Single-molecule tracker illuminates workings of cancer-related proteins

Good news! Cancer is history (soon)!

"Using a powerful single-molecule imaging method they developed, a research team ... unveiled a dynamic view of how some cancer-related proteins interact in living cells.

The technique relies on highly stable nanoparticle probes that brightly illuminate individual molecules for long periods of time. The researchers used their method to observe, for the first time, individual receptors as they move around the cell membrane, attaching to and then letting go of other receptors to alter signaling within the cell. ..."

From the highlights and abstract:

"Highlights

• Multicolor UCNPs enable specific ErbB labeling for long-term tracking (UCNP-SPT)

• Bayesian diffusion analysis and dimer lifetimes quantify ErbB receptor mutant dynamics

• UCNP-SPT shows HER2/HER3 homodimerization and how mutations affect dimer stability

• UCNP-SPT reveals EGFR/HER2/HER3 heterodimers and ligand effects on dimer stability

Summary

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."

Single-molecule tracker illuminates workings of cancer-related proteins | MIT News | Massachusetts Institute of Technology "Researchers can now use custom-built microscopy and nanotechnology to tag and follow the activity of individual proteins in real-time."

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

Graphical abstract