TGFβ(1 )signaling via α(V)β(6 )integrin

BACKGROUND: Transforming growth factor β(1 )(TGFβ(1)) is a potent inhibitor of epithelial cell growth, thus playing an important role in tissue homeostasis. Most carcinoma cells exhibit a reduced sensitivity for TGFβ(1 )mediated growth inhibition, suggesting TGFβ(1 )participation in the development of these cancers. The tumor suppresor gene DPC4/SMAD4, which is frequently inactivated in carcinoma cells, has been described as a key player in TGFβ(1 )mediated growth inhibition. However, some carcinoma cells lacking functional SMAD4 are sensitive to TGFβ(1 )induced growth inhibition, thus requiring a SMAD4 independent TGFβ(1 )pathway. RESULTS: Here we report that mature TGFβ(1 )is a ligand for the integrin α(V)β(6), independent of the common integrin binding sequence motif RGD. After TGFβ(1 )binds to α(V)β(6 )integrin, different signaling proteins are activated in TGFβ(1)-sensitive carcinoma cells, but not in cells that are insensitive to TGFβ(1). Among others, interaction of TGFβ(1 )with the α(V)β(6 )integrin resulted in an upregulation of the cell cycle inhibitors p21/WAF1 and p27 leading to growth inhibition in SMAD4 deleted as well as in SMAD4 wildtype carcinoma cells. CONCLUSIONS: Our data provide support for the existence of an alternate TGFβ(1 )signaling pathway that is independent of the known SMAD pathway. This alternate pathway involves α(V)β(6 )integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFβ(1)-sensitive tumor cells. The combined action of these two pathways seems to be necessary to elicit a complete TGFβ(1 )signal.