Since the discovery of the first member of TGF-β family in the early 1980s, related members have been identified and functionally characterized, in a superfamily now numbering more than 30 ligands in mammals. The TGF-β superfamily consists of a variety of proteins that regulate different physiological functions, including embryonic development, wound healing, chemotaxis and cell cycle regulation.
1. Components and Receptors of TGF-β Superfamily
2. Functions of TGF-β Superfamily
3. Common Characteristics of TGF-β Superfamily
Transforming growth factor β (TGF-β) superfamily is composed of many genes which coding secretory protein, mainly includes TGF-βs, the growth and differentiation factor (GDF) subfamily, an extensive bone morphogenetic protein (BMP) subfamily, activin, inhibin, anti-muller hormone, follistatin (FS), mullerian inhibitor substance (MIS), etc, as well as several additional members such as myostatin (Mstn) [1] cloned from mouse skeletal muscle. Specific components are shown in table 1:
Table 1 Ligand–receptor Usage in TGF-β Superfamily Signaling
Ligand | Type I receptor | Type II receptor | Co-receptors |
---|---|---|---|
Activin-βA | ALK4 | ACTRII and ACTRIIB | ND |
Activin-βB | ALK4 and ALK7 | ACTRII and ACTRIIB | ND |
Activin-βC | Unknown receptor | Unknown receptor | ND |
Activin-βE | Unknown receptor | Unknown receptor | ND |
AMH | ALK2 and ALK3 | AMHR2 | ND |
BMP10 | ALK1 | ACTRII and BMPR2 | ND |
BMP15 | ALK6 | BMPR2 | ND |
BMP2 | ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
BMP3 | No type I receptor | ACTRIIB | ND |
BMP3B(also known as GDF10) | ALK4 | ACTRII | ND |
BMP4 | ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
BMP5 | ALK2, ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
BMP6 | ALK2, ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
BMP7 | ALK2, ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
BMP8 | ALK2, ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
BMP9 | ALK1 | ACTRII and BMPR2 | ND |
GDF1 | ALK4 and ALK7 | ACTRII and ACTRIIB | CRIPTO and cryptic |
GDF11 | ALK4 and ALK5 | ACTRII and ACTRIIB | ND |
GDF15 | Unknown | TGFBR2 | ND |
GDF3 | ALK4 and ALK7 | ACTRII and ACTRIIB | CRIPTO and cryptic |
GDF5 (also known as BMP14) | ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
GDF6 | ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
GDF7 | ALK3 and ALK6 | ACTRII, ACTRIIB and BMPR2 | ND |
GDF9 | ALK4 | BMPR2 | ND |
Inhibin-α | No type I receptor | ACTRII | ND |
Myostatin(also known as GDF8) | ALK4 and ALK5 | ACTRIIB | ND |
Nodal | ALK4 and ALK7 | ACTRII and ACTRIIB | CRIPTO and cryptic |
TGFβ1 | ALK1‡and ALK5 | TGFBR2 | β-glycan and endoglin |
TGFβ2 | ALK1 and ALK5 | TGFBR2 | β-glycan and endoglin |
TGFβ3 | ALK1 and ALK5 | TGFBR2 | β-glycan and endoglin |
*The table is derived from the literature “Beyond TGF expression: roles of other TGF expression superfamily members in cancer”[2]. (ACTR, activin receptor; ALK, activin receptor-like kinase; AMH, anti‑mullerian hormone; AMHR, AMH receptor; BMP, bone morphogenetic protein; BMPR, BMP receptor; GDF, growth and differentiation factor; ND, not determined; TGF-β, transforming growth factor-β; TGFBR, TGF-β receptor. ‡ALK1 is endothelial specific).
TGF-β subfamily regulates a wide range of physiological functions, and plays an extremely important role in growth control and substance metabolism, the details are as follows:
TGF-β/activin-nodal: Inhibition of mitosis; induction of extracellular matrix synthesis; induction of dorsal mesoderm formation; induction of reticulocyte differentiation; inducing the release of follicular stimulating hormone. It has an important role in reproduction, embryo development and the immune response. It also is an important cytokine that regulates tissue inflammation and repair.
Activin is produced in gonads, pituitary and placenta. It is related to cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response and endocrine functions, and is involved in the regulation of female menstruation.
BMP/GDF/MIS: Inducing the formation of ventral mesoderm; inducing cartilage and bone formation; inducing apoptosis. BMPs regulate the transcription of multiple genes during biological development, including osteogenesis, neurogenesis and ventral mesodermal differentiation.
Take GDF11 for example, its main functions include:
(i) It regulates the development of embryonic nerve, bone[3], pancreas, kidney, teeth and other tissue organs.
(ii) It can improve aging hypertrophy of myocardium, skeletal muscle structure and function, and the ability of the brain cognitive[4].
(iii) It is involved in the occurrence and development of certain diseases.
(iv) It is involved in spinal formation[5].
(v) It regulates the development of fetal rat retina[6].
(vi) GDF11 and myostatin GDF8 regulate muscle growth[7]. Recent studies have shown that there is some debate about whether GDF11 promotes skeletal muscle regeneration[8].
The functions of Mstn:
(i) It plays an important role in regulating skeletal muscle growth[9]. In mice that Mstn was knocked out, muscle fibers developed extensive hyperplasia and hypertrophy. Cattle that had a mutation in the myostatin coding sequence also showed a significant increase in muscle mass, showing"double muscling". It can be seen that Mstn can inhibit the growth of skeletal muscle and is a negative regulator of skeletal muscle growth[10].
(ii) It inhibits the proliferation of myoblasts[9]. The inhibition of myoblast proliferation is determined by dose - and time-dependent methods [11].
(i) The relative molecular mass of the synthesized prerequisite molecules is relatively large, including the N-terminal signal peptide, the precursor region and the mature region. Precursor molecules can release active molecules by enzymatic cleavage.
(ii) The mature bioactive forms are homologous or heterodimer. In most cases, these dimers are covalently linked by disulfide bonds between conserved Cys residues. Each ligand molecule contains seven highly conserved cysteine (Cys) residues, which are linked by disulfide bonds between the seventh Cys residues to form biologically active dimer (The disulfide bonds of GDF3H and GDF9 were missing, and the monomer was maintained by hydrophobic bonds).
TGF-β signaling pathway is a superfamily with a large number of multifunctional cytokines, and it was divided into two subfamilies based on the classification of the ligands: TGF-β/activin/nodal and BMP/GDF/MIS signaling pathways. To learn more about the TGF-β signaling pathway, please click this link: https://www.cusabio.com/c-20712.html
The receptors of activin (activin), nodals and GDF8 are ALK4, ALK5 and ALK7, which mainly phosphorylates Smad2 and Smad3[10].
The ligand BMP2, BMP7 and GDF5 bind to I receptor family of ALK2, ALK3 and ALK6, and finally phosphorylate Smad1, Smad5 and Smad8, and mediate BMP like signaling pathway[10].
There is mutual antagonism between TGF-β signaling pathway and BMP signaling pathways[12].
Type I and type II receptors are required for each ligand signaling pathway. For some ligands, co-receptors are also needed. This kind of co-receptor can provide the best binding site for ligand and type I, II receptor complex. The process of activating receptor complex: First, type II receptors are activated, and then type I receptors are phosphorylated. It provides a binding region for downstream substrate-receptor-regulated Smads (R-Smads). The substrate of receptor then binds to the Smad4 to form R-Smad-Smad4 complex that shuttles inside and outside the nucleus[7]. Therefore, Smad4 occupies a central position in all ligand signaling pathways[8-9]. The difference is that in TGF-β superfamily signals, BMPs and GDFs signal are mediated by Smad1, Smad5 and Smad8, while the TGF-β, activin and nodal signal mediated by Smad2 and Smad3.
The ligand BMP2, BMP7 and GDF5 bind to I receptor family of ALK2, ALK3 and ALK6, and finally phosphorylate Smad1, Smad5 and Smad8, and mediate BMP like signaling pathway[10].
(i) The related factors of cell proliferation cycle(Cyclins,CDKs and CDIs et al)
(ii) Transcription factors (c-myc, RB, c-fos, c-jun, myb and E2F)
(iii) Apoptosis-related factors (Bcl-2, Bax et al)
(iv) Tissue interstitial components
The expression of the members of the TGF-β superfamily is affected by some antagonistic substances.
BMP ligand antagonistic molecules: TSG, Nogginis.
The natural antagonists of GDF11: growth and differentiation related factor protein 1 (GASP-1); growth and differentiation related factor protein 2 (GASP-2); follistatin.
Myostatin inhibitor: the function of Mstn can be inhibited by its propeptide, follistatin, FL RG and other substances that block Mstn signal transduction, such as ActⅡR antagonist[13].
Various pathologies in adults may be considered diseases of abnormal development and differentiation. TGF-β family is important in both lineage selection and progression of differentiation. Therefore, TGF-β has an important role in the pathogenesis and regulation of diseases. Many diseases are associated with TGF-β.
POR (Poor ovarian response): At present, it is believed that the pathogenesis of POR is related to the TGF-β superfamily members. Further experimental studies on the TGF-β family and related pathways may provide more scientific and objective evidence for improving POR and play an important role in the treatment of infertility.
Tumor: TGF-β is an effective tumor suppressant at the initial stage of tumor formation, however, when tumor was formed, it promotes the growth and metastasis of the tumor.
Diabetic: Ziyadeh[14] overexpressed TGF-β in diabetic animals and find that the TGF-β receptor signaling system is triggered. The results showed that overactivity of the TGF-β system in the kidney is a crucial mediator of diabetic renal hypertrophy and mesangial matrix expansion.
Respiratory diseases: The transforming growth factor (TGF-β) cytokines also play a central role in development and progression of chronic respiratory diseases. TGF-β overexpression in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection[15]. Despite the overwhelming burden of respiratory diseases in the world, new pharmacological therapies have been limited in impact. So TGF-β inhibition as a therapeutic strategy carries great expectations.
Besides, TGF-β 1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans[16].
Recent research has focused on the following aspects:
(i) Related studies on TGF-β inhibitors and antibodies aiming to treat diseases by blocking TGF-β signal pathways, or to diagnose and treat diseases related to TGF-β through the specific recognition function of antibodies.
(ii) On the other hand, the study of TGF-β family related signaling pathway and its relationship with disease is still a hot topic. The main contents are as follows: The research progress of TGF-β in cervical cancer and tumors and urinary system[17], as well as in cardiac dysfunction[18].
(iii) There are also studies on the gene regulation of TGF-β superfamily, the effect of post-translational modification of other transcription factors on the regulation of cytokine genes of TGF-β family, and the regulation of transcription factors on the TGF-β signal transduction[19].
(iv) The role of follistatin and TGF-β superfamily in follicular atresia[20].
Application prospect of myostatin: Mstn is a negative regulator of muscle growth, Mstn removal can induce muscle cell hyperplasia and hypertrophy and muscle mass increase, so it has wide application prospect and commercial value in many aspects such as agriculture, fishery, animal husbandry and medicine. McPherron et al[20] found that Mstn inactivation can promote fat metabolism and sugar metabolism and partially inhibit the development of fat accumulation and hyperglycemia. Although its mechanism is unknown and has not been proved in the human body, Mstn can be used as a target for drug prevention and treatment of metabolic diseases such as obesity and diabetes.
With its excellent bone induction, BMP-2 plays an important role in fracture healing and the treatment of bone defects,it has been widely used in clinical practice. However, the clinical application of BMP-2 also has many complications. How to reduce the complications of clinical application of BMP-2 should be the main research direction in the future.
TGF-β has the functions of accelerating fracture healing, guiding skull defect healing, stimulating bone trabecula ossification and bone cortex formation. It is expected to be used in clinical practice to promote the reconstruction of various bone defects. However, as it is a polypeptide, it is easy to diffuse and decompose, so it needs to be combined with the carrier. At present, the most widely used carriers are: collagen, calcium phosphate ceramics, de-mineralized bone and freeze-dried de-mineralized bone, polyester, hyaluronic acid, implant and composite carriers.
References
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[21] McPherron A. C, Lee S.J. Suppression of body fat accumulation in myostatin-deficient mice [J]. Journal of Clinical Investigation, 2002, 109(5): 595-601.
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