The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes

• Published in: The EMBO journal Vol. 28; no. 5; pp. 477 - 489
• Main Authors: Nada, Shigeyki, Hondo, Akihiro, Kasai, Atsuko, Koike, Masato, Saito, Kazunobu, Uchiyama, Yasuo, Okada, Masato
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 04.03.2009; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Amino Acid Sequence; Animals; Cell adhesion & migration; Cells, Cultured; Cellular biology; Endocytosis - drug effects; Endocytosis - physiology; Endoderm - embryology; Endoderm - metabolism; endosome dynamics; Endosomes - metabolism; Epidermal Growth Factor - pharmacology; Extracellular Signal-Regulated MAP Kinases - physiology; late endosome; lipid rafts; Lipids; Lysosomes - metabolism; MAP Kinase Kinase 1 - metabolism; MAPK pathway; MEK1; Membrane Microdomains - metabolism; Membranes; Mice; Mice, Knockout; Molecular biology; Molecular Sequence Data; Nutrient dynamics; Protein Binding; Proteins; Proteins - metabolism; Signal Transduction
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2008.308

The regulation of endosome dynamics is crucial for fundamental cellular functions, such as nutrient intake/digestion, membrane protein cycling, cell migration and intracellular signalling. Here, we show that a novel lipid raft adaptor protein, p18, is involved in controlling endosome dynamics by anchoring the MEK1–ERK pathway to late endosomes. p18 is anchored to lipid rafts of late endosomes through its N‐terminal unique region. p18−/− mice are embryonic lethal and have severe defects in endosome/lysosome organization and membrane protein transport in the visceral endoderm. p18−/− cells exhibit apparent defects in endosome dynamics through perinuclear compartment, such as aberrant distribution and/or processing of lysosomes and impaired cycling of Rab11‐positive recycling endosomes. p18 specifically binds to the p14–MP1 complex, a scaffold for MEK1. Loss of p18 function excludes the p14–MP1 complex from late endosomes, resulting in a downregulation of the MEK–ERK activity. These results indicate that the lipid raft adaptor p18 is essential for anchoring the MEK–ERK pathway to late endosomes, and shed new light on a role of endosomal MEK–ERK pathway in controlling endosome dynamics.