Endocytosed epidermal growth factor (EGF) receptors contribute to the EGF-mediated growth arrest in A431 cells by inducing a sustained increase in p21/CIP1

Exp Cell Res. 1998 Aug 25;243(1):161-72. doi: 10.1006/excr.1998.4127.


We investigated the ability of endocytosed activated epidermal growth factor receptors (EGFR) to induce expression of the cyclin-interacting protein p21/CIP1 in A431 cells. Transforming growth factor alpha (TGFalpha) and EGF both induced tyrosine phosphorylation, induction of p21/CIP1, and thereby inhibition of DNA synthesis. TGFalpha is released from the EGFR when the TGFalpha-EGFR complex encounters low pH upon endocytosis. Consistently, we found more rapid dephosphorylation of the EGFR and less induction of p21/CIP1 by TGFalpha than by EGF. This difference was abolished upon neutralizing endosomal pH by the carboxylic ionophore monensin or the proton ATPase inhibitor bafilomycin A1. When surface-bound TGFalpha was removed by acid stripping and endosomal pH was neutralized with bafilomycin A1, TGFalpha stimulated EGFR tyrosine phosphorylation, induced p21/CIP1, and inhibited DNA synthesis. This strongly suggests that p21/CIP1 can be induced by endocytosed, activated EGFR and that endocytosed EGFR can affect cell growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Division
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism*
  • DNA / biosynthesis
  • Endocytosis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Macrolides*
  • Microscopy, Fluorescence
  • Monensin / pharmacology
  • Phosphorylation
  • Time Factors
  • Transforming Growth Factor alpha / pharmacology
  • Tumor Cells, Cultured


  • Anti-Bacterial Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Macrolides
  • Transforming Growth Factor alpha
  • Epidermal Growth Factor
  • bafilomycin A1
  • DNA
  • Monensin
  • ErbB Receptors
  • Calcium-Calmodulin-Dependent Protein Kinases