Tei Reika, Morstein Johannes, Shemet Andrej, Trauner Dirk, Baskin Jeremy M
Department of Chemistry and Chemical Biology and Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14850, United States.
Department of Chemistry, New York University, New York, New York 10003, United States.
ACS Cent Sci. 2021 Jul 28;7(7):1205-1215. doi: 10.1021/acscentsci.1c00444. Epub 2021 Jul 14.
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 and , 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 form and a relatively bent form. We found that - 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 forms of both and 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.
磷脂酸（PAs）是甘油磷脂，可调节控制细胞生长和增殖的关键细胞信号通路，包括mTOR和Hippo通路。它们的酰基链在尾巴长度和饱和度上有所不同，导致不同PA种类的信号功能存在显著差异。例如，在mTOR信号传导中，饱和形式的PA具有抑制作用，而不饱和形式则具有激活作用。为了实现对PA信号的快速控制，我们在此描述了PA的光开关类似物的开发，分别称为 和 ，它们在一个或两个脂尾中含有偶氮苯基团。这些光脂质能够对其尾巴结构进行光学控制，并可以在直的 形式和相对弯曲的 形式之间可逆地切换。我们发现 - 选择性地激活mTOR信号传导，模拟不饱和形式PA的生物活性。此外，在Hippo信号传导的背景下，其生长抑制活性被PA阻断，我们发现 和 的 形式都选择性地抑制该通路。总的来说，这些光开关PA类似物能够对mTOR和Hippo信号进行光学控制，我们设想这些探针未来可用于剖析生理和病理PA信号的多效性作用。
