Journal Article

Asymmetric kinase dimer formation is crucial for the activation of oncogenic EGFRvIII but not for ERBB3 phosphorylation

von Bubnoff, Nikolas, Duyster, Justus, Kancha, Rama Krishna

2013

Overview

Background Formation of asymmetric kinase dimers is required for wt-EGFR activation upon ligand stimulation. The role of receptor dimerization in oncogenic EGFRvIII mutant activation is not completely understood and the molecular details of EGFRvIII interactions within homo-dimers and hetero-dimers are not elucidated yet. Findings By employing mutations that disrupt the asymmetric kinase dimer interface in EGFRvIII, we demonstrate that the mechanism of oncogenic EGFRvIII mutant activation is similar to that of the full-length wild-type EGFR. Surprisingly, the monomeric EGFRvIII lacks autophosphorylation and the formation of asymmetric kinase dimers is indispensable for oncogenic kinase activation. In addition, we show that ERBB3 can act as an activator of EGFRvIII by forming asymmetric kinase dimer in a ligand-independent manner. Interestingly, we found that the formation of asymmetric kinase dimer is dispensable for ERBB3 phosphorylation by the activated EGFR kinase as well as the ERBB2 kinase thus revealing a novel model for receptor function. Conclusions Lateral signaling is a novel mechanism of signal propagation via ERBB3 upon activation by EGFR/ERBB2 kinase even in the absence of their ability to form asymmetric kinase dimers.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Analysis / Biomedical and Life Sciences / Cell Biology / Cytokines and Growth Factors / Gene mutations / HEK293 Cells / Humans / Life Sciences / Oncogenes / Phosphorylation / Protein Multimerization / Protein-Ligand Interactions / Receptor, Epidermal Growth Factor - metabolism / Receptor, ErbB-3 - metabolism / Receptors / Short Report