Inverse correlation between T hr‐669 and constitutive tyrosine phosphorylation in the asymmetric epidermal growth factor receptor dimer conformation

• Published in: Cancer science 2013-10, Vol.104 (10), p.1315-1322
• Main Authors: Sato, Kanae, Shin, Myoung‐Sook, Sakimura, Ayaka, Zhou, Yue, Tanaka, Tomohiro, Kawanishi, Miho, Kawasaki, Yuki, Yokoyama, Satoru, Koizumi, Keiichi, Saiki, Ikuo, Sakurai, Hiroaki
• Format: Article
• Language: English
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12225

We have recently identified tumor necrosis factor ( TNF )‐α‐induced phosphorylation of epidermal growth factor receptor ( EGFR ) at T hr‐669 and S er‐1046/1047 via ERK and p38 pathways, respectively. In the present study, we investigated the roles of ligand‐induced phosphorylation of serine and threonine residues in EGFR ‐overexpressing MDA ‐ MB ‐468 breast cancer cells. E pidermal growth factor and heregulin, an E rb B 3 ligand, induced the phosphorylation of T hr‐669 and S er‐1046/1047. Inversely, constitutive tyrosine phosphorylation of the C ‐terminal domain, including T yr‐1068, was significantly downregulated on ligand stimulation. Inhibition of the ERK pathway by U 0126 blocked ligand‐induced T hr‐669 phosphorylation as well as T yr‐1068 dephosphorylation. Downregulation of constitutive tyrosine phosphorylation of EGFR in HEK 293 cells stably expressing the wild type was abolished by substitution of T hr‐669 for A la. In an asymmetric EGFR homodimer structure, one T hr‐669 in the receiver kinase of the dimer was involved in downregulation. Similarly, T hr‐669 in an EGFR ‐ E rb B 3 heterodimer also participated in tyrosine dephosphorylation. These results indicate that ERK ‐mediated T hr‐669 phosphorylation suppresses constitutive tryrosine phosphosphorylation in the homo‐ and heterodimer asymmetric conformations of the EGFR .