TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells

Zoi Diamantopoulou, Gavin White, Muhammad Z H Fadlullah, Marcel Dreger, Karen Pickering, Joe Maltas, Garry Ashton, Ruth MacLeod, George S. Baillie, Valerie Kouskoff, Georges Lacaud, Graeme I Murray, Owen J. Sansom, Adam F.L. Hurlstone, Angeliki Malliri

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Abstract

Aberrant WNT signaling drives colorectal cancer (CRC). Here, we identify TIAM1 as a critical antagonist of CRC progression through inhibiting TAZ and YAP, effectors of WNT signaling. We demonstrate that TIAM1 shuttles between the cytoplasm and nucleus antagonizing TAZ/YAP by distinct mechanisms in the two compartments. In the cytoplasm, TIAM1 localizes to the destruction complex and promotes TAZ degradation by enhancing its interaction with βTrCP. Nuclear TIAM1 suppresses TAZ/YAP interaction with TEADs, inhibiting expression of TAZ/YAP target genes implicated in epithelial-mesenchymal transition, cell migration, and invasion, and consequently suppresses CRC cell migration and invasion. Importantly, high nuclear TIAM1 in clinical specimens associates with increased CRC patient survival. Together, our findings suggest that in CRC TIAM1 suppresses tumor progression by regulating YAP/TAZ activity.


Original languageEnglish
Pages (from-to)621-634.e6
Number of pages21
JournalCancer Cell
Volume31
Issue number5
Early online date13 Apr 2017
DOIs
Publication statusPublished - 8 May 2017

Bibliographical note

This work was supported by MRC (grant number MR/L007495/1) and Cancer Research UK (grant number C5759/A12328) to A.M. We thank members of the Cell Signalling Group for helpful discussions and critical reading of the manuscript. We also thank the Molecular Biology Core Facility of CRUK Manchester Institute (CRUK MI) for performing next generation sequencing as well as the CRUK MI Computational Biology Group for preliminary bioinformatics analysis.

Keywords

  • TIAM1
  • TAZ
  • YAP
  • WNT
  • intestinal tumorigenesis
  • colorectal cancer
  • cell migration
  • invasion
  • malignant progression

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