Journal
CELL REPORTS
Volume 38, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.110285
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Funding
- National Institutes of Health [CA122216, GM109176]
- Susan G. Komen Foundation [CCR14299947]
- American Association for Cancer Research-Genentech BioOncology Fellowship
- Ramon Areces Foundation
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This article presents an extensive structure-function analysis of HER2 and HER3 signaling in cancer treatment. It reveals that the extracellular domains (ECDs) of these receptors are not essential for tumorigenic signaling and their conformational changes do not affect the dimerization interface. Additionally, disruptive receptor engineering fails to disturb tumorigenic signaling. The overexpression of HER2 uncouples intracellular signaling from extracellular constraints.
Surface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immuno-stimulation or chemodelivery but have failed to produce effective inhibitors of constitutive HER2-HER3 signaling. We report an extensive structure-function analysis of this tumor driver, revealing complete uncoupling of intracellular signaling and tumorigenic function from regulation or constraints from their extracellular domains (ECDs). The canonical HER3 ECD conformational changes and exposure of the dimerization interface are nonessential, and the entire ECDs of HER2 and HER3 are redundant for tumorigenic signaling. Restricting the proximation of partner ECDs with bulk and steric clash through extremely disruptive receptor engineering leaves tumorigenic signaling unperturbed. This is likely due to considerable conformational flexibilities across the span of these receptor molecules and substantial undulations in the plane of the plasma membrane, none of which had been foreseen as impediments to targeting strategies. The massive overexpression of HER2 functionally and physically uncouples intracellular signaling from extracellular constraints.
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