Transforming Growth Factor-β Signaling Through the Smad Pathway: Role in Extracellular Matrix Gene Expression and Regulation

Abstract

Transforming growth factor (TGF)-beta represents a prototype of multifunctional cytokine. Its broad activities include, among others, context-specific inhibition or stimulation of cell proliferation, control of extracellular matrix (ECM) synthesis and degradation, control of mesenchymal-epithelial interactions during embryogenesis, mediation of cell and tissue responses to injury, control of carcinogenesis, and modulation of immune functions. Regulation of production and turnover of ECM components is essential for tissue homeostasis and function. TGF-beta exerts its effects on cell proliferation, differentiation, and migration in part through its capacity to modulate the deposition of ECM components. Specifically, TGF-beta isoforms have the ability to induce the expression of ECM proteins in mesenchymal cells, and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the ECM. Deregulation of these functions is associated with abnormal connective tissue deposition, as observed, for example, during scarring or fibrotic processes. In this review we discuss the current understanding of the signaling mechanisms used by TGF-beta to elicit its effects on target genes, focusing primarily on Smad proteins and their role in the transcriptional regulation of ECM gene expression. Other signaling mechanisms, such as the MAP/SAP kinase or Ras pathways, although potentially important for transmission of some of the TGF-beta signals, will not be described. Transforming growth factor-beta (TGF-beta) plays a critical role in the regulation of extracellular matrix gene expression. Its overexpression is believed to contribute to the development of tissue fibrosis. The recent identification of Smad proteins, TGF-beta receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, has increased our understanding of the molecular mechanisms underlying TGF-beta action. This review focuses primarily on the mechanisms underlying Smad modulation of gene expression and how they relate to wound healing. Potential implications for the development of therapeutic approaches against tissue fibrosis are discussed.

Proinflammatory cytokines TNF-α and IFN-γ alter laminin expression under an apoptosis-independent mechanism in human intestinal epithelial cells

“…The main functional target for TGF-␤ during intestinal inflammation appears to be the epithelial cell (20). Indeed, this multifunctional cytokine has been shown to exert a crucial function on epithelial healing after injury (42), in part through its capacity to modulate extracellular matrix molecule expression and regulation (55). In this study, treatment of HIEC with TGF-␤ significantly promotes laminin-5 and -10 production in epithelial cells.…”

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

“…S1). As TGF‐β pathway is the major regulator of ECM production (Verrecchia & Mauviel, 2002; Quan et al ., 2010), we confirmed that blocking of TGF‐β signaling by TGF‐β type I receptor kinase inhibitor (SB431542) resulted in significant reduction of Smad3 phosphorylation, type I collagen, fibronectin, and CTGF/CCN2 in constrained cultures (Fig. 2A).…”

“…The TGF‐β pathway is well established as a major regulator of ECM production (Varga, 2002; Verrecchia & Mauviel, 2002; Pohlers et al ., 2009; Quan et al ., 2010). It is regulated by a variety of mechanisms including ligand processing, phosphorylation, and inhibitory Smad proteins (Massague, 2012).…”

“…Interestingly, many of the dermal ECM‐related genes that are down‐regulated in aged human skin are regulated by the TGF‐β pathway (Verrecchia & Mauviel, 2002; Quan et al ., 2010). Importantly, components of the TGF‐β pathway itself are reduced in aged human skin (Quan et al ., 2010), raising the possibility that impairment of TGF‐β signaling may be a major contributor to reduced ECM production in aged skin.…”

FAK Is Required for TGFβ-induced JNK Phosphorylation in Fibroblasts: Implications for Acquisition of a Matrix-remodeling Phenotype

“…In vitro and in vivo studies have consistently shown that application of TGF␤ promotes ECM production and contraction, leading to granulation tissue deposition and the promotion of scarring (Roberts et al, 1986;Mori et al, 1999). Prior reports have focused on general TGF␤ signaling pathway, including TGF␤ receptors and Smads, in the production and remodeling of ECM (Verrecchia and Mauviel, 2002;Verrecchia et al, 2006). However, it is now appreciated that selective modulation of profibrotic signaling downstream of TGF␤ would be beneficial in promoting and controlling the wound healing and scarring while leaving other effects of TGF␤ unaltered (Leask et al, 2003;Leask and Abraham, 2004;Chen et al, 2006).…”