Article
Developmental Biology
Laura Currey, Stefan Thor, Michael Piper
Summary: The balance between stem cell potency and lineage specification relies on the integration of extrinsic and intrinsic cues to influence gene expression through transcription factors. The Hippo signalling pathway, particularly involving YAP, TAZ, and TEAD proteins, plays a key role in regulating organ size and progenitor self-renewal during development. Studies are revealing the intricate roles of TEAD proteins in maintaining the balance between stem cell self-renewal and differentiation in various developmental stages.
Article
Clinical Neurology
Liyam Laraba, Lily Hillson, Julio Grimm de Guibert, Amy Hewitt, Maisie R. Jaques, Tracy T. Tang, Leonard Post, Emanuela Ercolano, Ganesha Rai, Shyh-Ming Yang, Daniel J. Jagger, Waldemar Woznica, Philip Edwards, Aditya G. Shivane, C. Oliver Hanemann, David B. Parkinson
Summary: The study reports new roles for the Hippo signalling pathway in NF2-null meningioma and schwannoma, and identifies the cancer stem cell marker ALDH1A1 as a target of Hippo signalling. The novel TEAD inhibitor used in the study effectively blocks the growth of these tumour types, providing potential clinical applications.
Review
Biochemistry & Molecular Biology
Hyeryun Kwon, Jiyoung Kim, Eek-hoon Jho
Summary: The Hippo pathway is a crucial signaling mechanism for inhibiting cell and organ growth, which plays a role in diseases such as cancer. Activation of the Hippo pathway can suppress cell proliferation, while inhibition of this pathway leads to nuclear localization of YAP/TAZ and induction of cell proliferation-related genes. Therefore, studying the signaling mechanisms of the Hippo pathway is crucial for identifying new therapeutic targets for treating diseases like cancer.
Article
Biology
Omar Salem, Siyang Jia, Bin-Zhi Qian, Carsten Gram Hansen
Summary: The Hippo signalling pathway plays a crucial role in regulating cell growth, proliferation, and cancer. In prostate cancer, androgens activate YAP/TAZ through the androgen receptor (AR), with AR regulating YAP translation and inducing TAZ transcription. The activation of YAP/TAZ by AR is mediated by the transcriptional mediator SRF. This study highlights the interplay between YAP, TAZ, and SRF in prostate cancer cells and their potential therapeutic implications.
LIFE SCIENCE ALLIANCE
(2023)
Review
Chemistry, Medicinal
Mengxin Luo, Yongjin Xu, Haifeng Chen, Yiquan Wu, Ao Pang, Junjie Hu, Xiaowu Dong, Jinxin Che, Haiyan Yang
Summary: This review discusses the role of the Hippo pathway in the tumorigenesis of breast cancer, oral cancer, rectal cancer, colloid cancer, and more. It analyzes the structural basis of the YAP/TAZ-TEAD complex and summarizes the targeting inhibitors within medicinal chemistry classification. The clinical status and current challenges of these drug candidates are also discussed, providing guidance for future development of inhibitors, particularly targeting the YAP/TAZ-TEAD complex.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Xu Li, Shu Zhuo, Yong Suk Cho, Yuchen Liu, Yingzi Yang, Jian Zhu, Jin Jiang
Summary: Hippo signaling inhibits the oncogenic potential of YAP/TAZ-TEAD transcriptional complex, restricting tumor growth. In AR-positive prostate cancer, YAP acts as a tumor suppressor by counteracting TEAD-mediated AR signaling. YAP competes with AR for TEAD binding, disrupting AR-TEAD interaction and preventing TEAD from promoting AR signaling. Targeting the Hippo signaling pathway may provide a therapeutic opportunity to treat therapy resistant AR variants-driven prostate cancer.
Article
Biochemistry & Molecular Biology
Chunle Zhao, Jun Gong, Yu Bai, Taoyuan Yin, Min Zhou, Shutao Pan, Yuhui Liu, Yang Gao, Zhenxiong Zhang, Yongkang Shi, Feng Zhu, Hang Zhang, Min Wang, Renyi Qin
Summary: With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A study found that the transcriptional coactivator TAZ could be a potential therapeutic target in PDAC. Through unbiased deubiquitinase (DUB) library screening, researchers identified USP14 as a key regulator of TAZ stabilization, and the USP14-TAZ loop was found to promote cancer progression and liver metastasis in PDAC models. Inhibition of USP14 with the small molecule inhibitor IU1 showed promising anti-cancer effects in PDAC models.
CELL DEATH AND DIFFERENTIATION
(2023)
Review
Biochemistry & Molecular Biology
Angel Ortega, Ivana Vera, Maria P. Diaz, Carla Navarro, Milagros Rojas, Wheeler Torres, Heliana Parra, Juan Salazar, Juan B. De Sanctis, Valmore Bermudez
Summary: Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are essential for cell growth regulation, embryonic development, regeneration, proliferation, and cancer. Their activation leads to the release of the transcriptional enhanced associate domain (TEAD) from its repressors, resulting in various biological effects. Overexpression of YAP/TAZ is associated with cancer stem cells and tumor resistance.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Jing Cai, Kyungsuk Choi, Hongde Li, Katiuska Daniela Pulgar Prieto, Yonggang Zheng, Duojia Pan
Summary: This study reveals that the essential role of YAP in liver and lung development can be bypassed by inactivation of the TEAD corepressor VGLL4, indicating that YAP's major physiological function is to antagonize VGLL4. The findings highlight the central importance of VGLL4-mediated transcriptional repression in regulating the Hippo pathway and provide insights into potential strategies for modulating Hippo signaling in cancer and regenerative medicine.
GENES & DEVELOPMENT
(2022)
Article
Multidisciplinary Sciences
Kepeng Che, Ajaybabu Pobbati, Caleb N. Seavey, Yuriy Fedorov, Anton A. Komar, Ashley Burtscher, Shuang Ma, Brian P. Rubin
Summary: In this study, the researchers identified a pharmacologically active small molecule called aurintricarboxylic acid (ATA) that can disrupt the formation of the TAZ-TEAD complex. They found that ATA inhibits TC/TEAD transcriptional activity and prevents anchorage-independent growth associated with dysregulated TAZ/TEAD activity.
Review
Chemistry, Medicinal
Benjamin Zagiel, Patricia Melnyk, Philippe Cotelle
Summary: The Hippo pathway presents a new opportunity for cancer treatment, with YAP/TAZ-TEAD transcriptional complex being a promising target. Since 2018, approximately 30 international patents regarding TEAD transcriptional inhibitors have been filed, with drugs categorized into external TEAD ligands, non-covalent TEAD ligands, and covalent TEAD ligands. The first molecules entering clinical trial phase 1 are non-covalent TEAD ligands.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2022)
Article
Chemistry, Medicinal
Timo Heinrich, Carl Peterson, Richard Schneider, Sakshi Garg, Daniel Schwarz, Jakub Gunera, Anita Seshire, Lisa Koetzner, Sarah Schlesiger, Djordje Musil, Heike Schilke, Benjamin Doerfel, Patrizia Diehl, Pia Boepple, Ana R. Lemos, Pedro M. F. Sousa, Filipe Freire, Tiago M. Bandeiras, Emma Carswell, Nicholas Pearson, Sameer Sirohi, Mollie Hooker, Elisabeth Trivier, Rebecca Broome, Alexander Balsiger, Abigail Crowden, Christian Dillon, Dirk Wienke
Summary: The dysregulated Hippo pathway and hyperactivity of the YAP/TAZ-TEAD transcriptional complexes are associated with diseases like cancer. This study describes the discovery and optimization of a P-site binding fragment to target the TEAD transcription factors. The optimized in vivo tool, MSC-4106, exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Ana Sousa-Ortega, Javier Vazquez-Marin, Estefania Sanabria-Reinoso, Jorge Corbacho, Rocio Polvillo, Alejandro Campoy-Lopez, Lorena Buono, Felix Loosli, Maria Almuedo-Castillo, Juan R. Martinez-Morales
Summary: YAP signaling is involved in regulating cell migration during embryonic axis assembly by sustaining intracellular tension. Knockout of yap and yap1b in medaka disrupts axis assembly and reduces cell displacement and migratory persistence. Yap targets genes involved in cytoskeletal organization and cell-ECM adhesion to promote cortical actin and focal adhesions recruitment in migratory cells.
NATURE COMMUNICATIONS
(2023)
Article
Medicine, Research & Experimental
Iwao Shimomura, Naoaki Watanabe, Tomofumi Yamamoto, Minami Kumazaki, Yuji Tada, Koichiro Tatsumi, Takahiro Ochiya, Yusuke Yamamoto
Summary: The study found that verteporfin can effectively inhibit the viability of KRAS-mutant lung cancer cells and suppress KRAS-driven lung tumors. The mechanism of verteporfin action is partially independent of YAP1 inhibition and leads to apoptotic cell death in KRAS-mutant lung cancer cells by inducing endoplasmic reticulum stress pathway.
Review
Biochemistry & Molecular Biology
Boon Chin Heng, Xuehui Zhang, Dominique Aubel, Yunyang Bai, Xiaochan Li, Yan Wei, Martin Fussenegger, Xuliang Deng
Summary: YAP and TAZ are crucial proteins involved in maintaining tissue/organ size and have diverse roles in various biological processes, including cell proliferation, tissue regeneration, cell fate determination, tumorigenesis, and mechanosensing.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
