Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 28, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2024596118
Keywords
GAS6-AXL; TAM receptors; actin; membrane ruffles; macropinocytosis
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Funding
- SONATA Grant from the National Science Center [2015/19/D/NZ3/03270]
- Federation of European Biochemical Societies
- TEAM Grant from the Foundation for Polish Science [POIR.04.04.00-00-20CE/16-00]
- TEAM-TECH Core Facility Plus/2017-2/2 from the Foundation for Polish Science [POIR.04.04.00-00-23C2/17-00]
- European Union under the European Regional Development Fund
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The study identified an interactome of AXL and its associations with proteins regulating actin dynamics. GAS6-mediated AXL activation triggered actin remodeling and macropinocytosis, promoting the survival of cancer cells under glutamine-deprived conditions. AXL activation by GAS6 drove invasion of cancer cells through actin-driven cytoskeletal rearrangements.
AXL, a member of the TAM (TYRO3, AXL, MER) receptor tyrosine kinase family, and its ligand, GAS6, are implicated in oncogenesis and metastasis of many cancer types. However, the exact cellular processes activated by GAS6-AXL remain largely unexplored. Here, we identified an interactome of AXL and revealed its associations with proteins regulating actin dynamics. Consistently, GAS6-mediated AXL activation triggered actin remodeling manifested by peripheral membrane ruffling and circular dorsal ruffles (CDRs). This further promoted macropinocytosis that mediated the internalization of GAS6-AXL complexes and sustained survival of glioblastoma cells grown under glutamine-deprived conditions. GAS6-induced CDRs contributed to focal adhesion turnover, cell spreading, and elongation. Consequently, AXL activation by GAS6 drove invasion of cancer cells in a spheroid model. All these processes required the kinase activity of AXL, but not TYRO3, and downstream activation of PI3K and RAC1. We propose that GAS6-AXL signaling induces multiple actin-driven cytoskeletal rearrangements that contribute to cancer-cell invasion.
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