TGFB1

Official Full Name

transforming growth factor beta 1

Organism

Homo sapiens

GeneID

7040

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 TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

Synonyms

CED; LAP; DPD1; TGFB; IBDIMDE; TGFbeta; TGF-beta1;

Bio Chemical Class

mRNA target

Protein Sequence

MPPSGLRLLLLLLPLLWLLVLTPGRPAAGLSTCKTIDMELVKRKRIEAIRGQILSKLRLASPPSQGEVPPGPLPEAVLALYNSTRDRVAGESAEPEPEPEADYYAKEVTRVLMVETHNEIYDKFKQSTHSIYMFFNTSELREAVPEPVLLSRAELRLLRLKLKVEQHVELYQKYSNNSWRYLSNRLLAPSDSPEWLSFDVTGVVRQWLSRGGEIEGFRLSAHCSCDSRDNTLQVDINGFTTGRRGDLATIHGMNRPFLLLMATPLERAQHLQSSRHRRALDTNYCFSSTEKNCCVRQLYIDFRKDLGWKWIHEPKGYHANFCLGPCPYIWSLDTQYSKVLALYNQHNPGASAAPCCVPQALEPLPIVYYVGRKPKVEQLSNMIVRSCKCS

Open

Approved Drug

1 +

Clinical Trial Drug

6 +

Discontinued Drug

1 +

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Detailed Information

Transforming Factor Essential member of the TGF-β superfamily of proteins, beta 1 (TGF-β1) is known for its multifarious function in cellular control and signaling. Originally discovered in the 1970s, TGF-β1 surfaced from studies on soluble molecules able to cause non-dependent development of normal cells, therefore enabling a metamorphosis akin to the change from normality to cancer. Under the direction of famous molecular scientists Michael B. Sporn and Anita Roberts, this foundational work set the stage for much of the study on TGF-β1, exposing its complicated structure, sophisticated signaling pathways, and consequences in many disorders, including cancer.

Molecular Structure and Activation of TGF-β1

The precursor protein, known as pre-pro-TGF-β1, consists of 390 amino acids divided into three primary domains: an N-terminal signal peptide of 29 amino acids, the latency-associated peptide (LAP) comprising 249 amino acids, and a C-terminal mature peptide containing 112 amino acids. TGF-β1 maturation is the proteolytic breakdown of this precursor wherein the signal peptide is eliminated, therefore enabling non-covalent dimerization to produce pro-TGF-β1. The pro-TGF-β1 then changes even further by furin cleavage, releasing several peptide fragments. Forming a latent complex stored in the extracellular matrix (ECM), the matured TGF-β1 homodimer stays non-covalently attached to the LAP.

Different "milieu molecules" including LTBP1 (Latent TGF-β Binding Protein 1) and LRRC32/GARP might cause the LAP to dissociate, hence activating TGF-β1. TGF-β1 activation is regulated in part by these interactions, which also help it to stay dormant until required. TGF-β1 binds to its receptors, mostly type 2 (TGFBR2) and type 1 (TGFBR1), upon release from LAP, therefore starting downstream signaling cascades mostly mediated by SMAD transcription factors.

TGF-β1 Signaling Pathways

TGF-β1's signaling pathway epitomizes a standard type of receptor-mediated gene transcription. TGF-β1 causes receptor phosphorylation when it binds to them, therefore activating and oligomerizing SMAD proteins. These turned-on SMADs migrate into the nucleus where they couple with certain genomic locations to control the expression of several genes. Remarkably conserved among species, this route is essential for several cellular functions including proliferation, differentiation, and death.

Although TGF-β1 also stimulates other pathways like PI3K and MAPK, the SMAD-mediated effects fully represent the contextual character of TGF-β1 activity. TGF-β1 may have many effects depending on the cellular environment; for instance, it could either encourage the differentiation of embryonic stem cells or stop the proliferation of epithelial progenitor cells. This duality emphasizes TGF-β1's complex regulating power and thereby highlights its importance in development and illness.

Figure 1 describes the activation of latent TGF-β and its signaling through receptors and Smad proteins, leading to gene regulation and involvement in non-Smad pathways like MAPK and Akt signaling. Figure 1. The activation of latent TGF-β and the initiation of TGF-β signaling via receptors and Smads. (Derynck R, et al., 2021)

The Dual Role of TGF-β1 in Cancer Progression

Among the many purposes TGF-β1 serves, its influence on the development of cancer is most remarkable. TGF-β1 is a pleiotropic cytokine that, in a context-dependent sense helps tumors grow. Early on in carcinogenesis, TGF-β1 acts as a tumor suppressor, stopping cell cycle progression and hence reducing tumor cell growth. Cell cycle arrest in the G1 phase mediates this antiproliferative action by thus blocking the shift to the S phase and so stopping tumor development.

The dynamics of TGF-β1 signaling change dramatically, nevertheless, as cancer advances. Usually, utilizing TGF-β signaling system alterations, tumor cells may gain resistance to TGF-β1-mediated growth inhibition. This resistance lets tumor cells evade TGF-β1's suppressive effects and instead make use of its features to advance invasion and metastases. TGF-β1, which inhibits the activation and development of important immune cells like T cells, B cells, and natural killer (NK) cells, is secreted by tumor cells in later stages of cancer, therefore improving immune evasion. This immune suppression makes tumor development and metastases easier, therefore fostering a hostile environment for strong immune responses.

TGF-β1 and the Tumor Microenvironment

The behavior of cancer cells is greatly shaped by the tumor microenvironment (TME), hence TGF-β1 is a fundamental mediator in this framework. TGF-β1 alters the relationships of cancer cells, stromal cells, and extracellular components, therefore influencing the characteristics of the TME. TGF-β1 increases the deposition of extracellular matrix components supporting tumor development by helping fibroblasts to differentiate into myofibroblasts. Influencing the immunological terrain of the TME is TGF-β1, which tilts the differentiation of naïve T cells towards regulatory T cells (Tregs), hence fostering immune tolerance and enabling tumor development.

Moreover, linked to the epithelial-to-mesenchymal transition (EMT), a mechanism that gives epithelial cells mesenchymal traits and hence increases their migratory and invasive capacity, is TGF-β1. Promoting EMT helps TGF-β1 acquire metastatic characteristics in cancer cells so they may spread from the main tumor and colonize far-off areas.

References:

Stockis J, Dedobbeleer O, Lucas S. Role of GARP in the activation of latent TGF-β1. Mol Biosyst. 2017;13(10):1925-1935.
Derynck R, Turley SJ, Akhurst RJ. TGF-β biology in cancer progression and immunotherapy. Nat Rev Clin Oncol. 2021;18(1):9-34.
Batlle E, Massagué J. Transforming Growth Factor-β Signaling in Immunity and Cancer. Immunity. 2019;50(4):924-940.
Mullard A. Cancer drug approvals and setbacks in 2021. Nat Cancer. 2021;2(12):1246-1247.

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