Autocrine transforming growth factor-β signaling mediates Smad-independent motility in human cancer cells

Nancy Dumont, Andrei V. Bakin, Carlos L. Arteaga

Research output: Contribution to journalArticle

131 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) is a pleiotropic growth factor that plays a critical role in modulating cell growth, differentiation, and plasticity. There is increasing evidence that after cells lose their sensitivity to TGF-β-mediated growth inhibition, autocrine TGF-β signaling may potentially promote tumor cell motility and invasiveness. To understand the molecular mechanisms by which autocrine TGF-β may selectively contribute to tumor cell motility, we have generated MDA-MB-231 breast cancer cells stably expressing a kinase-inactive type II TGF-β receptor (TβRII-K277R). Our data indicate that TβRII-K277R is expressed, can associate with the type I TGF-β receptor, and block both Smad-dependent and -independent signaling pathways activated by TGF-β. In addition, wound closure and transwell migration assays indicated that the basal migratory potential of TβRII-K277R expressing cells was impaired. The impaired motility of TβRII-K277R cells could be restored by reconstituting TGF-β signaling with a constitutively active TGF-β type I receptor (ALK5TD) but not by reconstituting Smad signaling with Smad2/4 or Smad3/4 expression. In addition, the levels of ALK5TD expression sufficient to restore motility in the cells expressing TβRII-K277R were associated with an increase in phosphorylation of Akt and extracellular signal-regulated kinase 1/2 but not Smad2. These data indicate that different signaling pathways require different thresholds of TGF-β activation and suggest that TGF-β promotes motility through mechanisms independent of Smad signaling, possibly involving activation of the phosphatidylinositol 3-kinase/Akt and/or mitogen-activated protein kinase pathways.

Original languageEnglish (US)
Pages (from-to)3275-3285
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number5
DOIs
StatePublished - Jan 31 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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