Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways

Biao Ma; Hongcheng Cheng; Ruize Gao; Chenglong Mu; Ling Chen; Shian Wu; Quan Chen; Yushan Zhu

doi:10.1038/ncomms11123

Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways

Nat Commun. 2016 Mar 31:7:11123. doi: 10.1038/ncomms11123.

Authors

Biao Ma¹, Hongcheng Cheng¹, Ruize Gao¹, Chenglong Mu¹, Ling Chen¹, Shian Wu¹, Quan Chen^{1

2}, Yushan Zhu¹

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin 300071, China.
² State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

Abstract

The evolutionarily conserved Hippo pathway is a regulator that controls organ size, cell growth and tissue homeostasis. Upstream signals of the Hippo pathway have been widely studied, but how microenvironmental factors coordinately regulate this pathway remains unclear. In this study, we identify LIM domain protein Zyxin, as a scaffold protein, that in response to hypoxia and TGF-β stimuli, forms a ternary complex with Lats2 and Siah2 and stabilizes their interaction. This interaction facilitates Lats2 ubiquitination and degradation, Yap dephosphorylation and subsequently activation. We show that Zyxin is required for TGF-β and hypoxia-induced Lats2 downregulation and deactivation of Hippo signalling in MDA-MB-231 cells. Depletion of Zyxin impairs the capability of cell migration, proliferation and tumourigenesis in a xenograft model. Zyxin is upregulated in human breast cancer and positively correlates with histological stages and metastasis. Our study demonstrates that Zyxin-Lats2-Siah2 axis may serve as a potential therapeutic target in cancer treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Animals
Carcinogenesis / genetics
Cell Hypoxia
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cellular Microenvironment
Female
HEK293 Cells
Heterografts / metabolism
Heterografts / pathology
Hippo Signaling Pathway
Humans
Mice
Mice, Inbred BALB C
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Nuclear Proteins / physiology*
Phosphoproteins / metabolism
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Protein Serine-Threonine Kinases / physiology*
Proteolysis
Signal Transduction
Transcription Factors
Transforming Growth Factor beta / metabolism
Transforming Growth Factor beta / physiology*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism
Tumor Suppressor Proteins / physiology*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism
Ubiquitin-Protein Ligases / physiology*
Ubiquitination
YAP-Signaling Proteins
Zyxin / genetics
Zyxin / metabolism
Zyxin / physiology*

Substances

Adaptor Proteins, Signal Transducing
Nuclear Proteins
Phosphoproteins
Transcription Factors
Transforming Growth Factor beta
Tumor Suppressor Proteins
YAP-Signaling Proteins
YAP1 protein, human
ZYX protein, human
Zyxin
Ubiquitin-Protein Ligases
seven in absentia proteins
LATS2 protein, human
Protein Serine-Threonine Kinases