PUBLICATION
TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells
- 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., Malliri, A.
- ID
- ZDB-PUB-170822-11
- Date
- 2017
- Source
- Cancer Cell 31: 621-634.e6 (Journal)
- Registered Authors
- Hurlstone, Adam
- Keywords
- TAZ, TIAM1, WNT, YAP, cell migration, colorectal cancer, intestinal tumorigenesis, invasion, malignant progression
- MeSH Terms
-
- Phosphoproteins/genetics
- Phosphoproteins/metabolism*
- Intracellular Signaling Peptides and Proteins/metabolism*
- Mice, 129 Strain
- Cell Nucleus/metabolism
- Mice, Inbred C57BL
- Gene Expression Regulation, Neoplastic
- Humans
- Guanine Nucleotide Exchange Factors/deficiency
- Guanine Nucleotide Exchange Factors/genetics
- Guanine Nucleotide Exchange Factors/metabolism*
- Genetic Predisposition to Disease
- Active Transport, Cell Nucleus
- Zebrafish/embryology
- Proteolysis
- Transcription, Genetic
- Wnt Signaling Pathway
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism*
- Colorectal Neoplasms/pathology
- Caco-2 Cells
- Intestinal Mucosa/metabolism*
- Intestinal Mucosa/pathology
- Transfection
- Mice, Knockout
- Animals
- Cytoplasm/metabolism
- Epithelial Cells/metabolism*
- Epithelial Cells/pathology
- RNA Interference
- Neoplasm Invasiveness
- Cell Movement*
- Phenotype
- beta-Transducin Repeat-Containing Proteins/genetics
- beta-Transducin Repeat-Containing Proteins/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism*
- Cell Proliferation
- Epithelial-Mesenchymal Transition
- PubMed
- 28416184 Full text @ Cancer Cell
Citation
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. 31:621-634.e6.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping