p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration.
Internalization and proteolytic degradation of epidermal growth factor (EGF) receptor (R) following ligand binding is an important mechanism for regulating EGF-stimulated signals. Using pharmacological and RNA interference inhibition of p38 mitogen-activated protein kinase, we show that p38 is required for efficient EGF-induced EGFR destruction but not internalization. In the absence of p38 activity, EGF fails to stimulate the ubiquitin ligase Cbl or ubiquitinylation of EGFR, and internalized EGFR accumulates in intracellular vesicles containing caveolin-1. These effects are accompanied by loss of EGFR phosphorylation on Y1045, a phosphorylation site required for Cbl activation. Furthermore, similar to cells treated with p38 inhibitors, intestinal epithelial cells expressing Y1045F EGFR mutants show increased proliferation but not migration in response to EGF, thus uncoupling these biological responses. Together these data position p38 as a modulator of ligand-stimulated EGFR processing and demonstrate that this processing has a profound impact on the cellular outcome of EGFR signaling.
Frey
Mark R
MR
Division of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA.
Dise
Rebecca S
RS
Edelblum
Karen L
KL
Polk
D Brent
DB
D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002522:Chlorocebus aethiops; D003106:Colon / Q000166:cytology / Q000187:drug effects; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D066246:ErbB Receptors / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051379:Mice; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D004791:Enzyme Inhibitors; D025801:Ubiquitin; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14