures spatial and temporal fidelity of mitogen-activated protein kinase signaling.
Mitogen-activated protein kinase (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 whether epidermal growth factor receptor (EGFR) traffic through the endosomal system provides spatial information for MAPK signaling. To mislocalize 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 extracellular signal-regulated kinase 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.
Taub
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Division of Cell Biology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria.
Teis
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Ebner
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HL
Hess
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MW
Huber
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LA
D020285:Cryoelectron Microscopy; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000648:ultrastructure; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D016253:Microscopy, Immunoelectron; D021381:Protein Transport; D013997:Time Factors; D033921:Vesicular Transport Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D052118:Lysosomal-Associated Membrane Protein 1; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020691:rab GTP-Binding Proteins