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. 2017 May 8;31(5):621-634.e6. doi: 10.1016/j.ccell.2017.03.007. Epub 2017 Apr 13.

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: 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 Cycle Proteins
  • 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
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • Wnt Signaling Pathway
  • Zebrafish / embryology
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • BTRC protein, human
  • Cell Cycle Proteins
  • Guanine Nucleotide Exchange Factors
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • TIAM1 protein, human
  • Tiam1 protein, mouse
  • Transcription Factors
  • WWTR1 protein, human
  • Wwtr1 protein, mouse
  • YAP1 (Yes-associated) protein, human
  • Yap protein, mouse
  • beta-Transducin Repeat-Containing Proteins