Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 38, Pages E3595-E3604Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220050110
Keywords
mutation; TKI; lapatinib; WZ-4002
Categories
Funding
- V Foundation
- National Cancer Institute [R01-CA121210, P01-CA129243, U54-CA143798, R01-CA116020, P01-CA154303, R01-CA079992]
- Vanderbilt Unversity [CA90949]
- Vanderbilt-Ingram Cancer Center Core Grant [P30-CA68485]
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The initiation of epidermal growth factor receptor (EGFR) kinase activity proceeds via an asymmetric dimerization mechanism in which a donor tyrosine kinase domain (TKD) contacts an acceptor TKD, leading to its activation. In the context of a ligand-induced dimer, identical wild-type EGFR TKDs are thought to assume the donor or acceptor roles in a random manner. Here, we present biochemical reconstitution data demonstrating that activated EGFR mutants found in lung cancer preferentially assume the acceptor role when coexpressed with WT EGFR. Mutated EGFRs show enhanced association with WT EGFR, leading to hyperphosphorylation of the WT counterpart. Mutated EGFRs also hyperphosphorylate the related erythroblastic leukemia viral oncogene (ErbB) family member, ErbB-2, in a similar manner. This directional superacceptor activity is particularly pronounced in the drug-resistant L834R/T766M mutant. A 4-angstrom crystal structure of this mutant in the active conformation reveals an asymmetric dimer interface that is essentially the same as that in WT EGFR. Asymmetric dimer formation induces an allosteric conformational change in the acceptor subunit. Thus, superacceptor activity likely arises simply from a lower energetic cost associated with this conformational change in the mutant EGFR compared with WT, rather than from any structural alteration that impairs the donor role of the mutant. Collectively, these findings define a previously unrecognized mode of mutant-specific intermolecular regulation for ErbB receptors, knowledge of which could potentially be exploited for therapeutic benefit.
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