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ZFIN ID: ZDB-PUB-170822-11
TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells
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.
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:
  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing/genetics
  • Adaptor Proteins, Signal Transducing/metabolism*
  • Animals
  • Caco-2 Cells
  • Cell Movement*
  • Cell Nucleus/metabolism
  • Cell Proliferation
  • Colorectal Neoplasms/genetics
  • Colorectal Neoplasms/metabolism*
  • Colorectal Neoplasms/pathology
  • Cytoplasm/metabolism
  • Epithelial Cells/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
  • Guanine Nucleotide Exchange Factors/metabolism*
  • Humans
  • Intestinal Mucosa/metabolism*
  • Intestinal Mucosa/pathology
  • Intracellular Signaling Peptides and Proteins/metabolism*
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Invasiveness
  • Phenotype
  • Phosphoproteins/genetics
  • Phosphoproteins/metabolism*
  • Proteolysis
  • RNA Interference
  • Transcription, Genetic
  • Transfection
  • Wnt Signaling Pathway
  • Zebrafish/embryology
  • beta-Transducin Repeat-Containing Proteins/genetics
  • beta-Transducin Repeat-Containing Proteins/metabolism
PubMed: 28416184 Full text @ Cancer Cell
FIGURES
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 ╬▓TrCP. 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.
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