Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase.
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 HIF1? and is essential for HIF1? 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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Breast Neoplasms, Cell Hypoxia, Cell Line, Tumor, Cell Transformation, Neoplastic, Down-Regulation, Female, HEK293 Cells, HeLa Cells, Hippo Signaling Pathway, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Nude, Neoplasm Transplantation, Nuclear Proteins, Phosphoproteins, Phosphorylation, Protein Serine-Threonine Kinases, RNA Interference, RNA, Small Interfering, Signal Transduction, Transcription Factors, Transplantation, Heterologous, Tumor Microenvironment, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, YAP-Signaling Proteins
Adaptor Proteins, Signal Transducing, Animals, Breast Neoplasms, Cell Hypoxia, Cell Line, Tumor, Cell Transformation, Neoplastic, Down-Regulation, Female, HEK293 Cells, HeLa Cells, Hippo Signaling Pathway, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Nude, Neoplasm Transplantation, Nuclear Proteins, Phosphoproteins, Phosphorylation, Protein Serine-Threonine Kinases, RNA Interference, RNA, Small Interfering, Signal Transduction, Transcription Factors, Transplantation, Heterologous, Tumor Microenvironment, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, YAP-Signaling Proteins
Nat Cell Biol
Date: Jan. 01, 2015
PubMed ID: 25438054
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