Latent transforming growth factor-β: Structural features and mechanisms of activation

Abstract

Transforming growth factor-beta are cytokines with a wide range of biological effects. They play a pathologic role in inflammatory and fibrosing diseases such as nephrosclerosis. TGF-beta s are secreted in a latent form due to noncovalent association with latency associated peptide (LAP), which is a homodimer formed from the propeptide region of TGF-beta. LAP is disulfide linked to another protein, latent TGF-beta binding protein (LTBP). LTBP has features in common with extracellular matrix proteins, and targets latent TGF-beta to the matrix. Activation of latent TGF-beta can be accomplished in vitro by denaturing treatments, plasmin digestion, ionizing radiation and interaction with thrombospondin. The mechanisms by which latent TGF-beta is activated physiologically are not well understood. Results to date suggest an important role for proteases, particularly plasmin, although other mechanisms probably exist. A general model of activation is proposed in which latent TGF-beta is released from the extracellular matrix by proteases, localized to cell surfaces, and activated by cell-associated plasmin.

CITED1 homozygous null mice display aberrant pubertal mammary ductal morphogenesis

“…Thrombospondin-1 is an adhesive glycoprotein component of the extracellular matrix (Sid et al, 2004). It binds and activates latent TGFb (Negoescu et al, 1995;Munger et al, 1997). Quantitative real-time RT-PCR analysis confirmed that the expression of both amphiregulin and thrombospondin-1 parallels the expansion of the ductal tree at puberty in a similar way to CITED1 (compare Figure 5B (a), (c) to Figure 1b).…”

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

“…20 Activation can be achieved by multiple tissue-and disease-specific mechanisms, including modification of the latent complex by reactive oxygen species, proteolysis, integrin binding, cellular contractility, and shear forces, or through binding to thrombospondin 1 (TSP1). [21][22][23][24] We identified the role of TSP1 as a major physiologic activator of latent TGF-␤.…”

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

“…Latent-TGFβ1 must undergo cleavage from this complex in order to become activated. LTBP targets latent TGFβ1 to the extracellular matrix, where it interacts with the insulin-like growth factor II receptor (IGFIIR), itself a putative tumour suppressor gene (Munger et al, 1997). It is thought that IGFIIR orientates latent-TGFβ1 for proteolytic cleavage.…”