title: Asymmetric kinase dimer formation is crucial for the activation of oncogenic EGFRvIII but not for ERBB3 phosphorylation.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Department Medicine I, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Rama Krishna
authors.initials: RK
authors.lastname: Kancha
authors.forename: Nikolas
authors.initials: N
authors.lastname: von Bubnoff
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
mesh_terms: D066246:ErbB Receptors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D055503:Protein Multimerization; D020893:Receptor, ErbB-3 / Q000378:metabolism*
chemical_list: C410723:epidermal growth factor receptor VIII; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3