Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling

Marcia R. Campbell, Ana Ruiz-Saenz, Yuntian Zhang, Elliott Peterson, Veronica Steri, Julie Oeffinger, Maryjo Sampang, Natalia Jura, Mark M. Moasser*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
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Abstract

Surface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immunostimulation 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.

Original languageEnglish
Article number110285
JournalCell Reports
Volume38
Issue number5
DOIs
Publication statusPublished - 1 Feb 2022

Bibliographical note

Funding Information:
This work was funded by National Institutes of Health CA122216 (to M.M.M.) and GM109176 (to N.J.), Susan G. Komen Foundation CCR14299947 (to N.J.), and postdoctoral fellowship grants from the Susan G. Komen Foundation (to M.R.C.), the American Association for Cancer Research – Genentech BioOncology Fellowship (to M.R.C.), and the Ramon Areces Foundation (to A.R.S.). The authors would like to thank James Lee for technical assistance with cell-based studies.

Funding Information:
This work was funded by National Institutes of Health CA122216 (to M.M.M.) and GM109176 (to N.J.), Susan G. Komen Foundation CCR14299947 (to N.J.), and postdoctoral fellowship grants from the Susan G. Komen Foundation (to M.R.C.), the American Association for Cancer Research ? Genentech BioOncology Fellowship (to M.R.C.), and the Ramon Areces Foundation (to A.R.S.). The authors would like to thank James Lee for technical assistance with cell-based studies. M.M.M. and M.R.C. designed the study and wrote the manuscript. M.R.C. J.O. E.P. Y.Z. and M.S. performed most of the cell-based studies. V.S. and M.S. performed most of the mouse studies. A.R.-S. performed the CRISPR knockout. N.J. designed many of the HER3 mutations and structural modifications. All authors have read, commented on, and approved the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2021 The Authors

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