Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2024-05-28 DOI:10.1126/scisignal.ado6266

Lavinia Palamiuc, Jared L. Johnson, Zeinab Haratipour, Ryan M. Loughran, Woong Jae Choi, Gurpreet K. Arora, Vivian Tieu, Kyanh Ly, Alicia Llorente, Sophia Crabtree, Jenny C. Y. Wong, Archna Ravi, Thorsten Wiederhold, Rabi Murad, Raymond D. Blind, Brooke M. Emerling

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引用次数: 0

Abstract

Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P₂, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease.

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Hippo和PI5P4K信号交叉控制YAP的转录激活。

磷酸肌酸是重要的信号分子。磷酸肌酸激酶 PI5P4K 家族及其底物和产物 PI5P 和 PI4,5P2 正在成为细胞内代谢和应激传感器。我们进行了无偏筛选，研究这些激酶传递的信号以及控制这一信号节点的特定上游调节因子。我们发现，Hippo 通路核心激酶 MST1/2 磷酸化了 PI5P4Ks，并抑制了它们在体外和细胞内的信号转导。我们进一步发现，PI5P4K 的活性调节了几种与 Hippo 和 YAP 相关的表型，特别是减少了关键 Hippo 蛋白 MOB1 和 LATS 之间的相互作用，并刺激了 YAP 介导的上皮向间质转化的遗传程序。从机理上讲，我们发现 PI5P 与 MOB1 相互作用，并增强了其与 LATS 的相互作用，从而在 Hippo 通路和 PI5P4K 之间建立了信号连接。这些发现揭示了这两种重要的进化保守信号通路是如何整合在一起调控后生动物的发育和人类疾病的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.