The Activation Sequence of Thrombospondin-1 Interacts with the Latency-associated Peptide to Regulate Activation of Latent Transforming Growth Factor-β

• Published in: The Journal of biological chemistry Vol. 274; no. 19; pp. 13586 - 13593
• Main Authors: Ribeiro, Solange M.F., Poczatek, Maria, Schultz-Cherry, Stacey, Villain, Matteo, Murphy-Ullrich, Joanne E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.05.1999
• Subjects: Amino Acid Sequence; Animals; Cattle; Cells, Cultured; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Humans; Peptide Fragments; Protein Binding; Protein Precursors; Proteins - isolation & purification; Proteins - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Thrombospondin 1 - chemistry; Thrombospondin 1 - isolation & purification; Thrombospondin 1 - metabolism; Thrombospondins - chemistry; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.19.13586

One of the primary points of regulation of transforming growth factor-β (TGF-β) activity is control of its conversion from the latent precursor to the biologically active form. We have identified thrombospondin-1 as a major physiological regulator of latent TGF-β activation. Activation is dependent on the interaction of a specific sequence in thrombospondin-1 (K412RFK415) with the latent TGF-β complex. Platelet thrombospon-din-1 has TGF-β activity and immunoreactive mature TGF-β associated with it. We now report that the latency-associated peptide (LAP) of the latent TGF-β complex also interacts with thrombospondin-1 as part of a biologically active complex. Thrombospondin·LAP complex formation involves the activation sequence of thrombospondin-1 (KRFK) and a sequence (LSKL) near the amino terminus of LAP that is conserved in TGF-β1–5. The interactions of LAP with thrombospondin-1 through the LSKL and KRFK sequences are important for thrombospondin-mediated activation of latent TGF-β since LSKL peptides can competitively inhibit latent TGF-β activation by thrombospondin or KRFK-containing peptides. In addition, the association of LAP with thrombospondin-1 may function to prevent the re-formation of an inactive LAP·TGF-β complex since thrombospondin-bound LAP no longer confers latency on active TGF-β. The mechanism of TGF-β activation by thrombospondin-1 appears to be conserved among TGF-β isoforms as latent TGF-β2 can also be activated by thrombospondin-1 or KRFK peptides in a manner that is sensitive to inhibition by LSKL peptides.