The logic of TGFβ signaling

Abstract

The identification of the TGFb cytokine signaling pathway, including membrane receptor serine/threonine kinases and Smad transcription factors as their substrates, has allowed the delineation of a process for conversion of these signals into programs of gene activation and repression that underlie critical cell fate and developmental decisions. The deconstruction of one of these responses -the cell cycle arrest response -into its elemental molecular parts has shed light into the mechanisms used by tumors to evade surveillance and cause metastasis.

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

“…If this complex does not enter the nucleus, it cannot bind to transcriptional co-activators and DNA to regulate the expression of downstream genes, including ␣-SMA and collagen I. 20,21 Aside from phosphorylation by the activated TGF␤ receptor complex, site-specific phosphorylation of Smad2/3 can also occur by a variety of other kinases and has been shown, depending on the context, to augment or interfere with downstream Smad signaling. 41 This serves as a convergence point for different signaling pathways and is largely responsible for the diverse, context-specific effects of TGF␤1 signaling.…”

“…21 This association allows for translocation of the Smad2/3/4 complex to the nucleus and initiation of TGF␤1-induced transcriptional responses. 20,21 Although the overall mechanism of TGF␤1 signaling has been well studied, unrecognized regulatory factors that modulate the pathway may remain. This study is the first to suggest that the aryl hydrocarbon receptor (AhR) ligand 2-(1=H-indole-3=-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) may play such a role.…”

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

“…The transforming growth factor (TGF)-␤ superfamily encompasses structurally related proteins that include TGF-␤ isoforms, activins, inhibins, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). Isoforms TGF-␤1, -␤2, and -␤3 regulate processes of development, cell proliferation, and extracellular matrix production, typically by means of binding to three high-affinity cell surface receptors: TGF-␤ type I (TGF-␤RI), type II (TGF-␤RII), and type III receptors (Massague, 1998;Massague and Gomis, 2006). Extracellular matrix (ECM) proteins under TGF-␤ regulation include collagens, decorin, and fibronectin (Balza et al, 1988;Saed et al, 1999;Klein et al, 2002;Fu et al, 2005).…”

The origin of the myofibroblast in fibroproliferative vasculopathy: Does the endothelial cell steer the pathophysiology of systemic sclerosis?

“…Indeed, TGF␤ activation and signaling cascades are extremely complex and involve multiple intracellular molecules and pathways (21). Bioactive TGF␤ in a dimeric form binds to a constitutively active serine/ threonine transmembrane kinase known as TGF␤ receptor type II (TGF␤RII).…”

“…The classic pathway of TGF␤ signal transduction into the cell nucleus involves the ligand-bound TGF␤RII, which recruits and then transphosphorylates TGF␤RI. Signaling from phosphorylated TGF␤RI to the nucleus then may occur through the Smad family of proteins or through different nonSmad pathways, such as the activation of the nonreceptor protein tyrosine kinase c-Abl (21,22).…”