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.