The Transforming Growth Factor Beta (TGF-β) family is a key group of growth and differentiation factors with crucial roles in various biological processes in mammals. This family consists of 33 genes that encode both homodimers and heterodimers, essential for cell proliferation, differentiation, wound healing, immune regulation, and a range of pathological conditions. The complexity of the TGF-β family is evident not only in the diversity of its members but also in their different roles and regulatory mechanisms across various biological contexts.

The significance of the TGF-β family is highlighted by its widespread expression and functional diversity. These factors are found in nearly all mammalian tissues and are vital for processes such as embryonic development, tissue repair, immune regulation, and inflammatory responses in adults. Moreover, the TGF-β family is closely linked to the development of major diseases, including cancer, fibrosis, and cardiovascular disorders.

Members of the TGF-β Family

In mammals, the 33 genes encoding TGF-β family polypeptides are categorized into several subgroups, including three TGF-β isoforms (TGF-β1, TGF-β2, TGF-β3), inhibins, Nodal proteins, Bone Morphogenetic Proteins (BMPs), and Growth and Differentiation Factors (GDFs). These polypeptides usually exist as homodimers, but some also exhibit biological activity as heterodimers. For instance, TGF-β1, TGF-β2, and TGF-β3 share a high structural similarity, consisting of 112 amino acids, and have overlapping biological functions. However, they show different expression patterns and functional differences across various tissues and cell types.

Figure 1. Phylogenetic tree of human TGF-β family polypeptides showing their evolutionary relationships. (Morikawa M, et al., 2016)

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1. TGF-β Isoforms

TGF-β1, TGF-β2, and TGF-β3 are the most well-known members of the TGF-β family. They play critical roles in cell growth, differentiation, apoptosis, and matrix production. Although these isoforms are highly similar in structure, they differ in tissue specificity, developmental regulation, and functions in disease. TGF-β1 is expressed in most cells, especially in immune cells and fibroblasts, and is crucial for immune regulation and fibrosis promotion. TGF-β2 is primarily involved in embryonic development, essential for cell differentiation and organ formation. TGF-β3 plays a significant role in oral and facial development and wound healing, with some overlapping functions with TGF-β1 and TGF-β2 but also unique regulatory effects.

2. Inhibins and Nodal Proteins

The inhibin family includes activins A, B, and AB, which play key roles in reproductive regulation, embryonic development, and immune modulation. Nodal proteins are crucial for left/right asymmetry formation during early embryonic development. Inhibins affect reproductive processes by regulating follicle-stimulating hormone (FSH) secretion, while Nodal proteins primarily regulate cell fate determination and body axis formation during embryonic development.

3. Bone Morphogenetic Proteins (BMPs)

BMPs constitute an important subgroup of the TGF-β family, involved in bone and cartilage formation and playing significant roles in embryonic development and tissue regeneration. BMPs include BMP2, BMP4, and BMP6, which are essential not only in bone and cartilage tissues but also in the development and repair of kidneys, heart, and nervous system. BMPs regulate target gene expression through specific receptor binding, activating Smad and non-Smad signaling pathways.

4. Growth and Differentiation Factors (GDFs)

GDFs, including GDF1, GDF5, and GDF9, are involved in various biological processes such as embryonic development, skeletal formation, and nervous system development. GDF5 is critical for bone joint development and regeneration, while GDF9 plays a key role in ovarian function regulation and follicle development.

Figure 2. Diagram showing the selective binding interactions of TGF-β superfamily receptors. (Gu S, et al., 2018)

Molecular Mechanisms of TGF-β Signaling Pathways

The TGF-β family signaling pathway involves several critical steps, including ligand-receptor binding, downstream signal activation, and regulation of nuclear transcription factors. At the heart of this process are the Smad proteins. The signaling begins with the formation of receptor complexes; upon ligand binding, the type II receptor activates the type I receptor, which in turn phosphorylates downstream Smad proteins. In mammalian cells, TGF-β and inhibins typically lead to the phosphorylation of Smad2 and Smad3, while BMPs phosphorylate Smad1, Smad5, and Smad8.

These phosphorylated receptor-regulated Smads (R-Smads) then form complexes with the co-Smad (such as Smad4) and translocate to the nucleus to regulate specific target genes. Additionally, TGF-β family proteins can influence cellular behavior through the activation of the PI3K-Akt and MAP kinase pathways, though these are usually less dominant compared to the Smad-dependent pathways.

Figure 3. Synthesis and release of active TGF-β. (Batlle E, et al., 2019)

1. Smad-Dependent TGF-β Signaling Pathways

The Smad protein family is a core component of the TGF-β signaling pathway, playing a crucial role in signal transduction. Smad proteins are classified into three types: R-Smads (such as Smad1, 2, 3, 5, 8), Co-Smads (such as Smad4), and I-Smads (such as Smad6, 7). R-Smads are phosphorylated upon receptor activation and then associate with Co-Smads to form complexes that move to the nucleus to regulate target gene transcription. I-Smads inhibit TGF-β signaling by competing with R-Smads for receptor binding, thus negatively regulating TGF-β signals.

Smad proteins precisely regulate TGF-β target gene expression through interactions with nuclear transcription factors, co-activators, or co-repressors. The diversity and complexity of these nuclear regulatory factors provide TGF-β signaling with great flexibility, allowing it to perform different functions in various biological contexts. For example, Smad3 can bind to the transcription factor AP-1 to enhance the transcriptional activity of certain genes, whereas in other contexts, Smad3 interacts with transcriptional repressor Ski to inhibit specific gene expression.

2. Non-Smad-Dependent TGF-β Signaling Pathways

Beyond the classical Smad-dependent pathways, TGF-β family members can regulate cellular behavior through various non-Smad-dependent signaling pathways. For instance, TGF-β can enhance cell survival and growth by activating the PI3K-Akt pathway, which plays a crucial role in promoting cell survival by inhibiting apoptotic factors such as Bad and Caspase-9. Additionally, TGF-β influences cell proliferation, differentiation, and stress responses through MAP kinase pathways, including ERK, JNK, and p38 MAPK. These non-Smad pathways significantly shape the overall impact of TGF-β signaling depending on the biological context. Furthermore, TGF-β can affect cytoskeletal reorganization and cell migration by activating Rho family GTPases, which are essential for processes such as wound healing and tumor metastasis.

3. The Dual Regulatory Role of TGF-β

TGF-β's role has evolved from being perceived merely as a growth factor to a complex regulator with dual functions depending on the context. It can inhibit cell proliferation in some environments while promoting it in others. This duality is influenced by cell type, microenvironment, and the interplay of various signaling pathways.

In epithelial and immune cells, TGF-β typically acts as an inhibitor of proliferation and a promoter of differentiation. It helps maintain tissue homeostasis and normal immune function by regulating a range of downstream signaling molecules. TGF-β blocks cell cycle progression and guides cells toward specific differentiation paths through both Smad-dependent and non-Smad-dependent mechanisms. For example, in immune cells, TGF-β suppresses T cell proliferation and encourages the differentiation of regulatory T cells (Tregs), contributing to an immunosuppressive effect.

In mesenchymal cells, TGF-β exhibits complex effects. It stimulates cell proliferation and supports cell migration and tissue repair by modulating extracellular matrix formation and remodeling. Additionally, under specific conditions, TGF-β can drive tumor progression and metastasis through various signaling pathways. Consequently, TGF-β is frequently associated with tissue repair, fibrosis, and cancer progression in mesenchymal cells.

TGF-β and Disease

1. TGF-β and Fibrosis

Fibrosis is a classic pathological manifestation of abnormal TGF-β signaling activation. During fibrosis, TGF-β causes excessive extracellular matrix deposition and irreversible tissue damage by activating fibroblast proliferation, promoting matrix protein synthesis, and inhibiting the expression of matrix-degrading enzymes. For example, in liver fibrosis, TGF-β activates hepatic stellate cells (HSCs) and promotes their secretion of large amounts of collagen, leading to liver structural damage and functional decline.

In pulmonary fibrosis, TGF-β controls the activation and proliferation of pulmonary fibroblasts, resulting in excessive accumulation of extracellular matrix and damage to alveolar structures. This process is driven by abnormal activation of the TGF-β/Smad signaling pathway and may be further worsened by non-Smad pathways, such as the PI3K-Akt and MAPK pathways.

2. TGF-β and Cardiovascular

TGF-β plays a crucial regulatory role in the cardiovascular system, and the dysregulation of its signaling pathways is closely related to the development of various cardiovascular diseases. In atherosclerosis, TGF-β regulates the proliferation and migration of vascular smooth muscle cells and promotes extracellular matrix synthesis, leading to vascular wall hardening and decreased elasticity. Additionally, TGF-β affects the formation and stability of atherosclerotic plaques by suppressing inflammatory responses of macrophages and other immune cells.

In myocardial fibrosis, TGF-β drives the proliferation of cardiac fibroblasts and enhances collagen synthesis, leading to increased stiffness of the heart muscle and decreased contractile function. This not only disrupts the heart's normal function but can also contribute to heart failure. The intricate role of TGF-β in cardiovascular health underscores its potential as a therapeutic target. However, its dual effects in various pathological conditions make the precise regulation of its signaling pathways a significant challenge.

3. TGF-β and Autoimmune Diseases

The role of TGF-β in autoimmune diseases is multifaceted. On one hand, TGF-β is crucial for maintaining immune balance by inhibiting the activation and differentiation of immune cells, especially through the promotion of regulatory T (Treg) cells. On the other hand, in some autoimmune diseases, disruptions in TGF-β signaling can result in a loss of immune tolerance, leading to increased inflammation and tissue damage.

For instance, in systemic lupus erythematosus (SLE), abnormalities in the TGF-β signaling pathway may lead to immune system dysregulation, promote the activation of autoreactive T cells, and exacerbate inflammatory responses. In multiple sclerosis (MS), TGF-β dysregulation may result in inflammatory damage to the central nervous system and destruction of myelin. Although the exact mechanisms of TGF-β in autoimmune diseases require further research, its potential as a therapeutic target has garnered significant attention.

The TGF-β gene family is essential for many biological processes and has a critical role in both normal physiology and disease. Its complex regulatory functions are mediated through Smad-dependent and non-Smad-dependent pathways. Disruption of TGF-β signaling can contribute to various conditions such as fibrosis, cancer, and cardiovascular diseases. Gaining a deeper understanding of how TGF-β signaling works and its different roles in health and disease offers valuable insights for developing targeted therapies and improving treatment strategies.