TY - JOUR
T1 - Optical Control of Phosphatidic Acid Signaling
AU - Tei, Reika
AU - Morstein, Johannes
AU - Shemet, Andrej
AU - Trauner, Dirk
AU - Baskin, Jeremy M.
N1 - Funding Information:
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.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/7/28
Y1 - 2021/7/28
N2 - 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.
AB - 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.
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U2 - 10.1021/acscentsci.1c00444
DO - 10.1021/acscentsci.1c00444
M3 - Article
AN - SCOPUS:85111204284
VL - 7
SP - 1205
EP - 1215
JO - ACS Central Science
JF - ACS Central Science
SN - 2374-7943
IS - 7
ER -