Enhanced Dendritic Actin Network Formation in Extended Lamellipodia Drives Proliferation in Growth-Challenged Rac1P29S 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

doi:10.1016/j.devcel.2019.04.007

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

Dev Cell. 2019 May 6;49(3):444-460.e9. doi: 10.1016/j.devcel.2019.04.007.

Authors

Affiliations

¹ Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Department of Physics, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biomedical Engineering, Michigan Technological University, Houghton, MI 49931, USA.
⁷ Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: gaudenz.danuser@utsouthwestern.edu.

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.

Keywords: NF2; Rac1; actin assembly; lamellipodia; melanoma; merlin; proliferation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism
Animals
Cell Line, Tumor
Cell Movement / physiology
Cell Proliferation / physiology
Dendrites / metabolism
Dendrites / pathology
Dendritic Cells / metabolism*
Female
Heterografts
Humans
MAP Kinase Signaling System
Melanoma / metabolism*
Melanoma / pathology
Mice
Mice, Inbred NOD
Mice, SCID
Mutation
Neoplasm Metastasis
Pseudopodia / metabolism*
Pseudopodia / pathology
rac1 GTP-Binding Protein / genetics
rac1 GTP-Binding Protein / metabolism*

Substances

Actins
RAC1 protein, human
rac1 GTP-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding