TIAM1 antagonizes TAZ/YAP both in the destruction complex in the cytoplasm and in the nucleus to inhibit invasion of intestinal epithelial cells

Diamantopoulou, Z. et al. (2017) TIAM1 antagonizes TAZ/YAP both in the destruction complex in the cytoplasm and in the nucleus to inhibit invasion of intestinal epithelial cells. Cancer Cell, 31(5), pp. 621-634. (doi:10.1016/j.ccell.2017.03.007) (PMID:28416184)

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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.

Item Type:Articles
Additional Information:This work was supported by MRC (grant number MR/L007495/1) and Cancer Research UK (grant number C5759/A12328) to A.M.
Keywords:TAZ, TIAM1, WNT, YAP, cell migration, colorectal cancer, intestinal tumorigenesis, invasion, malignant progression.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Sansom, Professor Owen and MacLeod, Miss Ruth
Authors: Diamantopoulou, Z., White, G., Fadlullah, M. Z.H., Dreger, M., Pickering, K., Maltas, J., Ashton, G., MacLeod, R., Baillie, G. S., Kouskoff, V., Lacaud, G., Murray, G. I., Sansom, O. J., Hurlstone, A. F.L., and Malliri, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cancer Cell
Publisher:Elsevier
ISSN:1535-6108
ISSN (Online):1878-3686
Published Online:13 April 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Cancer Cell 31(5):621-634
Publisher Policy:Reproduced under a Creative Commons License

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