The GAS6-AXL signaling pathway triggers actin remodeling that drives membrane ruffling, macropinocytosis, and cancer-cell invasion
Menée à l'aide de lignées cellulaires, cette étude met en évidence un mécanisme par lequel la voie de signalisation de la tyrosine kinase AXL et de son ligand GAS6 déclenche, via le remodelage de l'actine, le froissement des membranes des cellules cancéreuses, la macropinocytose et le processus invasif
Metastasis remains the major cause of cancer-related deaths. Overactivation of receptor tyrosine kinase AXL has been correlated with cancer invasion and metastasis, resistance to therapies, and poor patient prognosis. However, the cellular processes activated by AXL and its ligand, GAS6, are largely unknown. Here, we identified a proximity interactome of AXL and revealed actin-dependent processes activated by GAS6-AXL, including membrane ruffling and macropinocytosis, that provide insights into the role of AXL in cancer progression. The identified AXL interactors can be used in translational research toward development of effective therapies for metastatic and/or chemoresistant cancers with AXL overactivation. Moreover, our data provide a mechanistic explanation for previous studies reporting that AXL might contribute to macropinocytic uptake of viruses.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.The mass-spectrometry proteomics data have been deposited to the Proteomics Identification Database partner repository (82) with the dataset identifier PXD017933 (83). All other study data are included in the article and/or supporting information.