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Review
. 2022 Dec 19;3(1):45.
doi: 10.1186/s43556-022-00109-9.

TGF-beta signal transduction: biology, function and therapy for diseases

Yan Tie #  1 , Fan Tang #  1   2 , Dandan Peng #  1 , Ye Zhang  3 , Huashan Shi  4
Affiliations
Review

TGF-beta signal transduction: biology, function and therapy for diseases

Yan Tie et al. Mol Biomed. .

Abstract

The transforming growth factor beta (TGF-β) is a crucial cytokine that get increasing concern in recent years to treat human diseases. This signal controls multiple cellular responses during embryonic development and tissue homeostasis through canonical and/or noncanonical signaling pathways. Dysregulated TGF-β signal plays an essential role in contributing to fibrosis via promoting the extracellular matrix deposition, and tumor progression via inducing the epithelial-to-mesenchymal transition, immunosuppression, and neovascularization at the advanced stage of cancer. Besides, the dysregulation of TGF-beta signal also involves in other human diseases including anemia, inflammatory disease, wound healing and cardiovascular disease et al. Therefore, this signal is proposed to be a promising therapeutic target in these diseases. Recently, multiple strategies targeting TGF-β signals including neutralizing antibodies, ligand traps, small-molecule receptor kinase inhibitors targeting ligand-receptor signaling pathways, antisense oligonucleotides to disrupt the production of TGF-β at the transcriptional level, and vaccine are under evaluation of safety and efficacy for the forementioned diseases in clinical trials. Here, in this review, we firstly summarized the biology and function of TGF-β in physiological and pathological conditions, elaborated TGF-β associated signal transduction. And then, we analyzed the current advances in preclinical studies and clinical strategies targeting TGF-β signal transduction to treat diseases.

Keywords: Anemia; Fibrosis; TGF-beta; Targeted therapy; Tumor microenvironment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic diagram and activation of latent TGF-β. The pro-TGF-β precursor consists of an N-terminal peptide with latency-associated peptide (LAP) and a mature C-terminal fragment. The pro-TGF-β precursor is cleaved by the convertase furin, and then the LAP dimer binds to mature TGF-β and forms the small latent complex (SLC). Proteases including plasmin, cathepsin and matrix metalloproteinase 9/14 (MMP9/14)) can cleave LAP and release active TGF-β in the extracellular matrix (ECM). SLC binds to latent TGF-β-binding protein (LTBP) with ECM proteins, including fibronectin and fibrillin, mediating the release of active TGF-β via interaction with αβ-integrin. TGF-β can also be activated through SLC anchoring to glycoprotein A repetition predominant protein (GARP)
Fig. 2
Fig. 2
TGF-β induced canonical and noncanonical signaling pathways. TGF-β is presented to TGF-βRII, which phosphorylates TGF-βRI to initiate the subsequent TGF-β pathway. In the canonical pathway, TGF-βRI phosphorylates SMAD2/3 to form the SMAD2/3-SMAD4 complex. SMAD2/3, SMAD4 and transcription factor (TF) complexes are transferred to the cell nucleus, modulating the expression of target genes. SMAD7, one of the target genes, regulates the duration and intensity of TGF-β with a negative feedback loop. In the noncanonical pathway, TGF-β can activate PI3K, RHO, PAR6, RAS, TRAF4/6, JNK, P38, NF-κB and ERK signaling
Fig. 3
Fig. 3
The functions of TGF-β in the TME. Tumor cells, endothelial cells, mesenchymal stem cells, cancer-associated fibroblasts, and macrophages can induce the production and secretion of TGF-β in the TME. TGF-β suppresses tumor immune responses by modulating the multiple functions of immune cells in the TME, as depicted
Fig. 4
Fig. 4
The functions of TGF-β in fibrosis. Tumor cells, endothelial cells, mesenchymal stem cells, cancer-associated fibroblasts, and macrophages can induce the production and secretion of TGF-β, which induces fibrosis, including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, cardiac fibrosis and systematic sclerosis, through SMAD and non-SMAD pathways
Fig. 5
Fig. 5
Potential therapeutic strategies based on the TGF-β signaling pathway in disease. Antagonists targeting the TGF-β pathway, including neutralizing antibodies, ligand traps, small-molecule receptor kinase inhibitors, antisense oligonucleotides and vaccines, have recently been evaluated in clinical trials. Representative drugs are shown
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