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) (PMCID:PMC5425402)
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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 > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| 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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