TGFB2

Official Full Name

transforming growth factor beta 2

Organism

Homo sapiens

GeneID

7042

Background

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

Synonyms

LDS4; G-TSF; TGF-beta2;

Bio Chemical Class

Growth factor

Protein Sequence

MHYCVLSAFLILHLVTVALSLSTCSTLDMDQFMRKRIEAIRGQILSKLKLTSPPEDYPEPEEVPPEVISIYNSTRDLLQEKASRRAAACERERSDEEYYAKEVYKIDMPPFFPSENAIPPTFYRPYFRIVRFDVSAMEKNASNLVKAEFRVFRLQNPKARVPEQRIELYQILKSKDLTSPTQRYIDSKVVKTRAEGEWLSFDVTDAVHEWLHHKDRNLGFKISLHCPCCTFVPSNNYIIPNKSEELEARFAGIDGTSTYTSGDQKTIKSTRKKNSGKTPHLLLMLLPSYRLESQQTNRRKKRALDAAYCFRNVQDNCCLRPLYIDFKRDLGWKWIHEPKGYNANFCAGACPYLWSSDTQHSRVLSLYNTINPEASASPCCVSQDLEPLTILYYIGKTPKIEQLSNMIVKSCKCS

Open

Disease

Colorectal cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

1 +

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Detailed Information

The TGFB2 gene is located on human chromosome 1q41 and encodes Transforming Growth Factor Beta 2 (TGF-β2), a key member of the TGF-β superfamily. The gene transcription produces a preproprotein that undergoes proteolytic processing to generate the Latency-Associated Peptide (LAP) and the mature peptide chain. Under physiological conditions, TGF-β2 primarily exists as a latent complex, composed of the mature peptide homodimer, the LAP homodimer, and Latency-Associated TGF-β Binding Protein (LTBP), stored in the extracellular matrix. Upon specific stimuli, the complex dissociates to release active TGF-β2 dimers, which exert biological effects via autocrine or paracrine signaling. Similar to TGF-β1 and TGF-β3, TGF-β2 initiates signaling by binding to type II and type I serine/threonine kinase receptors (TβRII and TβRI) on the cell surface. Phosphorylation of TβRI by TβRII further activates the SMAD2/3 transcription factors, which then form complexes with SMAD4 and translocate to the nucleus to regulate target gene transcription.

Figure 1. TGF-isoforms, TGF-receptors, TGF-intracellular signaling pathways. (Ciebiera M, et al. 2017)

Role in Embryonic Development

TGFB2 plays an indispensable role during embryonic development, especially in cardiovascular system formation and eye development. TGF-β2 knockout mice exhibit various congenital abnormalities, including heart valve defects, abnormal aortic arch development, and ocular chamber malformations, which closely resemble human Peters anomaly (a congenital anterior chamber developmental defect). Studies suggest that chromosomal translocation-induced TGFB2 gene disruption is directly linked to Peters anomaly. In angiogenesis, TGF-β2 promotes vascular network formation by coordinating endothelial cell proliferation, migration, and lumen formation. During cardiac development, TGF-β2 regulates epithelial-to-mesenchymal transition (EMT) in the endocardial cushion, influencing atrioventricular valve and aortic valve formation. Dysregulated expression of TGF-β2 can lead to congenital heart defects.

Immune Regulation

In immune regulation, TGF-β2 exhibits multiple, seemingly contradictory functional characteristics. On one hand, it limits excessive immune activation by suppressing T cell homing and antigen presentation. On the other hand, it promotes the differentiation of regulatory T cells (Treg) in specific microenvironments, enhancing immune tolerance. This dual role makes TGF-β2 a key factor in maintaining immune homeostasis, while also contributing to its complex role in the tumor immune microenvironment. During tissue repair, TGF-β2 stimulates fibroblast proliferation and extracellular matrix (ECM) protein synthesis, promoting wound healing. However, persistent TGF-β2 signaling can lead to excessive fibrosis, playing a pathological role in various organ fibrosis diseases.

Pathological Mechanisms and Disease Association

TGFB2 gene mutations are closely associated with various hereditary connective tissue diseases. In Loeys-Dietz syndrome type 4 (LDS4), heterozygous mutations in TGFB2 lead to TGF-β signaling dysregulation, with patients exhibiting characteristics such as aortic aneurysms, arterial tortuosity, thin and transparent skin, and hyperextended joints. Unlike Marfan syndrome, LDS4 patients often present with craniofacial developmental abnormalities, including cleft palates and craniosynostosis. At the molecular level, mutant TGFB2 alleles exert a dominant negative effect or cause haploinsufficiency, disrupting TGF-β signaling balance. Clinical studies have found increased levels of phosphorylated SMAD2 in the aortic tissue of LDS4 patients and elevated circulating TGF-β2 concentrations, presenting a typical TGF-β signaling overactivation state, which contradicts the traditional notion of "loss-of-function mutations." This suggests that mutations may interfere with latent complex formation or activation, leading to abnormal signal release.

TGF-β2 in Cancer and Tumor Progression

TGF-β2 plays a dual role in cancer development. In the early stages, it exerts tumor-suppressive effects by inducing expression of cyclin-dependent kinase inhibitors (such as p21 and p15), inhibiting epithelial cell proliferation. However, as tumors progress, TGF-β2 transforms into a pro-tumor factor by inducing epithelial-mesenchymal transition (EMT), promoting tumor invasion and metastasis. In esophageal cancer studies, immunohistochemical analysis of tumor tissue from 68 patients showed that TGFB2 expression was significantly higher than in normal esophageal mucosa, correlating positively with tumor T stage (invasion depth) and N stage (lymph node metastasis). Mechanistically, TGF-β2 upregulates SREBF1 (sterol regulatory element-binding factor 1) and its downstream lipogenic enzymes via the PI3K-AKT signaling pathway, driving lipid metabolic reprogramming, which provides new insights into understanding tumor metabolic abnormalities.

In pancreatic ductal adenocarcinoma (PDAC), breakthroughs have been made in studying TGF-β2-mediated drug resistance mechanisms. A team from Sun Yat-sen University found that TGF-β2 expression was significantly upregulated in gemcitabine-resistant PDAC cells, correlating with poor patient prognosis. Mechanistically, METTL14-mediated m6A methylation stabilizes TGFB2 mRNA, enhancing its expression. Elevated TGF-β2 activates SREBF1 through the PI3K-AKT signaling pathway, promoting triglyceride accumulation and lipid droplet formation, granting tumor cells chemoresistance. Patient-derived xenograft (PDX) models confirmed that silencing TGFB2 expression restored gemcitabine sensitivity, while the TGF-β2 inhibitor imperatorin exhibited synergistic anti-tumor effects when combined with gemcitabine.

Cardiovascular Disease and TGFB2

In cardiovascular diseases, TGFB2 is involved in the pathological remodeling process of ischemic heart failure. Using bioinformatics analysis of the GSE116250 and GSE203160 datasets, researchers identified 132 differentially expressed genes (DEGs) in ischemic heart failure, with TGFB2 identified as one of the nine core genes. In a rat model of left anterior descending coronary artery ligation, TGFB2 expression in ischemic myocardium was significantly elevated. In vitro experiments confirmed that TGFB2 expression in oxygen-glucose deprivation (OGD) treated H9c2 cardiomyocytes promoted Caspase-3 cleavage, upregulated pro-apoptotic Bax expression, and inhibited anti-apoptotic Bcl-2 expression, inducing cardiomyocyte apoptosis. In contrast, silencing TGFB2 enhanced cell viability and inhibited apoptosis, suggesting its potential as a therapeutic target for heart failure.

Reference

Turati M, Mousset A, Issa N, et al. TGF-β mediated drug resistance in solid cancer. Cytokine Growth Factor Rev. 2023 Jun-Aug;71-72:54-65.
Ogata FT, Verma S, Coulson-Thomas VJ, et al. TGF-β-Based Therapies for Treating Ocular Surface Disorders. Cells. 2024 Jun 26;13(13):1105.
Pervan CL. Smad-independent TGF-β2 signaling pathways in human trabecular meshwork cells. Exp Eye Res. 2017 May;158:137-145.
Ciebiera M, Włodarczyk M, Wrzosek M, et al. Role of Transforming Growth Factor β in Uterine Fibroid Biology. Int J Mol Sci. 2017 Nov 17;18(11):2435.

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