TGF-β Family Ligands and Receptor

TGF-β: A Key Regulator of Cell Growth and Differentiation

Transforming growth factor-β (TGF-β) is a member of the TGF-β superfamily that plays a crucial role in regulating cellular growth and differentiation processes. Along with activins, inhibitors, Mullerian inhibitor substances (MIS), and bone morphogenetic proteins (BMPs), TGF-β forms a diverse family of signaling molecules. The name "TGF-β" stems from its ability to transform the growth characteristics of fibroblasts, enabling them to grow in agar medium and override density-dependent growth inhibition, when combined with epidermal growth factor (EGF). Initially identified in BSC-1 renal epithelial cells of African green monkeys, TGF-β has been recognized as a growth inhibitor.

Production and Activation of TGF-β

(1) Secretion of Inactive TGF-β: Various cells in the body have the ability to secrete inactive TGF-β. In laboratory settings, this inactive form, known as latency-associated peptide (LAP), can be transiently activated by acid. In the body, acidic environments can be found near fractures and healing wounds, facilitating the activation of the TGF-β complex. Tissues with active cell differentiation, such as osteoblasts, hematopoietic cells in the kidney, bone marrow, and fetal liver, generally exhibit higher levels of TGF-β. Human platelets and mammalian bone contain the highest levels of TGF-β1, while porcine platelets and mammalian bone have the highest levels of TGF-β2. TGF-β3 is primarily produced by mesenchymal cells.

(2) Enhanced Production by Activated T and B Cells: Upon activation, T and B cells significantly increase their production of TGF-β compared to resting cells.

(3) TGF-β Expression in Tumor Cells: TGF-β mRNA can be detected in almost all tumor cells. Gliomas, in particular, have been found to secrete higher levels of TGF-β in vivo.

Classification of TGF-β Receptors

The TGF-β family consists of nearly 40 members in mammals, which can be categorized into three main subfamilies based on their homology: TGFβ subtypes (β1, β2, β3), Activin, and BMP. Each subfamily comprises multiple members that share structural similarities but exhibit distinct functions [1]. The signaling of the TGF-β family is mediated through receptors, which can be classified into three types based on their structural and functional characteristics: type I receptors (TβRI), type II receptors (TβRII), and type III receptors (TβRIII). These receptor types have molecular weights of 53 kDa, 70-80 kDa, and 280-330 kDa, respectively.

TβRI and TβRII are single transmembrane serine/threonine kinase receptors that possess intrinsic kinase activity, playing a crucial role in TGF-β signal transduction. The extracellular regions of type I and type II receptors share similar structural features, characterized by a conserved sequence containing 5 cysteines near the N-terminal position. This conserved sequence is unique to these receptors and is not found in other serine/threonine kinases, suggesting its involvement in TGF-β binding. Both type I and type II TGF-β receptors are glycoproteins, with a higher affinity for TGF-β1 (10-80 times greater) compared to TGF-β2. TβRIII, also known as Endoglin or CD105, is a proteoglycan. Although it is a transmembrane protein, its intracellular segment lacks kinase activity and does not directly participate in signal transduction. TβRIII primarily regulates the binding of TGF-β to the signaling receptors. It exhibits similar affinity for TGF-β1, TGF-β2, and TGF-β3, with TGF-β1 and TGF-β3 being its main ligands.

TGF-β Signaling Pathway

The TGF-β (transforming growth factor-β) signaling pathway plays a crucial role in regulating stem cell activity and organ formation. Dysregulation of this pathway can lead to spontaneous development of various cancers, highlighting the integral role of TGF-β-mediated stem cell regulation in cancer formation. The TGF-β superfamily encompasses nearly 30 growth and differentiation factors, including TGF-βs, activins, inhibitors, and bone morphogenetic proteins (BMPs). Downstream of the TGF-β superfamily, multiple SMAD proteins act as transmembrane receptors that play a vital role in transmitting signals and undergo precise regulation at various levels.

Upon binding of TGF-β to the TGF-β type II receptor (TGF-βRII), a dimer receptor complex is formed and activated. TGF-βRII phosphorylates the glycine-serine rich region (GS sequence) of the TGF-β type I receptor (TGF-βRI), thereby activating its serine/threonine activity. Subsequently, the activated TGF-βRI phosphorylates receptor-associated SMAD proteins.

Clinical Significance of TGF-β

TGF-β (transforming growth factor-β) holds significant clinical importance and plays a pivotal role in the development and treatment of numerous diseases.

1. Tumor Therapy: TGF-β has a complex role in tumor occurrence, growth, and metastasis. It suppresses immune cell activity, impeding tumor immune surveillance. Additionally, TGF-β promotes tumor cell invasion, metastasis, immunosuppression, and angiogenesis in the tumor microenvironment. Targeting the TGF-β signaling pathway through drug intervention has become a promising avenue for tumor treatment, aiming to inhibit tumor growth and progression by blocking the effects of TGF-β.
2. Treatment of Fibrotic Diseases: TGF-β plays a crucial role in fibrotic diseases, including liver fibrosis, lung fibrosis, and kidney fibrosis. It regulates the synthesis and deposition of extracellular matrix, promoting fibrous tissue proliferation and remodeling. Interfering with the TGF-β signaling pathway can reduce fibrotic tissue formation, thereby halting the progression of fibrotic diseases.
3. Immunomodulation: TGF-β exerts a significant regulatory effect on the immune system. It inhibits immune cell activity, modulates immune cell differentiation and function, and contributes to immune tolerance maintenance. Consequently, targeting the TGF-β signaling pathway in the treatment of autoimmune diseases may help restore immune balance and suppress excessive immune responses.
4. Tissue Repair and Regeneration: TGF-β plays a crucial role in tissue repair and regeneration processes, including wound healing, bone regeneration, and nerve regeneration. By regulating cell proliferation, differentiation, and matrix synthesis, TGF-β promotes the repair and regeneration of damaged tissues.

TGF-β Summary

In summary, TGF-β serves as a critical cytokine that significantly influences various biological processes. Extensive research on the TGF-β signaling pathway is crucial for understanding its involvement in normal physiological functions and disease development. Moreover, it holds the potential to unveil novel therapeutic strategies and targets for the treatment of related diseases.

References:
[1] Heldin, C. H. , &  Moustakas, A. . (2016). Signaling Receptors for TGF-beta Family Members.
[2] Sulaiman, A. ,  Chambers, J. ,  Chilumula, S. C. ,  Vinod, V. ,  Kandunuri, R. , &  Mcgarry, S. , et al. (2022). At the intersection of cardiology and oncology: tgfβ as a clinically translatable therapy for tnbc treatment and as a major regulator of post-chemotherapy cardiomyopathy. Cancers, 14(6), 1577.