p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration

Mark R. Frey, Rebecca S. Dise, Karen L. Edelblum, D. Brent Polk

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5683-5692
Number of pages10
JournalEMBO Journal
Issue number24
StatePublished - Dec 13 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Molecular Biology
  • Neuroscience(all)


  • EGF receptor
  • Intestinal epithelium
  • Ubiquitinylation
  • Wound healing
  • p38 MAPK


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