ALK5 and ALK1 play antagonistic roles in transforming growth factor β-induced podosome formation in aortic endothelial cells

Mol Cell Biol. 2014 Dec;34(24):4389-403. doi: 10.1128/MCB.01026-14. Epub 2014 Sep 29.

Abstract

Transforming growth factor β (TGF-β) and related cytokines play a central role in the vascular system. In vitro, TGF-β induces aortic endothelial cells to assemble subcellular actin-rich structures specialized for matrix degradation called podosomes. To explore further this TGF-β-specific response and determine in which context podosomes form, ALK5 and ALK1 TGF-β receptor signaling pathways were investigated in bovine aortic endothelial cells. We report that TGF-β drives podosome formation through ALK5 and the downstream effectors Smad2 and Smad3. Concurrent TGF-β-induced ALK1 signaling mitigates ALK5 responses through Smad1. ALK1 signaling induced by BMP9 also antagonizes TGF-β-induced podosome formation, but this occurs through both Smad1 and Smad5. Whereas ALK1 neutralization brings ALK5 signals to full potency for TGF-β-induced podosome formation, ALK1 depletion leads to cell disturbances not compatible with podosome assembly. Thus, ALK1 possesses passive and active modalities. Altogether, our results reveal specific features of ALK1 and ALK5 signaling with potential clinical implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Activin Receptors / metabolism*
  • Animals
  • Aorta / cytology
  • Aorta / metabolism*
  • Cattle
  • Endothelial Cells / metabolism
  • Growth Differentiation Factor 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Smad Proteins, Receptor-Regulated / metabolism
  • Transforming Growth Factor beta / metabolism*

Substances

  • Growth Differentiation Factor 2
  • Receptors, Transforming Growth Factor beta
  • Smad Proteins, Receptor-Regulated
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Activin Receptors
  • Receptor, Transforming Growth Factor-beta Type I
  • Tgfbr1 protein, mouse