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Sci. Signal., 30 November 2010
Vol. 3, Issue 150, p. ra86
[DOI: 10.1126/scisignal.2001195]


Editor's Summary

Repulsive Potential
Receptor tyrosine kinases (RTKs) consist of an extracellular region that binds to ligand, a single-pass transmembrane region, and an intracellular tyrosine kinase domain. Activation of RTKs requires receptor dimerization followed by ligand binding, which is thought to stabilize the dimer and alter its structure and activity. However, dimerization of RTKs can occur in the absence of ligand; indeed, some mutations in certain RTKs result in ligand-independent dimerization and activation. The contributions of the various extracellular domains of RTKs to ligand-independent receptor dimerization are unclear. Chen et al. used their quantitative imaging Förster resonance energy transfer technique to monitor ligand-independent dimerization of fluorescently tagged fibroblast growth factor receptor 3 (FGFR3) in plasma membrane–derived vesicles from transfected cells. They found that the extracellular domain, which is known to contribute to ligand-dependent dimerization, inhibited ligand-independent dimerization of the receptor. Thermodynamic analysis showed that the magnitude of this inhibitory effect was similar in extent, but opposite in effect, to that of activating mutations of FGFR3. Together, these data highlight the dual nature of the extracellular domain of FGFR3, which promotes RTK dimerization in the presence of ligand but inhibits dimerization when ligand is absent.

Citation: L. Chen, J. Placone, L. Novicky, K. Hristova, The Extracellular Domain of Fibroblast Growth Factor Receptor 3 Inhibits Ligand-Independent Dimerization. Sci. Signal. 3, ra86 (2010).

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Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization.
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