The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta

One of the primary points of regulation of transforming growth factor-beta (TGF-beta) activity is control of its conversion from the latent precursor to the biologically active form. We have identified thrombospondin-l as a m ajor physiological regulator of latent TGF-beta activation. Activation is d ependent on the interaction of a specific sequence in thrombospondin-l ((KR FK415)-R-412) with the latent TGF-beta complex. Platelet thrombospondin-1 h as TGF-beta activity and immunoreactive mature TGF-beta associated with it. We now report that the latency-associated peptide (LAP) of the latent TGF- beta complex also interacts with thrombospondin-l as part of a biologically active complex. Thrombospondin LAP complex formation involves the activati on sequence of thrombospondin-l (KRFK) and a sequence (LSKL) near the amino terminus of LAP that is conserved in TGF-beta(1-5). The interactions of LA P with thrombospondin-l through the LSKL and KRFK sequences are important f or thrombospondin-mediated activation of latent TGF-beta since LSKL peptide s can competitively inhibit latent TGF-beta activation by thrombospondin or KRFK-containing peptides. In addition, the association of LAP with thrombo spondin-1 may function to prevent the reformation of an inactive LAP TGF-be ta complex since thrombospondin-bound LAP no longer confers latency on acti ve TGF-beta. The mechanism of TGF-beta activation by thrombospondin-1 appea rs to be conserved among TGF-beta isoforms as latent TGF-beta(2) can also b e activated by thrombospondin-1 or KRFK peptides in a manner that is sensit ive to inhibition by LSKL peptides.