TGFβ1 signaling via αVβ6 integrin

Abstract

BackgroundTransforming growth factor β1 (TGFβ1) is a potent inhibitor of epithelial cell growth, thus playing an important role in tissue homeostasis. Most carcinoma cells exhibit a reduced sensitivity for TGFβ1 mediated growth inhibition, suggesting TGFβ1 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 TGFβ1 mediated growth inhibition. However, some carcinoma cells lacking functional SMAD4 are sensitive to TGFβ1 induced growth inhibition, thus requiring a SMAD4 independent TGFβ1 pathway.ResultsHere we report that mature TGFβ1 is a ligand for the integrin αVβ6, independent of the common integrin binding sequence motif RGD. After TGFβ1 binds to αVβ6 integrin, different signaling proteins are activated in TGFβ1-sensitive carcinoma cells, but not in cells that are insensitive to TGFβ1. Among others, interaction of TGFβ1 with the αVβ6 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.ConclusionsOur data provide support for the existence of an alternate TGFβ1 signaling pathway that is independent of the known SMAD pathway. This alternate pathway involves αVβ6 integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFβ1-sensitive tumor cells. The combined action of these two pathways seems to be necessary to elicit a complete TGFβ1 signal.