TGF-β/Smad Signaling Through DOCK4 Facilitates Lung Adenocarcinoma Metastasis

Genes Dev. 2015 Feb 1;29(3):250-61. doi: 10.1101/gad.248963.114.

Abstract

The mechanisms by which TGF-β promotes lung adenocarcinoma (ADC) metastasis are largely unknown. Here, we report that in lung ADC cells, TGF-β potently induces expression of DOCK4, but not other DOCK family members, via the Smad pathway and that DOCK4 induction mediates TGF-β's prometastatic effects by enhancing tumor cell extravasation. TGF-β-induced DOCK4 stimulates lung ADC cell protrusion, motility, and invasion without affecting epithelial-to-mesenchymal transition. These processes, which are fundamental to tumor cell extravasation, are driven by DOCK4-mediated Rac1 activation, unveiling a novel link between TGF-β and Rac1. Thus, our findings uncover the atypical Rac1 activator DOCK4 as a key component of the TGF-β/Smad pathway that promotes lung ADC cell extravasation and metastasis.

Keywords: DOCK180 proteins; Rac1; TGF-β signaling; cell motility; lung adenocarcinoma metastasis; tumor cell extravasation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / physiopathology*
  • Adenocarcinoma of Lung
  • Animals
  • Cell Line, Tumor
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / physiopathology*
  • Mice
  • Neoplasm Metastasis
  • Signal Transduction*
  • Smad Proteins / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • DOCK4 protein, human
  • GTPase-Activating Proteins
  • Smad Proteins
  • Transforming Growth Factor beta