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

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


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*


  • 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