Abstract
Transforming growth factor-beta (TGF-beta) is a bifunctional growth regulator. It inhibits growth of many cell types, including epithelial cells, but stimulates growth of others (e.g. fibroblasts). The active site on the TGF-beta molecule, which mediates its growth regulatory activity, has not been defined. Here, we show that antibody to a TGF-beta(1) peptide containing the motif WSLD (52nd to 55th amino acid residues) completely blocked both (125)I-TGF-beta(1) binding to TGF-beta receptors and TGF-beta(1)-induced growth inhibition in mink lung epithelial cells. Site-directed mutagenesis analysis revealed that the replacement of Trp(52) and Asp(55) by alanine residues diminished the growth inhibitory activity of TGF-beta(1) by approximately 90%. Finally, while wild-type TGF-beta(1) was able to stimulate growth of transfected NIH 3T3 cells, the double mutant TGF-beta(1) W52A/D55A was much less active. These results support the hypothesis that the WSLD motif is an active site of TGF-beta(1), which is important for growth inhibition of epithelial cells and growth stimulation of fibroblasts.
Highlights
Transforming growth factor- (TGF-)[1] is a family of 25-kDa structurally homologous dimeric proteins containing one interchain and four intrachain disulfide bonds (1–3)
We predicted that antibody raised to 125-(41– 65) containing this motif would block both TGF-1 binding to TGF- receptors and the biological activities of TGF-1
The effect of antibody to 125-(41– 65) on 125I-TGF-1 binding to TGF- receptors in Mv1Lu cells was determined
Summary
Transforming growth factor- (TGF-)[1] is a family of 25-kDa structurally homologous dimeric proteins containing one interchain and four intrachain disulfide bonds (1–3). We show that antibody to a TGF-1 peptide containing the motif WSLD (52nd to 55th amino acid residues) completely blocked both 125ITGF-1 binding to TGF- receptors and TGF-1-induced growth inhibition in mink lung epithelial cells.
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