Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase.

Abstract	The Hippo signalling pathway plays important roles in animal development, physiology and tumorigenesis. Understanding how the activity of this pathway is regulated by the cellular microenvironment remains a major challenge. Here we elucidate a molecular mechanism by which hypoxia deactivates Hippo signalling. We demonstrate that the E3 ubiquitin ligase SIAH2 stimulates YAP by destabilizing LATS2, a critical component of the Hippo pathway, in response to hypoxia. Loss of SIAH2 suppresses tumorigenesis in a LATS2-dependent manner in a xenograft mouse model. We further show that YAP complexes with HIF1α and is essential for HIF1α stability and function in tumours in vivo. LATS2 is downregulated in human breast tumours and negatively correlates with SIAH2 expression levels, indicating that the SIAH2-LATS2 pathway may have a role in human cancer. Our data uncover oxygen availability as a microenvironment signal for the Hippo pathway and have implications for understanding the regulation of Hippo signalling in tumorigenesis.
Authors	Biao Ma, Yan Chen, Ling Chen, Hongcheng Cheng, Chenglong Mu, Jie Li, Ruize Gao, Changqian Zhou, Lei Cao, Jinhua Liu, Yushan Zhu, Quan Chen, Shian Wu
Journal	Nature cell biology (Nat Cell Biol) Vol. 17 Issue 1 Pg. 95-103 (Jan 2015) ISSN: 1476-4679 [Electronic] England
PMID	25438054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Nuclear Proteins Phosphoproteins RNA, Small Interfering Transcription Factors Tumor Suppressor Proteins YAP-Signaling Proteins YAP1 protein, human Ubiquitin-Protein Ligases seven in absentia proteins LATS2 protein, human Protein Serine-Threonine Kinases
Topics	Adaptor Proteins, Signal Transducing (biosynthesis, metabolism) Animals Breast Neoplasms (genetics) Cell Hypoxia (physiology) Cell Line, Tumor Cell Transformation, Neoplastic (genetics) Down-Regulation Female HEK293 Cells HeLa Cells Hippo Signaling Pathway Humans Hypoxia-Inducible Factor 1, alpha Subunit (metabolism) Mice Mice, Nude Neoplasm Transplantation Nuclear Proteins (biosynthesis, genetics, metabolism) Phosphoproteins (biosynthesis, metabolism) Phosphorylation Protein Serine-Threonine Kinases (biosynthesis, metabolism) RNA Interference RNA, Small Interfering Signal Transduction Transcription Factors Transplantation, Heterologous Tumor Microenvironment Tumor Suppressor Proteins (biosynthesis, metabolism) Ubiquitin-Protein Ligases (biosynthesis, genetics, metabolism) YAP-Signaling Proteins

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!