Abstract
Transforming growth factor-β (TGF-β) represents an evolutionarily conserved family of secreted polypeptide factors that regulate many aspects of physiological embryogenesis and adult tissue homeostasis. The TGF-β family members are also involved in pathophysiological mechanisms that underlie many diseases. Although the family comprises many factors, which exhibit cell type-specific and developmental stage-dependent biological actions, they all signal via conserved signaling pathways. The signaling mechanisms of the TGF-β family are controlled at the extracellular level, where ligand secretion, deposition to the extracellular matrix and activation prior to signaling play important roles. At the plasma membrane level, TGF-βs associate with receptor kinases that mediate phosphorylation-dependent signaling to downstream mediators, mainly the SMAD proteins, and mediate oligomerization-dependent signaling to ubiquitin ligases and intracellular protein kinases. The interplay between SMADs and other signaling proteins mediate regulatory signals that control expression of target genes, RNA processing at multiple levels, mRNA translation and nuclear or cytoplasmic protein regulation. This article emphasizes signaling mechanisms and the importance of biochemical control in executing biological functions by the prototype member of the family, TGF-β.
Highlights
Biological signals regulate every aspect of physiological development of multicellular organisms and are important for the communication and coordination of cellular, tissue, and organ functions throughout life [1]
This article will focus on the three transforming growth factor β (TGF-β) (TGF-β1, -β2, -β3), which are collectively referred as TGF-β, and with occasional references to other family members
At the level of extracellular ligand synthesis and activation-presentation to signaling receptors, a major current open area is the question of homodimeric and heterodimeric TGF-β family members
Summary
Biological signals regulate every aspect of physiological development of multicellular organisms and are important for the communication and coordination of cellular, tissue, and organ functions throughout life [1]. This is plausible, as protease activity may primarily work on the ECM components, e.g., LTBPs, leading to a first intermediate with a more “accessible” LAP-mature TGF-β complex, to which integrin can complete the activation process (Figure 2) Another exciting possibility worth scrutinizing further and via structural analysis of the relevant components is the delivery of active mature TGF-β directly on the surface of its signaling receptors or possibly on the surface of a coreceptor that mediates ligand presentation to the signaling receptors. TGF-β complex, to which integrin can complete the activation process (Figure 2) Another exciting possibility worth scrutinizing further and via structural analysis of the relevant components Biomisoltehcueledse2l0i2v0e,r1y0,o4f8a7ctive mature TGF-β directly on the surface of its signaling receptors or possibly o5nof 38 the surface of a coreceptor that mediates ligand presentation to the signaling receptors. Receptor oligomerization is of great importance for transmission of signals by TGF-β, a process that is further regulated by the association of the signaling receptor with a varBieiotmyoloecfucleos r2e02c0e,p10t,oxr proteins
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