Thrombospondin-Dependent Activation of Latent TGF-β in Fibrosis and Disease

Abstract

TGF-β is a pleotrophic cytokine with effects on cell growth and survival, immune cell regulation and inflammation, and extracellular matrix remodeling. Its activity must be carefully regulated for homeostasis of the organism. Control of latent TGF-β activation is a major means of regulating appropriate levels of TGF-β activity. The matricellular protein, thrombospondin-1 (TSP1), is an important physiologic regulator of latent TGF-β activation. TSP1 binding to the latent complex through the lysine-arginine-phenylalanine-lysine (KRFK) sequence of TSP1 competes for binding of the leucineserine-lysine-leucine (LSKL) sequence in the latency associated peptide (LAP) of TGF-β to the mature domain of TGF-β, altering folding of the latent complex which renders TGF-β active. In this review, we discuss this and other mechanisms by which TSP1 induces activation of latent TGF-β. We also review the evidence for participation of TSP1 in the regulation of TGF-β activation in renal, pulmonary, hepatic, cardiovascular, and dermal fibrotic diseases. The use of peptide antagonists of TSP1-dependent TGF-β activation as a therapeutic strategy to treat fibrotic disease will be considered. The role of TSP1 in regulating TGF-β activity in cancer and wound healing and in host responses to infectious agents will also be discussed.