1. TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells.
- Author
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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, and Malliri A
- Subjects
- Active Transport, Cell Nucleus, Adaptor Proteins, Signal Transducing genetics, Animals, Caco-2 Cells, Cell Cycle Proteins, Cell Nucleus metabolism, Cell Proliferation, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Cytoplasm metabolism, Epithelial Cells pathology, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Guanine Nucleotide Exchange Factors deficiency, Guanine Nucleotide Exchange Factors genetics, Humans, Intestinal Mucosa pathology, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Invasiveness, Phenotype, Phosphoproteins genetics, Proteolysis, RNA Interference, T-Lymphoma Invasion and Metastasis-inducing Protein 1, Trans-Activators, Transcription Factors, Transcription, Genetic, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Transfection, Wnt Signaling Pathway, YAP-Signaling Proteins, Zebrafish embryology, beta-Transducin Repeat-Containing Proteins genetics, beta-Transducin Repeat-Containing Proteins metabolism, Adaptor Proteins, Signal Transducing metabolism, Cell Movement, Colorectal Neoplasms metabolism, Epithelial Cells metabolism, Guanine Nucleotide Exchange Factors metabolism, Intestinal Mucosa metabolism, Intracellular Signaling Peptides and Proteins metabolism, Phosphoproteins metabolism
- 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., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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