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  3. ErbB family receptor dimerization dynamics and dysregulation via long-term single-molecule imaging

ErbB family receptor dimerization dynamics and dysregulation via long-term single-molecule imaging

  • Cell. 2026 May 28;189(11):3413-3431.e19. doi: 10.1016/j.cell.2026.04.010.
Kaibo Ma 1,  Xiaojie Ma 2,  João F Shida 2,  Zijian Niu 3,  Yuzhu Karlie Lin 2,  Saptarshi Mandal 2,  Alexandra Dobbins 4,  Lior Golomb 4,  Michael J Eck 5,  Heidi Greulich 6,  Matthew Meyerson 7,  Chunte Sam Peng 8
Affiliations

Affiliations

  • 1 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 2 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 3 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • 8 Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: [email protected].
PMID: 42054992 DOI: 10.1016/j.cell.2026.04.010
Abstract

Dimerization is crucial for the activation of ErbB family receptors, yet the real-time dynamics and effects of oncogenic mutations remain unclear. Here, we performed long-term, multicolor single-particle tracking (SPT) of EGFR, HER2, and HER3 in living cells using upconverting nanoparticles (UCNPs), which do not photobleach. Our technique enables continuous observation of receptor interactions, revealing details of their dimerization dynamics. Oncogenic EGFR mutations promote stable, ligand-independent dimerization. Unexpectedly, both HER2 and HER3 exhibit constitutive homodimerization, prompting a revised model for their activation mechanisms. HER2 mutations modestly enhance homodimer stability compared with EGFR mutations, while HER3 mutations destabilize homodimers, suggesting that HER3 homodimerization sequesters HER3 and limits heterodimerization with Other receptors. We also identified stable, ligand-independent heterodimers among all three receptors, further stabilized by ligand stimulation. These insights offer a comprehensive ErbB interaction network, elucidating diverse dimerization mechanisms and implications for oncogenic signaling.

Keywords

ErbB receptor family; dimerization network; long-term single-particle tracking; oncogenic signaling; upconverting nanoparticles.

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