Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex.
Author
Summary, in English
A central tenet of signal transduction in eukaryotic cells is that extra-cellular ligands activate specific cell surface receptors, which orchestrate downstream responses. This ''protein-centric" view is increasingly challenged by evidence for the involvement of specialized membrane domains in signal transduction. Here, we propose that membrane perturbation may serve as an alternative mechanism to activate a conserved cell-death program in cancer cells. This view emerges from the extraordinary manner in which HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) kills a wide range of tumor cells in vitro and demonstrates therapeutic efficacy and selectivity in cancer models and clinical studies. We identify a ''receptor independent" transformation of vesicular motifs in model membranes, which is paralleled by gross remodeling of tumor cell membranes. Furthermore, we find that HAMLET accumulates within these de novo membrane conformations and define membrane blebs as cellular compartments for direct interactions of HAMLET with essential target proteins such as the Ras family of GTPases. Finally, we demonstrate lower sensitivity of healthy cell membranes to HAMLET challenge. These features suggest that HAMLET-induced curvature-dependent membrane conformations serve as surrogate receptors for initiating signal transduction cascades, ultimately leading to cell death.
Department/s
- Division of Microbiology, Immunology and Glycobiology - MIG
- Division of Molecular Medicine and Gene Therapy
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2015
Language
English
Publication/Series
Scientific Reports
Volume
5
Links
Document type
Journal article
Publisher
Nature Publishing Group
Topic
- Cell and Molecular Biology
Status
Published
ISBN/ISSN/Other
- ISSN: 2045-2322