Abstract
Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell–matrix interactions, including thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, periostin, and fibulins. Fibulin family members consist of eight ECM glycoproteins characterized by a tandem array of calcium-binding epidermal growth factor-like modules and a common C-terminal domain. Fibulins not only participate in structural integrity of basement membrane and elastic fibers, but also serve as mediators for cellular processes and tissue remodeling as they are highly upregulated during embryonic development and certain disease processes, especially at the sites of epithelial–mesenchymal transition (EMT). Emerging studies have indicated a close relationship between fibulins and TGF-β signaling, but each fibulin plays a different role in a context-dependent manner. In this review, regulatory interactions between fibulins and TGF-β signaling are discussed. Understanding biological roles of fibulins in TGF-β regulation may introduce new insights into the pathogenesis of some human diseases.
Highlights
Transforming growth factor-β (TGF-β) is a multifunctional peptide growth factor that plays a vital role in regulating cell proliferation, differentiation, inflammation, angiogenesis, and tissue repair [1,2]
After mRNA translation, TGF-β precursor is processed and secreted into the extracellular matrix (ECM), where it stays as a latent form with TGF-β binding proteins (LTBP) and latency-associated protein (LAP) [10]
TGF-β has to be cleaved from this latent complex to become a biologically active form, and several proteases including plasmin, matrix metalloproteinase (MMP)-2, and MMP-9 have been identified as latent TGF-β activators [7,11,12]
Summary
Transforming growth factor-β (TGF-β) is a multifunctional peptide growth factor that plays a vital role in regulating cell proliferation, differentiation, inflammation, angiogenesis, and tissue repair [1,2]. Extracellular regulation of TGF-β ligand activation is mediated, in part, by certain ECM proteins via matrix–matrix interactions [18]. These proteins are called matricellular proteins, which do not contribute to the structural integrity of tissues but mainly play a functional role in activating tissue enzymes and proteases during tissue remodeling [19,20]. Thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, and periostin are known to modulate TGF-β activity [18,21] These ECM proteins regulate TGF-β activation and in turn may be regulated by TGF-β, providing complex cross-talks via matrix–matrix and cell–matrix interactions. Biological roles of fibulins will be discussed in conjunction with extracellular regulation of TGF-β in pathogenesis of certain human diseases
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