Enhanced Dendritic Actin Network Formation in Extended Lamellipodia Drives Proliferation in Growth-Challenged Rac1 P29S Melanoma Cells

Ashwathi S. Mohan, Kevin M. Dean, Tadamoto Isogai, Stacy Y. Kasitinon, Vasanth S. Murali, Philippe Roudot, Alex Groisman, Dana K. Reed, Erik S. Welf, Sangyoon J. Han, Jungsik Noh, Gaudenz Danuser

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Actin assembly supplies the structural framework for cell morphology and migration. Beyond structure, this actin framework can also be engaged to drive biochemical signaling programs. Here, we describe how the hyperactivation of Rac1 via the P29S mutation (Rac1 P29S ) in melanoma hijacks branched actin network assembly to coordinate proliferative cues that facilitate metastasis and drug resistance. Upon growth challenge, Rac1 P29S -harboring melanoma cells massively upregulate lamellipodia formation by dendritic actin polymerization. These extended lamellipodia form a signaling microdomain that sequesters and phospho-inactivates the tumor suppressor NF2/Merlin, driving Rac1 P29S cell proliferation in growth suppressive conditions. These biochemically active lamellipodia require cell-substrate attachment but not focal adhesion assembly and drive proliferation independently of the ERK/MAPK pathway. These data suggest a critical link between cell morphology and cell signaling and reconcile the dichotomy of Rac1’s regulation of both proliferation and actin assembly by revealing a mutual signaling axis wherein actin assembly drives proliferation in melanoma. The RhoGTPase Rac1 is a regulator of cell morphology and proliferation. Mohan et al. report that these functions converge in Rac1 P29S -mutant melanoma cells. Under growth challenge, Rac1 P29S cells form extended lamellipodia that sequester and phospho-inactivate NF2/Merlin, resulting in sustained cell proliferation that is advantageous for metastasis and drug tolerance.

Original languageEnglish (US)
Pages (from-to)444-460.e9
JournalDevelopmental cell
Volume49
Issue number3
DOIs
StatePublished - May 6 2019

Keywords

  • NF2
  • Rac1
  • actin assembly
  • lamellipodia
  • melanoma
  • merlin
  • proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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