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

Rama Krishna Kancha,Justus Duyster,Nikolas Von Bubnoff

doi:10.1186/1478-811x-11-39

Rama Krishna Kancha, Justus Duyster + Show 1 more

Open Access

https://doi.org/10.1186/1478-811x-11-39

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Abstract

BackgroundFormation 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.FindingsBy 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.ConclusionsLateral 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.

Highlights

Formation of asymmetric kinase dimers is required for wt-EGFR activation upon ligand stimulation
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
This hypothesis is in accordance with the fact that EGFRvIII lacks the ligand-binding domain, which is critical for receptor dimerization

Summary

Introduction

Formation of asymmetric kinase dimers is required for wt-EGFR activation upon ligand stimulation. This data indicate that an intact asymmetric kinase dimer interface is essential for EGFRvIII kinase activation and was an unexpected finding given the previous observation that the receptor is not able to efficiently form stable dimers (Figure 1B, Additional file 2: Figure S1A) [1]. Additional EGFRvIII mutants with disrupted asymmetric kinase dimer interface both in wild-type and D837N background were taken as controls (lanes 6, 8, 9, 11 and 12) to demonstrate the absence of cis-autophosphorylation (Figure 1A-B, Additional file 2: Figure S1A).

Results

Conclusion