You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
Register for free to read this article
As a service to the community, this article is available for free. Existing users log in.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
Abstract
Dysregulation of the ligand-independent dimerization of receptor tyrosine kinases (RTKs), which is the first step in the activation of RTKs, leads to various pathologies. A mechanistic understanding of the dimerization process is lacking, and this lack of basic knowledge is one bottleneck in the development of effective RTK-targeted therapies. For example, the roles and relative contributions of the different domains of RTKs to receptor dimerization are unknown. Here, we used quantitative imaging Förster resonance energy transfer (QI-FRET) to determine the contribution of the extracellular domain of fibroblast growth factor receptor 3 (FGFR3) to the dimerization of the receptor. We provide evidence that the contribution of the extracellular domain of FGFR3 to dimerization is repulsive in the absence of ligand and is on the order of ~1 kcal/mol. The repulsive contribution of the extracellular domain is similar in magnitude, but opposite in sign, to the contribution of pathogenic single–amino acid mutations to RTK signaling, and is therefore likely to be important for biological function. Together, these results highlight the fine balance in the domain interactions that regulate RTK dimerization and signaling.
