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Analysis of the Role of the C-Terminal Tail in the Regulation of the Epidermal Growth Factor Receptor.

  • Author(s): Kovacs, Erika
  • Das, Rahul
  • Wang, Qi
  • Collier, Timothy S
  • Cantor, Aaron
  • Huang, Yongjian
  • Wong, Kathryn
  • Mirza, Amar
  • Barros, Tiago
  • Grob, Patricia
  • Jura, Natalia
  • Bose, Ron
  • Kuriyan, John
  • et al.

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The ∼230-residue C-terminal tail of the epidermal growth factor receptor (EGFR) is phosphorylated upon activation. We examined whether this phosphorylation is affected by deletions within the tail and whether the two tails in the asymmetric active EGFR dimer are phosphorylated differently. We monitored autophosphorylation in cells using flow cytometry and found that the first ∼80 residues of the tail are inhibitory, as demonstrated previously. The entire ∼80-residue span is important for autoinhibition and needs to be released from both kinases that form the dimer. These results are interpreted in terms of crystal structures of the inactive kinase domain, including two new ones presented here. Deletions in the remaining portion of the tail do not affect autophosphorylation, except for a six-residue segment spanning Tyr 1086 that is critical for activation loop phosphorylation. Phosphorylation of the two tails in the dimer is asymmetric, with the activator tail being phosphorylated somewhat more strongly. Unexpectedly, we found that reconstitution of the transmembrane and cytoplasmic domains of EGFR in vesicles leads to a peculiar phenomenon in which kinase domains appear to be trapped between stacks of lipid bilayers. This artifactual trapping of kinases between membranes enhances an intrinsic functional asymmetry in the two tails in a dimer.

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