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Transforming growth factor beta(chapter 1)
source:ELK Biotechnologydate:2022-05-19views:175

Overview

 

Transforming growth factor beta (TGF-beta) was originally discovered because of its ability to stimulate the growth of rat fibroblast cell lines. In the past three decades, TGF-β has been further studied, especially its dual role in the tumor microenvironment (TME), which is called the "TGF-β paradox", which can be used for the existence of both good and evil. .

 

In early-stage tumors, the TGF-β pathway induces apoptosis and inhibits tumor cell proliferation. Conversely, by late stages, it has tumor-promoting effects by regulating genomic instability, epithelial-mesenchymal transition (EMT), neovascularization, immune evasion, cell motility, and metastasis. TGF-β, as an immunosuppressive cytokine, has broad inhibitory effects on immune responses through different mechanisms.

 

Accumulating data in preclinical or clinical trials suggest that blocking TGF-β signaling is an effective approach for tumor therapy, which alleviates Treg-mediated immunosuppression, increases T cell toxicity, and promotes T cell infiltration into the tumor center. Thereby causing strong anti-tumor immunity and tumor regression. Furthermore, blocking TGF-β signaling enhances tumor responses to immune checkpoint inhibitors (ICIs), such as antibodies against programmed death receptor 1 (PD-1) or PD-1 ligand (PD-L1).

 

At present, TGF-β targeting agents have become a new hot research direction. Understanding the TGF-β signal transduction mechanism and the application status of TGF-β inhibitors are crucial for the curative effect of tumor therapy and the reduction of side effects.

TGF-β (transforming growth factor beta, transforming growth factor beta) is a pleiotropic and pleiotropic cytokine that regulates cell proliferation, cell proliferation, and cell proliferation in an autocrine or paracrine manner through receptor signaling pathways on the cell surface. differentiation and apoptosis. It plays an important role in regulating the synthesis of extracellular matrix, wound repair, and immune function.

TGF-β has three isomers, TGF-β1, TGF-β2, and TGF-β3:

TGF-β1: the most expressed in the kidney, distributed in the glomerulus, the renal tubule, and the activity is the strongest;

TGF-β2: only expressed in the paraglomerular apparatus;

TGF-β3: Similar in distribution to TGF-β1, but in smaller quantities

 

The newly synthesized TGF-β forms inactive dormant complexes with latently active-related proteins through non-covalent bonds and is stored in the α-granules of platelets. Under the action of strong acid, strong alkali, high temperature, plasmin and cathepsin, TGF-β is activated by removing latent activity-related proteins and binding to receptors on the target cell membrane, thereby exerting biological effects. Almost all tissue cells have TGF-β receptors, the currently known receptors are: TβR-, TβR-and TβR-. Among them, type I and type II receptors are involved in signal transduction, and type III receptors are not directly involved in signal transduction.

 

 

 

TGF-beta superfamily member

 

Since the discovery of TGF-β1, more than 30 members of the TGF-β superfamily have been identified and characterized, and they share commonalities in synthesis, signal transduction mechanisms, and functions. Based on their structural and functional similarities, the TGF-β superfamily is divided into TGF-β and bone morphogenetic protein (BMP) subfamilies.

 

Typically, the TGF-β subfamily includes TGF-βs, activins, and Nodal, while the BMP subfamily contains BMPs, growth and differentiation factors (GDFs), and anti-Mullerian hormones (AMHs).

 

There are three highly homologous TGF-β isoforms in mammals, namely TGF-β1, TGF-β2, and TGF-β3. In the TGF-β superfamily, TGF-β isoforms are the most widely studied. According to The Cancer Genome Atlas (TCGA) data, TGF-β1 is the most prevalently expressed isoform in most human cancers. Furthermore, the expression of TGF-β1 was most closely associated with TGF-β signaling activation compared to TGF-β2 and TGF-β3.

TGF-β secretion and activation

 

TGF-β is a protein synthesized from an inactive precursor and requires activation to function. The TGF-β precursor consists of three parts: a signal peptide, a long N-terminal precursor called a latency-associated peptide (LAP), and a short C-terminal fragment corresponding to the mature cytokine. After cleavage by the endonuclease Furin, the disulfide-linked TGF-β homodimer binds to the disulfide-linked LAP homodimer through disulfide bonds.

 

 

 

This molecule, known as the small latent complex (SLC), is often cross-linked by disulfide bonds to latent TGF-β binding protein (LTBP) to form the large latent complex (LLC), which interacts with the extracellular matrix (ECM) fibrin interactions, enabling stable storage of latent TGF-β rather than further activation.

 

In addition, latent TGF-β can also bind to the transmembrane glycoprotein A-dominated repeat protein (GARP) and LRRC33 on the surface of Treg or macrophages. TGF-β1 and TGF-β3 are allosterically released from their latent complexes after the Arg-Gly-Asp (RGD) sequence on LAP interacts with integrin αvβ6 or αvβ8. Only when released from the latent complex can TGF-β become active and activate its receptors.

 

This molecule, known as the small latent complex (SLC), is often cross-linked by disulfide bonds to latent TGF-β binding protein (LTBP) to form the large latent complex (LLC), which interacts with the extracellular matrix (ECM) fibrin interactions, enabling stable storage of latent TGF-β rather than further activation.

 

In addition, latent TGF-β can also bind to the transmembrane glycoprotein A-dominated repeat protein (GARP) and LRRC33 on the surface of Treg or macrophages. TGF-β1 and TGF-β3 are allosterically released from their latent complexes after the Arg-Gly-Asp (RGD) sequence on LAP interacts with integrin αvβ6 or αvβ8. Only when released from the latent complex can TGF-β become active and activate its receptors.

 

This also explains why when detecting TGF-β, the first step is to activate the sample in advance.

Cat.No

Description

48T/96T

ELK9583

TGF-β1 ELISA Kit

160/229