The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors.

Abstract

The Hippo signaling pathway regulates organ size and plays critical roles in maintaining tissue growth, homeostasis, and regeneration. Dysregulated in a wide spectrum of cancers, in mammals, this pathway is regulated by two key effectors, YAP and TAZ, that may functionally overlap. We found that TAZ promoted liver inflammation and tumor development. The expression of TAZ, but not YAP, in human liver tumors positively correlated with the expression of proinflammatory cytokines. Hyperactivated TAZ induced substantial myeloid cell infiltration into the liver and the secretion of proinflammatory cytokines through a TEAD-dependent mechanism. Furthermore, tumors with hyperactivated YAP and TAZ had distinct transcriptional signatures, which included the increased expression of inflammatory cytokines in TAZ-driven tumors. Our study elucidated a previously uncharacterized link between TAZ activity and inflammatory responses that influence tumor development in the liver.

• Authors: Thijs J Hagenbeek, Joshua D Webster, Noelyn M Kljavin, Matthew T Chang, Trang Pham, Ho-June Lee, Christiaan Klijn, Allen G Cai, Klara Totpal, Buvana Ravishankar, Naiying Yang, Da-Hye Lee, Kevin B Walsh, Georgia Hatzivassiliou, Cecile C de la Cruz, Stephen E Gould, Xiumin Wu, Wyne P Lee, Shuqun Yang, Zhixiang Zhang, Qingyang Gu, Qunsheng Ji, Erica L Jackson, Dae-Sik Lim, Anwesha Dey
• Journal: Science signaling (Sci Signal) Vol. 11 Issue 547 (09 11 2018) ISSN: 1937-9145 [Electronic] United States
• PMID: 30206136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Cell Cycle Proteins
• Cytokines
• DNA-Binding Proteins
• Intracellular Signaling Peptides and Proteins
• Nuclear Proteins
• TEA Domain Transcription Factors
• TEAD1 protein, human
• Trans-Activators
• Transcription Factors
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• WWTR1 protein, human
• YY1AP1 protein, human
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cell Cycle Proteins
• Cytokines (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Gene Expression Profiling (methods)
• Hippo Signaling Pathway
• Humans
• Inflammation (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Liver (metabolism, pathology)
• Liver Neoplasms (genetics, metabolism, pathology)
• Mice, Inbred C57BL
• Mutation
• Nuclear Proteins (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction (genetics)
• TEA Domain Transcription Factors
• Trans-Activators
• Transcription Factors (genetics, metabolism)
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• Transplantation, Heterologous