Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex
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 signa...
| Main Authors: | , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2015
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| Online Access: | https://hdl.handle.net/10356/81086 http://hdl.handle.net/10220/39063 |
| _version_ | 1826126190143864832 |
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| author | Nadeem, Aftab Sanborn, Jeremy Gettel, Douglas L. Ho, James C. S. Pedersen, Stine Falsig Lam, Matti Rydström, Anna Ngassam, Viviane N. Klausen, Thomas Kjær Parikh, Atul N. Svanbor, Catharina |
| author2 | School of Materials Science & Engineering |
| author_facet | School of Materials Science & Engineering Nadeem, Aftab Sanborn, Jeremy Gettel, Douglas L. Ho, James C. S. Pedersen, Stine Falsig Lam, Matti Rydström, Anna Ngassam, Viviane N. Klausen, Thomas Kjær Parikh, Atul N. Svanbor, Catharina |
| author_sort | Nadeem, Aftab |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:48:38Z |
| format | Journal Article |
| id | ntu-10356/81086 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:48:38Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/810862023-07-14T15:49:08Z Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex Nadeem, Aftab Sanborn, Jeremy Gettel, Douglas L. Ho, James C. S. Pedersen, Stine Falsig Lam, Matti Rydström, Anna Ngassam, Viviane N. Klausen, Thomas Kjær Parikh, Atul N. Svanbor, Catharina School of Materials Science & Engineering 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. Published version 2015-12-14T01:48:35Z 2019-12-06T14:21:07Z 2015-12-14T01:48:35Z 2019-12-06T14:21:07Z 2015 Journal Article Nadeem, A., Sanborn, J., Gettel, D. L., Ho, J. C. S., Rydström, A., Ngassam, V. N., et al. (2015). Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex. Scientific Reports, 5, 16432-. 2045-2322 https://hdl.handle.net/10356/81086 http://hdl.handle.net/10220/39063 10.1038/srep16432 26561036 en Scientific Reports This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ 14 p. application/pdf |
| spellingShingle | Nadeem, Aftab Sanborn, Jeremy Gettel, Douglas L. Ho, James C. S. Pedersen, Stine Falsig Lam, Matti Rydström, Anna Ngassam, Viviane N. Klausen, Thomas Kjær Parikh, Atul N. Svanbor, Catharina Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex |
| title | Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex |
| title_full | Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex |
| title_fullStr | Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex |
| title_full_unstemmed | Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex |
| title_short | Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex |
| title_sort | protein receptor independent plasma membrane remodeling by hamlet a tumoricidal protein lipid complex |
| url | https://hdl.handle.net/10356/81086 http://hdl.handle.net/10220/39063 |
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