Inverse correlation between Thr-669 and constitutive tyrosine phosphorylation in the asymmetric epidermal growth factor receptor dimer conformation.

Abstract

We have recently identified tumor necrosis factor (TNF)-α-induced phosphorylation of epidermal growth factor receptor (EGFR) at Thr-669 and Ser-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. Epidermal growth factor and heregulin, an ErbB3 ligand, induced the phosphorylation of Thr-669 and Ser-1046/1047. Inversely, constitutive tyrosine phosphorylation of the C-terminal domain, including Tyr-1068, was significantly downregulated on ligand stimulation. Inhibition of the ERK pathway by U0126 blocked ligand-induced Thr-669 phosphorylation as well as Tyr-1068 dephosphorylation. Downregulation of constitutive tyrosine phosphorylation of EGFR in HEK293 cells stably expressing the wild type was abolished by substitution of Thr-669 for Ala. In an asymmetric EGFR homodimer structure, one Thr-669 in the receiver kinase of the dimer was involved in downregulation. Similarly, Thr-669 in an EGFR-ErbB3 heterodimer also participated in tyrosine dephosphorylation. These results indicate that ERK-mediated Thr-669 phosphorylation suppresses constitutive tyrosine phosphosphorylation in the homo- and heterodimer asymmetric conformations of the EGFR.

• Authors: Kanae Sato, Myoung-Sook Shin, Ayaka Sakimura, Yue Zhou, Tomohiro Tanaka, Miho Kawanishi, Yuki Kawasaki, Satoru Yokoyama, Keiichi Koizumi, Ikuo Saiki, Hiroaki Sakurai
• Journal: Cancer science (Cancer Sci) Vol. 104 Issue 10 Pg. 1315-22 (Oct 2013) ISSN: 1349-7006 [Electronic] England
• PMID: 23822636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Japanese Cancer Association.

Chemical References

• Butadienes
• Ligands
• NRG1 protein, human
• Neoplasm Proteins
• Neuregulin-1
• Nitriles
• Protein Kinase Inhibitors
• Recombinant Proteins
• Tumor Necrosis Factor-alpha
• U 0126
• Phosphothreonine
• Epidermal Growth Factor
• EGFR protein, human
• ErbB Receptors

Topics

• Adenocarcinoma (enzymology)
• Breast Neoplasms (enzymology)
• Butadienes (pharmacology)
• Cell Line, Tumor (enzymology)
• Dimerization
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (chemistry, metabolism)
• Feedback, Physiological
• Female
• Humans
• Ligands
• MAP Kinase Signaling System
• Neoplasm Proteins (chemistry, metabolism)
• Neuregulin-1 (pharmacology)
• Nitriles (pharmacology)
• Phosphorylation
• Phosphothreonine (metabolism)
• Protein Conformation
• Protein Kinase Inhibitors (pharmacology)
• Protein Processing, Post-Translational
• Recombinant Proteins (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)