The overview of TGF-β signaling pathway


View:958 Time:2018-08-23


Transforming growth factor β signaling pathway is a series of signal transduction processes mediated by transforming growth factor. TGF-β signaling pathway plays a key role in cell proliferation, interstitial production, differentiation, apoptosis, embryonic development, organ formation, immune function and inflammatory response.

2. The members of TGF-β signaling pathway

The TGF-β signaling pathway involves receptors and some signal transduction molecules, as shown in the following table1:

Table 1 TGF-β signaling pathway Components

TGF β superfamily ligand Type II Receptor Type I receptor R-SMADs coSMAD Ligand inhibitors
Activin A ACVR2A ACVR1B (ALK4) SMAD2, SMAD3 SMAD4 Follistatin
GDF1 ACVR2A ACVR1B (ALK4) SMAD2,SMAD3 SMAD4 unknown
GDF11 ACVR2B ACVR1B (ALK4), TGFβRI (ALK5) SMAD2,SMAD3 SMAD4 unknown
Nodal ACVR2B ACVR1B (ALK4), ACVR1C (ALK7) SMAD2, SMAD3 SMAD4 Lefty
Bone morphogenetic proteins BMPR2 BMPR1A (ALK3), BMPR1B (ALK6) SMAD1,SMAD5,SMAD8 SMAD4 Noggin, Chordin, DAN
TGFβs TGFβRII TGFβRI (ALK5) SMAD2, SMAD3 SMAD4 LTBP1, THBS1, Decorin

Content of the Table 1 is derived from Wikipedia

3. The function of TGF-β signaling pathway

TGF-β plays a key role in the growth, development and differentiation of cells and tissues [14] and plays an important regulatory role in cell proliferation, interstitial production, differentiation, apoptosis, embryonic development, organ formation, immune function, inflammatory response and wound repair.

The immune function of TGF-β is mainly reflected in immunosuppression, TGF-β can inhibit the proliferation and differentiation of T and B lymphocytes. TGF-β can stimulate and inhibit the proliferation of cells, which depends on the type of cell and the state of differentiation. For example, TGF-β can promote the mitosis of osteoblasts and inhibit the growth of hepatocytes. In addition, TGF-β has a certain regulatory effect on cell adhesion.

4. Diseases associated with TGF-β signaling pathway

Abnormal TGF-β expression and signal transduction are associated with the development of many diseases, such as cancer, fibrosis, hereditary hemorrhagic capillary dilatation and family primary pulmonary hypertension [15].

TGF-β and tumor:

TGF-β is associated with tumor development, progression and metastasis. At the early stage of tumorigenesis, TGF-β inhibits the growth of tumor cells [16], but in the middle and late stages of the tumor, the effect of TGF-β on tumor was mainly manifested as promoting tumor progression. TGF-β also promotes tumor growth and metastasis. A large number of studies have found that TGF-β/Smad signaling pathway plays an important role in the pathogenesis of airway neoplasms, as well as in the pathogenesis of diabetic nephropathy (DN), mainly by inducing the accumulation of extracellular matrix (ECM) in glomerular and tubular cells.

TGF-β plays a key role in the process of fibrosis:

The increased expression of transforming growth factor-β is a common pathway of organic fibrosis and can be used as a target of treatment[17]. Only subcutaneous injection of TGF-β induced collagen deposition and fibrosis in rats, TGF-β mRNA expression was also found in glomeruli of diabetic rats[18].

Relationship between TGF-β and ocular diseases:

TGF-β plays an important role in the occurrence and development of cataract and can directly affect the occurrence and development of glaucoma. With the further study of the relationship between transforming growth factor β (TGF-β) and various diseases, people will have a deeper understanding of the role of TGF-β, which will be helpful to the diagnosis and treatment of various diseases.

6. The lastest research of TGF-β signaling pathway

At present, the research on TGF-β is mainly focused on its effect and regulation on different diseases, and the interaction between different factors and TGF-β. In recent years, many cytokines related to cardiovascular diseases have been found and studied. TGF-β/Smads signaling pathway is one of them. The signal pathway of TGF-β/Smads plays an important role in the progression of myocardial fibrosis and is thought to be closely related to the pathological process of fibrosis in various tissues and organs. Transforming growth factor β and bone morphogenetic protein (BMPs) pathway can also regulate the abnormal proliferation of pulmonary artery vascular smooth muscle cells, TGF-β and BMP signaling pathway have antagonistic effects on the proliferation of vascular smooth muscle cells[20][21].

In recent years, more and more studies have found[22][23] that integrin and TGF-β are related to each other in many diseases, For example, TGF-β induces the expression of integrin in fibrotic diseases, and the activation of integrin can enhance the role of TGF-β in collagen synthesis.

References

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[2] Lee MK, Pardoux C, Hall MC, et al. TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA [J]. EMBO J, 2007, 26(17): 3957-3967.

[3] Lin X, Duan X, Liang Y Y, et al. PPM1A Functions as a Smad Phosphatase to Terminate TGFβ Signaling [J]. Cell, 2006, 125(5): 915-928.

[4] Ma Biao, Cheng Hongcheng, Gao Ruize, et al. Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways [J]. Nature Communications, 2016, 7: 11123.

[5] Barouch D H, Ghneim K, Bosche W J, et al. Rapid Inflammasome Activation following Mucosal SIV Infection of Rhesus Monkeys [J]. Cell, 2016, 165(3): 656-667.

[6] Alonso-Merino E, Martín O R, Ruíz-Llorente L, et al. Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses [J]. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(24): E3451.

[7] Demagny H, Araki T, Derobertis E. The Tumor Suppressor Smad4/DPC4 Is Regulated by Phosphorylations that Integrate FGF, Wnt, and TGF-β Signaling [J]. Cell Reports, 2014, 9(2): 688-700.

[8] Yin S, Fan Y, Zhang H, et al. Differential TGF-β pathway targeting by miR-122 in humans and mice affects liver cancer metastasis [J]. Nature Communications, 2016, 7, 11012.

[9] Zhao J J, Hao S, Wang L L, et al. Long non-coding RNA ANRIL promotes the invasion and metastasis of thyroid cancer cells through TGF-β/Smad signaling pathway [J]. Oncotarget, 2016, 7, 57903–57918.

[10] Dupont S, Mamidi A, Cordenonsi M, et al. FAM/USP9x, a deubiquitinating enzyme essential for TGF β signaling, controls Smad4 monoubiquitination [J]. Cell, 2009, 136, 123–135.

[11] Taylor AW. Review of the activation of TGF-β in immunity [J]. J Leukoc Biol, 2009, 85(1): 29-33.

[12] Gatza1 CE, Oh SY, Blobe GC. Roles for the type Ⅲ TGF-β receptor in human cancer [J]. Cell Signal, 2010, 22(8): 1163-1174.

[13] Dennler S, Goumans M J, Ten D P. Transforming growth factor beta signal transduction [J]. J Leukoc Biol, 2002, 71(5): 731-740.

[14] Ji F, Fu S J, Shen S L, et al. The prognostic value of combined TGF-β1 and ELF in hepatocellular carcinoma [J]. Bmc Cancer, 2015, 15(1): 116.

[15] Schmierer B, Hill CS. TGF β-SMAD signal transduction: molecular specificity and functional flexibility [J]. Nat Rev Mol Cell Biol, 2007, 8(12): 970 -982.

[16] Pinkas J, Teicher B A. Role of TGF-β in Tumor Progression and Metastasis [M]. Cancer Drug Resistance. Humana Press, 2006: 469-489.

[17] Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor TGF-β signaling in cardiac remodeling [J]. J Mol Cell Cardiol, 2011, 51(4): 600-606.

[18] Wull, Cox A, Roe CJ, et al. Transforming growth factor beta and Renal injury following subtotal nephrectomy in the rat: role of the Renin-angiotensin system [J]. Kidney Int, 1997; 51: 1553.

[19] Hata A, Chen YG. TGF-β Signaling from Receptors to Smads [J]. Cold Spring Harb Perspect Biol 2016; 8.

[20] Morrell NW,Yang X,Upton PD,et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor -β1 and bone morphogenetic proteins [J]. Circulation, 2001, 104(7): 790-795.

[21] Sheares KK, Jeffery TK, Long L, et al. Differential effects of TGF-β 1 and BMP-4 on the hypoxic induction of cyclooxygenase-2 in human pulmonary artery smooth muscle cells [J]. Am J Physiol Lung Cell Mol Physiol, 2004, 287(5): L919-927.

[22] Hayashida T, Jones JC, Lee CK, et al. Loss of beta1-integrin enhances TGF-β 1-induced collagen expression in epithelial cells via increased alphavbeta3-integrin and Rac1 activity [J].J Biol Chem, 2010, 285(40): 30741-30751.

[23] Girgert R, Martin M, Kruegel J, et al. Integrin alpha2-deficient mice provide insights into specific functions of collagen receptors in the kidney [J]. Fibrogenesis Tissue Repair, 2010, 3: 19.

 

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