Journal
CELL REPORTS
Volume 9, Issue 4, Pages 1306-1317Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.10.010
Keywords
-
Categories
Funding
- National Cancer Institute [R01-CA079992, R01-CA112552]
- NIH [T32-GM008275]
- Great Rivers Affiliate of the American Heart Association [10PRE4140108]
Ask authors/readers for more resources
The epidermal growth factor receptor (EGFR) plays pivotal roles in development and is mutated or over-expressed in several cancers. Despite recent advances, the complex allosteric regulation of EGFR remains incompletely understood. Through efforts to understand why the negative cooperativity observed for intact EGFR is lost in studies of its isolated extracellular region (ECR), we uncovered unexpected relationships between ligand binding and receptor dimerization. The two processes appear to compete. Surprisingly, dimerization does not enhance ligand binding (although ligand binding promotes dimerization). We further show that simply forcing EGFR ECRs into preformed dimers without ligand yields ill-defined, heterogeneous structures. Finally, we demonstrate that extracellular EGFR-activating mutations in glioblastoma enhance ligand-binding affinity without directly promoting EGFR dimerization, suggesting that these oncogenic mutations alter the allosteric linkage between dimerization and ligand binding. Our findings have important implications for understanding how EGFR and its relatives are activated by specific ligands and pathological mutations.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available