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

doi:10.1016/j.ccell.2017.03.007

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 language	English
Pages (from-to)	621-634.e6
Number of pages	21
Journal	Cancer Cell
Volume	31
Issue number	5
Early online date	13 Apr 2017
DOIs	https://doi.org/10.1016/j.ccell.2017.03.007
Publication status	Published - 8 May 2017

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2017.03.007Licence: CC BY

TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells
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Final published version, 8.27 MBLicence: CC BY

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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., & Malliri, A. (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), 621-634.e6. https://doi.org/10.1016/j.ccell.2017.03.007

Diamantopoulou, Z, White, G, Fadlullah, MZH, Dreger, M, Pickering, K, Maltas, J, Ashton, G, MacLeod, R, Baillie, GS, Kouskoff, V, Lacaud, G, Murray, GI, Sansom, OJ, Hurlstone, AFL & Malliri, A 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, vol. 31, no. 5, pp. 621-634.e6. https://doi.org/10.1016/j.ccell.2017.03.007

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

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.",

keywords = "TIAM1, TAZ, YAP, WNT, intestinal tumorigenesis, colorectal cancer, cell migration, invasion, malignant progression",

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

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. ",

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doi = "10.1016/j.ccell.2017.03.007",

language = "English",

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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

KW - cell migration

KW - invasion

KW - malignant progression

U2 - 10.1016/j.ccell.2017.03.007

DO - 10.1016/j.ccell.2017.03.007

M3 - Article

VL - 31

SP - 621-634.e6

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 5

ER -

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

Abstract

Keywords

UN SDGs

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