Activation of p38 mitogen-activated protein kinase promotes epidermal growth factor receptor internalization

Traffic. 2006 Jun;7(6):686-98. doi: 10.1111/j.1600-0854.2006.00420.x.


Endocytic trafficking plays an important role in the regulation of the epidermal growth factor receptor (EGFR). To address if cellular kinases regulate EGFR internalization, we used anisomycin, a potent activator of kinase cascades in mammalian cells, especially the stress-activated mitogen-activated protein (MAP) kinase subtypes. Here, we report that activation of p38 MAP kinase by anisomycin is sufficient to induce internalization of EGFR. Anisomycin and EGF employ different mechanisms to promote EGFR endocytosis as anisomycin-induced internalization does not require tyrosine kinase activity or ubiquitination of the receptor. In addition, anisomycin treatment did not result in delivery and degradation of EGFR at lysosomes. Incubation with a specific inhibitor of p38, or depletion of endogenous p38 by small interfering RNAs, abolished anisomycin-induced internalization of EGFR while having no effect on transferrin endocytosis, indicating that the effect of p38 activation on EGFR endocytosis is specific. Interestingly, inhibition of p38 activation also abolished endocytosis of EGFR induced by UV radiation. Our results reveal a novel role for p38 in the regulation of EGFR endocytosis and suggest that stimulation of EGFR internalization by p38 might represent a general mechanism to prevent generation of proliferative or anti-apoptotic signals under stress conditions.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Anisomycin / pharmacology
  • Base Sequence
  • Coated Pits, Cell-Membrane / drug effects
  • Coated Pits, Cell-Membrane / metabolism
  • Endocytosis / drug effects
  • Endocytosis / radiation effects
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Genes, erbB-1
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • MAP Kinase Signaling System
  • Protein Transport / drug effects
  • RNA, Small Interfering / genetics
  • Recombinant Fusion Proteins / metabolism
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Enzyme Inhibitors
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • Anisomycin
  • ErbB Receptors
  • p38 Mitogen-Activated Protein Kinases