The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes.
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.
Nada
Shigeyki
S
Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Hondo
Akihiro
A
Kasai
Atsuko
A
Koike
Masato
M
Saito
Kazunobu
K
Uchiyama
Yasuo
Y
Okada
Masato
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D004707:Endoderm / Q000196:embryology / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C426009:LAMTOR2 protein, mouse; C539362:Lamtor1 protein, rat; C114559:Lamtor3 protein, mouse; D011506:Proteins; C539361:lipid raft adaptor p18 protein, mouse; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1