Journal
MOLECULAR CELL
Volume 72, Issue 2, Pages 328-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.08.038
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Funding
- NIH [GM126048, CA196878, GM51586, GM093040, GM0793830]
- American Cancer Society [RSG-18-009-01-CCG]
- American Association for Cancer Research Career Development Award - Breast Cancer Research Foundation [16-20-26-WANG]
- NATIONAL CANCER INSTITUTE [R35CA196878, P30CA062203] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM093040, R01GM126048, R01GM079383, R01GM051586] Funding Source: NIH RePORTER
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The Hippo pathway plays a crucial role in organ size control and tumor suppression, but its precise regulation is not fully understood. In this study, we discovered that phosphatidic acid (PA)-related lipid signaling is a key regulator of the Hippo pathway. Supplementing PA in various Hippo-activating conditions activates YAP. This PA-related lipid signaling is involved in Rho-mediated YAP activation. Mechanistically, PA directly interacts with Hippo components LATS and NF2 to disrupt LATS-MOB1 complex formation and NF2-mediated LATS membrane translocation and activation, respectively. Inhibition of phospholipase D (PLD)-dependent PA production suppresses YAP oncogenic activities. PLD1 is highly expressed in breast cancer and positively correlates with YAP activation, suggesting their pathological relevance in breast cancer development. Taken together, our study not only reveals a role of PLD-PA lipid signaling in regulating the Hippo pathway but also indicates that the PLD-PA-YAP axis is a potential therapeutic target for cancer treatment.
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