한빛사논문
- 조회1,123
Yong Joon Kima,b,1, Eunji Junga,1, Eunbie Shina, Sin-Hyoung Hongc,d, Hui Su Jeonge, Gayeong Hura,f, Hye Yun Jeonga, Seung-Hyo Leea, Ji Eun Leee,g,2, Gun-Hwa Kimc,d,2, and Joon Kima,2
aGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, 34141 Daejeon, Korea; bDepartment of Ophthalmology, Institute of Vision Research, Severance Hospital, Yonsei University College of Medicine, 06273 Seoul, Korea; cDrug & Disease Target Team, Division of Bioconvergence Analysis, Korea Basic Science Institute, 28119 Cheongju, Korea; dDepartment of Bio-Analytical Science, University of Science and Technology, 34113 Daejeon, Korea; eDepartment of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, 06355 Seoul, Korea; fR&D Division, GenoFocus Inc., 34014 Daejeon, Korea; and gSamsung Biomedical Research Institute, Samsung Medical Center, 06351 Seoul, Korea
1Y.J.K. and E.J. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
The transcriptional regulator YAP, which plays important roles in the development, regeneration, and tumorigenesis, is activated when released from inhibition by the Hippo kinase cascade. The regulatory mechanism of YAP in Hippo-low contexts is poorly understood. Here, we performed a genome-wide RNA interference screen to identify genes whose loss of function in a Hippo-null background affects YAP activity. We discovered that the coatomer protein complex I (COPI) is required for YAP nuclear enrichment and that COPI dependency of YAP confers an intrinsic vulnerability to COPI disruption in YAP-driven cancer cells. We identified MAP2K3 as a YAP regulator involved in inhibitory YAP phosphorylation induced by COPI subunit depletion. The endoplasmic reticulum stress response pathway activated by COPI malfunction appears to connect COPI and MAP2K3. In addition, we provide evidence that YAP inhibition by COPI disruption may contribute to transcriptional up-regulation of PTGS2 and proinflammatory cytokines. Our study offers a resource for investigating Hippo-independent YAP regulation as a therapeutic target for cancers and suggests a link between YAP and COPI-associated inflammatory diseases.
Hippo-YAP pathway, RNAi screen, coatomer
논문정보
- Research article
- 2020년 08월 (BRIC 등록일 2020-08-06)
- 국내 연구진
- 의약학 > 분자세포의학
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