NRas activity is regulated by dynamic interactions with nanoscale signaling clusters at the plasma membrane

Oren Yakovian, Julia Sajman, Michal Alon, Rand Arafeh, Yardena Samuels, Eilon Sherman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

NRas is a key mediator of the mitogenic pathway in normal cells and in cancer cells. Its dynamics and nanoscale organization at the plasma membrane (PM) facilitate its signaling. Here, we used two-color photoactivated localization microscopy to resolve the organization of individual NRas and associated signaling proteins in live melanoma cells, with resolution down to ∼20 nm. Upon EGF activation, a fraction of NRas and BRAF (dis)assembled synchronously at the PM in co-clusters. NRas and BRAF clusters associated with GPI-enriched domains, serving as possible nucleation sites for these clusters. NRas and BRAF association in mutual clusters was reduced by the NRas farnesylation inhibitor lonafarnib, yet enhanced by the BRAF inhibitor vemurafenib. Surprisingly, dispersed NRas molecules associated with the periphery of self-clusters of either Grb2 or NF1. Thus, NRas-mediated signaling, which is critical in health and disease, is regulated by dynamic interactions with functional clusters of BRAF or other related proteins at the PM.

Original languageAmerican English
Article number105282
JournaliScience
Volume25
Issue number11
DOIs
StatePublished - 18 Nov 2022

Bibliographical note

Publisher Copyright:
© 2022

Keywords

  • Biological sciences
  • Biophysics
  • Cell biology
  • Molecular biology

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