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

Publication date: Available online 13 April 2017
Source:Cancer Cell
Author(s): 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
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.

Graphical abstract

Teaser

Diamantopoulou et al. identify TIAM1 as a critical antagonist of colorectal cancer progression. Cytoplasmic TIAM1 promotes TAZ degradation by enhancing its interaction with βTrCP whereas nuclear TIAM1 suppresses TAZ/YAP interaction with TEADs, inhibiting expression of TAZ/YAP target genes.


http://ift.tt/2ocabSb