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 Fadlullah Wilmot; Marcel Dreger; Karen Pickering; Joe Maltas; Garry Ashton; Ruth MacLeod; George S. Baillie; Valerie Kouskoff; Georges Lacaud; Graeme I. Murray; Owen J. Sansom; Adam 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 Fadlullah Wilmot, Marcel Dreger, Karen Pickering, Joe Maltas, Garry Ashton, Ruth MacLeod, George S. Baillie, Valerie Kouskoff, Georges Lacaud, Graeme I. Murray, Owen J. Sansom, Adam Hurlstone, Angeliki Malliri

Research output: Contribution to journal › Article › peer-review

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
Article number	e6
Pages (from-to)	621–634
Number of pages	14
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

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

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

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Diamantopoulou, Z., White, G., Fadlullah Wilmot, M., 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., & 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. Article 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",

author = "Zoi Diamantopoulou and Gavin White and {Fadlullah Wilmot}, Muhammad 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 Adam Hurlstone and Angeliki Malliri",

year = "2017",

month = may,

day = "8",

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

language = "English",

volume = "31",

pages = " 621–634",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Diamantopoulou, Z, White, G, Fadlullah Wilmot, M, Dreger, M, Pickering, K, Maltas, J, Ashton, G, MacLeod, R, Baillie, GS, Kouskoff, V , Lacaud, G, Murray, GI, Sansom, OJ, Hurlstone, A & 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, e6, pp. 621–634. https://doi.org/10.1016/j.ccell.2017.03.007

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 Wilmot, Muhammad

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

AU - Malliri, Angeliki

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

SN - 1535-6108

VL - 31

SP - 621

EP - 634

JO - Cancer Cell

JF - Cancer Cell

IS - 5

M1 - e6

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

Research Beacons, Institutes and Platforms

UN SDGs

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