Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 621-634 |
| Number of pages | 14 |
| Journal | Cancer Cell |
| Volume | 31 |
| Issue number | 5 |
| Early online date | 13 Apr 2017 |
| DOIs | |
| Publication status | Published - 8 May 2017 |
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Keywords
- TIAM1
- TAZ
- YAP
- WNT
- intestinal tumorigenesis
- colorectal cancer
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TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells. / Diamantopoulou, Zoi ; White, Gavin; Fadlullah, Muhammad Z H; Dreger, Marcel; Pickering, Karen; Maltas, Joe ; Ashton, Garry ; MacLeod, Ruth; Baillie, George S. ; Kouskoff, Valerie ; Lacaud, Georges ; Murray, Graeme I; Sansom, Owen J.; Hurlstone, Adam F.L. ; Malliri, Angeliki .
In: Cancer Cell, Vol. 31, No. 5, 08.05.2017, p. 621-634.Research output: Contribution to journal › Article
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TY - JOUR
T1 - TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells
AU - Diamantopoulou, Zoi
AU - White, Gavin
AU - Fadlullah, Muhammad Z H
AU - Dreger, Marcel
AU - Pickering, Karen
AU - Maltas, Joe
AU - Ashton, Garry
AU - MacLeod, Ruth
AU - Baillie, George S.
AU - Kouskoff, Valerie
AU - Lacaud, Georges
AU - Murray, Graeme I
AU - Sansom, Owen J.
AU - Hurlstone, Adam F.L.
AU - Malliri, Angeliki
N1 - 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.
PY - 2017/5/8
Y1 - 2017/5/8
N2 - 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.
AB - 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.
KW - TIAM1
KW - TAZ
KW - YAP
KW - WNT
KW - intestinal tumorigenesis
KW - colorectal cancer
U2 - 10.1016/j.ccell.2017.03.007
DO - 10.1016/j.ccell.2017.03.007
M3 - Article
VL - 31
SP - 621
EP - 634
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 5
ER -