Optical Control of Phosphatidic Acid Signaling
Abstract
Phosphatidic acids (PAs) are glycerophospholipids that regulate key cell signaling pathways governing cell growth and proliferation, including the mTOR and Hippo pathways. Their acyl chains vary in tail length and degree of saturation, leading to marked differences in the signaling functions of different PA species. For example, in mTOR signaling, saturated forms of PA are inhibitory, whereas unsaturated forms are activating. To enable rapid control over PA signaling, we describe here the development of photoswitchable analogues of PA, termed AzoPA and dAzoPA, that contain azobenzene groups in one or both lipid tails, respectively. These photolipids enable optical control of their tail structure and can be reversibly switched between a straight trans form and a relatively bent cis form. We found that cis-dAzoPA selectively activates mTOR signaling, mimicking the bioactivity of unsaturated forms of PA. Further, in the context of Hippo signaling, whose growth-suppressing activity is blocked by PA, we found that the cis forms of both AzoPA and dAzoPA selectively inhibit this pathway. Collectively, these photoswitchable PA analogues enable optical control of mTOR and Hippo signaling, and we envision future applications of these probes to dissect the pleiotropic effects of physiological and pathological PA signaling.
Copyright and License
This publication is licensed under CC-BY-NC-ND 4.0. Copyright © 2021 The Authors. Published by American Chemical Society
Acknowledgement
J.M.B. acknowledges support from a Beckman Young Investigator award, a Sloan Research Fellowship, and the NSF (CAREER CHE-1749919). D.T. acknowledges support from NYU. R.T. was supported by Honjo International, Funai Overseas, and Cornell Fellowships. J.M. thanks the German Academic Scholarship Foundation for a fellowship, the New York University for a MacCracken fellowship and a Margaret and Herman Sokol fellowship, and the NCI for an F99/K00 award (1F99CA253758-01). We thank the Fromme lab for use of equipment.
Additional Information
the Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscentsci.1c00444.
-
1H and 13C NMR spectra, Python scripts, and Supplementary Figures (PDF)
Files
Name | Size | Download all |
---|---|---|
md5:698464b302e13f06142c82d6ac73d40a
|
7.4 MB | Preview Download |
md5:ed1c65f775ceaeb6ebb5efe0c499e828
|
2.3 MB | Preview Download |
Additional details
- ISSN
- 2374-7951
- CAREER CHE-1749919
- Division of Chemistry
- 1F99CA253758-01
- National Cancer Institute
- Sloan Research Fellowship
- Alfred P. Sloan Foundation
- German Academic Scholarship Foundation Fellowship
- German National Academic Foundation
- Beckman Young Investigator
- Arnold and Mabel Beckman Foundation
- Cornell Graduate Fellowship
- Cornell University
- MacCracken fellowship
- New York University
- Margaret and Herman Sokol fellowship
- New York University
- Honjo International Fellowship
- Honjo International Scholarship Foundation
- Funai Overseas Fellowship
- Funai Foundation
- Available
-
2021-07-14Published online
- Publication Status
- Published