Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology.
Regulation of the activation of latent TGF-beta is essential for health as too much or too little TGF-beta activity can have serious, deleterious consequences. The processes that control conversion of the precursor to the biologically active form of TGF-beta in vivo are not well characterized. We have identified a mechanism for the activation of latent TGF-beta that involves binding of the secreted and extracellular matrix protein, thrombospondin-1 (TSP-1), to the latent precursor. Specific sequences in TSP-1 and in the precursor portion (the latency associate peptide-LAP) have been determined to be essential for activation of latent TGF-beta by TSP-1. It is thought that binding of TSP-1 to the latent complex induces a conformational rearrangement of the LAP in such a manner as to prevent the LAP from conferring latency on the mature domain of TGF-beta. A TSP-dependent mechanism of activation may be locally important during wound healing and in post-natal development of epithelial structures. The possible involvement of TSP-1 in TGF-beta activation during several disease processes is also discussed.
Murphy-Ullrich
J E
JE
Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, 35294-0019, USA. murphy@path.uab.edu
Poczatek
M
M
D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure; D015432:Glomerulonephritis, Membranoproliferative / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D051381:Rats; D013629:Tamoxifen / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000378:metabolism* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology; D053773:Transforming Growth Factor beta1; D014945:Wound Healing
D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013629:Tamoxifen