Identification of EGF receptor C-terminal sequences 1005-1017 and di-leucine motif 1010LL1011 as essential in EGF receptor endocytosis

Exp Cell Res. 2007 Sep 10;313(15):3349-63. doi: 10.1016/j.yexcr.2007.06.014. Epub 2007 Jun 30.

Abstract

Most studies regarding the role of epidermal growth factor (EGF) receptor (EGFR) C-terminal domain in EGFR internalization are done in the context of EGFR kinase activation. We recently showed that EGF-induced EGFR internalization is directly controlled by receptor dimerization, rather than kinase activation. Here we studied the role of EGFR C-terminus in EGF-induced EGFR internalization with or without EGFR kinase activation. We showed that graduate truncation of EGFR from C-terminus to 1044 did not affect EGF-induced EGFR endocytosis with or without kinase activation. However, truncation to 991 or further completely inhibited EGFR endocytosis. Graduate truncation within 991-1044 progressively lower EGF-induced EGFR endocytosis with most significant effects observed for residues 1005-1017. The endocytosis patterns of mutant EGFRs are independent of EGFR kinase activation. The residues 1005-1017 were also required for EGFR internalization triggered by non-ligand-induced receptor dimerization. This indicates that residues 1005-1017 function as an internalization motif, rather than a dimerization motif, to mediate EGFR internalization. Furthermore, we showed that the di-leucine motif 1010LL1011 within this region is essential in mediating EGF-induced rapid EGFR internalization independent of kinase activation. We conclude that EGFR C-terminal sequences 1005-1017 and the 1010LL1011 motif are essential for EGF-induced EGFR endoytosis independent of EGFR kinase activation and autophosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Dimerization
  • Endocytosis / physiology*
  • Enzyme Activation
  • Epidermal Growth Factor / pharmacology
  • Epidermal Growth Factor / physiology
  • ErbB Receptors / metabolism*
  • Humans
  • Leucine / metabolism*
  • Mice
  • Mutation
  • Phosphorylation
  • Protein Structure, Tertiary

Substances

  • Epidermal Growth Factor
  • ErbB Receptors
  • Leucine