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The transforming growth factor-β (TGF-β) superfamily is a class of regulatory cytokines ubiquitously found in eukaryotes with numerous family members. According to sequence structural features and biological functions, they are mainly divided into the TGF-β subfamily, Decapentaplegic/vg-1-related (DVR) subfamily, bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs), and activin/inhibin subfamily. Numerous studies have shown that members of the TGF-β superfamily can regulate a variety of physiological and biochemical processes, including extracellular matrix synthesis, embryonic development, organ formation, bone regeneration, tissue injury repair, immunity, and tumorigenesis. Studies have shown that aberrant expression of many ligands in the TGF-β superfamily is associated with developmental defects and human diseases.
Figure 1. The TGF-β superfamily. (Luo J, et al., 2019)
In mammals, TGF-β is the predominant cytokine in the fibrotic process of many tissues, and it can cause tissue and organ fibrosis through various signaling pathways such as p38α/β, Smad, protein kinase C (PKC), and mitogen-activated protein kinase MAPK, which affects the normal function of the body. TGF-β has a duality, which can either inhibit or promote the progression of cancer according to the staging of the disease. TGF-β activity is associated with developmental defects and human disease progression. Excessive TGF-β activity leads to immunosuppression that supports tumorigenesis, whereas insufficient activity leads to inflammation that induces fibrosis.
The DVR subfamily is the largest protein family in the TGF-β superfamily and consists mainly of BMP and GDF. Among them, BMP has a broad role in mammalian bone formation and development. During osteoblast differentiation and bone formation, the BMP signaling pathway cross-interacts with a variety of signaling pathways, including MAPK, Wnt, Hedgehog, Notch, and Fibroblast growth factor (FGF), to regulate the process of bone formation through different modes.
Activins and inhibins are important multifunctional growth and differentiation factors. In mammals, activins and inhibins are gonadal glycoprotein hormones that regulate gonadal development. However, recent findings have shown that activin/inhibin are also expressed in brain regions and central nervous system, suggesting that both may play intercellular and intracellular functions in multiple systems and that activin has a role in inhibiting the growth of multiple myeloma cells.
Nodal is an important regulator during mammalian embryonic development. As a key component in inducing early embryonic signaling, it is involved in a series of critical events such as the formation between mesoderm and endoderm, the determination of the position of anterior and posterior body axes, and the development of asymmetry between left and right body axes, etc. It has an important role in the early development of mammals. With the deepening of research, it has been further discovered that Nodal proteins can participate in the formation of human malignant tumors by promoting processes such as neoplastic tumor angiogenesis or malignant transformation of epithelial cells.
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