IDENTIFICATION OF A STRUCTURAL DOMAIN THAT DISTINGUISHES THE ACTIONS OF THE TYPE-1 AND TYPE-2 ISOFORMS OF TRANSFORMING GROWTH-FACTOR-BETA ON ENDOTHELIAL-CELLS

A chimeric transforming growth factor-beta (TGF-beta) molecule has been synthesized to map the amino acids responsible for the substantially greater activity of TGF-beta-1 than TGF-beta-2 on growth and migration of endothelial cells. This chimera consists of a dimer of a monomeric unit composed of amino acids 1-39 of TGF-beta-2, 40-82 of TGF-beta-1, and 83-112 of TGF-beta-2. Structural identity of the purified recombinant protein has been confirmed by immunoblotting and NH2-terminal sequencing. The biological potency of the TGF-beta-2-1-2 chimera was equal to that of TGF-beta-1 in inhibition of growth of both fetal bovine heart endothelial cells and rat epididymal fat pad microvascular endothelial cells. Similarly, the TGF-beta-2-1-2 chimera was nearly equivalent to TGF-beta-1 and at least 10-fold more active than TGF-beta-2 in inhibiting migration of bovine aortic endothelial cells. These results identify the sequence between amino acids 40-82 as an important region within TGF-beta that functions to specify a TGF-beta-1- or TGF-beta-2-like activity.