A specialized integrin-binding motif enables proTGF- beta 2 activation by integrin alpha V beta 6 but not alpha V beta 8

Activation of latent transforming growth factor (TGF)-beta 2 is incompletely understood. Unlike TGF-beta 1 and beta 3, the TGF-beta 2 prodomain lacks a seven-residue RGDLXX (L/I) integrin-recognition motif and is thought not to be activated by integrins. Here, we report the surprising finding that TGF-beta 2 contains a related but divergent 13-beta residue integrin-beta recognition motif (YTSGDQKTIKSTR) that specializes it for activation by integrin alpha V beta 6 but not alpha V beta 8. Both classes of motifs compete for the same binding site in aV beta 6. Multiple changes in the longer motif underlie its specificity. ProTGF-beta 2 structures define interesting differences from proTGF-beta 1 and the structural context for activation by alpha V beta 6. Some integrin-independent activation is also seen for proTGF-beta 2 and even more so for proTGF-beta 3. Our findings have important implications for therapeutics to alpha V beta 6 in clinical trials for fibrosis, in which inhibition of TGF-beta 2 activation has not been anticipated.