title: Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex.
abstract: 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.
authors.affiliation: Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden.
authors.forename: Aftab
authors.initials: A
authors.lastname: Nadeem
authors.affiliation: Departments of Applied Science, Biomedical Engineering, and Chemical Engineering &Materials Science, University of California, Davis, CA 95616 USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sanborn
authors.affiliation: Departments of Applied Science, Biomedical Engineering, and Chemical Engineering &Materials Science, University of California, Davis, CA 95616 USA.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Gettel
authors.affiliation: Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden.|Centre for Biomimetic Sensor Science, School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Drive, 637553, Singapore.
authors.forename: Ho C S
authors.initials: HC
authors.lastname: James
authors.affiliation: Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Rydström
authors.affiliation: Departments of Applied Science, Biomedical Engineering, and Chemical Engineering &Materials Science, University of California, Davis, CA 95616 USA.
authors.forename: Viviane N
authors.initials: VN
authors.lastname: Ngassam
authors.affiliation: Department of Biology, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark.
authors.forename: Thomas Kjær
authors.initials: TK
authors.lastname: Klausen
authors.affiliation: Department of Biology, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark.
authors.forename: Stine Falsig
authors.initials: SF
authors.lastname: Pedersen
authors.affiliation: Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Lam
authors.affiliation: Departments of Applied Science, Biomedical Engineering, and Chemical Engineering &Materials Science, University of California, Davis, CA 95616 USA.|Centre for Biomimetic Sensor Science, School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Drive, 637553, Singapore.
authors.forename: Atul N
authors.initials: AN
authors.lastname: Parikh
authors.affiliation: Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Svanborg
mesh_terms: D017209:Apoptosis; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability; D006801:Humans; D007768:Lactalbumin / Q000378:metabolism*; D008024:Ligands; D008051:Lipid Bilayers / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D009829:Oleic Acids / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: C506422:HAMLET complex, human; D008024:Ligands; D008051:Lipid Bilayers; D008563:Membrane Lipids; D009829:Oleic Acids; D011956:Receptors, Cell Surface; D007768:Lactalbumin; D018631:ras Proteins