Transforming Growth Factor beta

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Transforming Growth Factor β
Transforming Growth Factor β
PDB ID: 3VI4. Rainbow colors, blue N-terminus, red C-terminus

Existing structure data : PDB  1KLC , PDB  2TGI , PDB  1TGK , PDB  3RJR , PDB  5FFO

Mass / length primary structure TGFβ1 / 2/3: signal peptide: 29/20/23; LAP: 249/282/277; TGFβ: 111/111/111
External IDs

Transforming Growth Factor β (TGFβ) refers to three cytokines that together make up the TGFβ family. There are three forms of TGFβin vertebrates : TGFβ1, TGFβ2, and TGFβ3 (human gene names: TGFB1, TGFB2, TGFB3). Despite the similarity of names, there is no close structural or evolutionary relationship with the TGFα growth factors .

Knockout mice have shown that

  • TGFβ1 dampens the immune system,
  • TGFβ2 is involved in the development of the lungs, heart, bones and urogenital tract,
  • TGFβ3 also contributes to lung development. TGFβ3 signals are also important to prevent the development of cleft palates.

All three TGFβ appear to be able to transform cells of various origins into myofibroblasts . These are characterized by increased contractility and secretion of EZM proteins. On the one hand, these are prerequisites for successful wound healing , but on the other hand they lead to scar formation, which in pathological cases leads to fibrosis and in extreme cases to organ failure.

TGFβ are deposited by cells in an inactive form in the extracellular matrix (ECM). The actual cytokine TGFβ is only released through activation and can bind to cellular surface receptors. These TGFβ receptors belong to the family of serine / threonine kinases . Activated TGFβ receptors activate proteins of the Smad family intracellularly , which then reach the cell nucleus and influence gene expression with cofactors . The three members of the TGFβ family have specific functions in the development of vertebrates, and persistent activation of the TGFβ signaling pathway has been implicated in various diseases.


TGFβ1 homodimer consisting of the actual growth factor (light and dark green) and the surrounding cage that is formed by LAP (light and dark pink). Several central disulfide bridges stabilize the growth factor. The LAP cage is stabilized by a disulfide bridge in the upper part and by the disulfide bond of the lower alpha helices to other proteins such as LTBP or GARP (not shown here). Figure is based on PDB ID 3VI4.

TGFβ1-3 are only three members of the entire TGFβ family. This consists of the following subgroups:

All 33 genes of the representatives of the TGFβ family lead to a polypeptide that is split into a secretion signal peptide , a pro domain (approx. 250 amino acids, approx. 30 kDa) and the actual cytokine (approx. 110 amino acids, approx. 13 kDa). The cleavage of the polypeptide into the functional prodomain cytokine complex takes place in the Golgi apparatus . This complex is then secreted into the extracellular space . In TGFβ1-3 in particular, the cytokine is closely linked to the prodomain and this complex keeps the cytokine in an inactive state in which TGFβ cannot bind to the receptor. The TGFβ prodomain, called latency-associated peptide (LAP), and TGFβ form a homodimer with another LAP / TGFβ complex . The two LAP proteins form a clamp around the TGFβ dimer. Other members of the TGFβ family can also form heterodimers. Whether this is also possible with TGFβ1-3, whether z. B. a TGFβ1 can form a dimer with a TGFβ2 is currently unclear.

The "LAP clamp" around the TGFβ1 dimer is stabilized by a disulfide bridge at one end of the LAP. TGFβ itself is stabilized intramolecularly in the so-called cystine node by four disulfide bridges; Another disulfide bridge forms the intermolecular connection to the second TGFβ and thereby forms the homodimer. This cystine knot is not only typical for the entire TGFβ family, but also for the superfamily of the cystine knot growth factors (CKGF superfamily). In addition to the TGFβ family, this CKGF superfamily also includes the Dan family (BMP antagonists), the glycoprotein hormone family (e.g. FSH ), the family of Bursicon hormones (only found in invertebrates), and platelet-derived growth factor (PDGF) family, and the family of nerve growth factors (NGFs).

The TGFβ cytokines have a very highly conserved amino acid sequence. Protein structures for all three TGFβ cytokines are available and also show a high structural similarity. For complete LAP-TGFβ, on the other hand, protein structures are only available for TGFβ1. Since the various LAP proteins are evolutionarily conserved much less well, it is to be expected that the various TGFβ in this area also differ more structurally.

The complex of LAP and TGFβ can be secreted by cells. Often the LAP-TGFβ complex is bound to another protein by means of LAP before the complex is secreted. In most cells this is a binding of LAP to the protein LTBP (latent TGFβ binding protein). In contrast, the protein GARP is expressed in regulatory T cells and platelets and the LAP-TGFβ complex binds to GARP. A LAP / TGFβ / LTBP complex is bound to proteins of the ECM via LTBP ; often fibronectin or fibrillin . A LAP / TGFβ / GARP complex, on the other hand, is presented on the cell surface via GARP. Both LAP proteins of the homodimer bind with disulfide bridges to LTBP or GARP and thus also stabilize the LAP / TGFβ homodimer.


Structural view of the binding between αVβ6 integrin (αV: red, β6: blue) and TGFβ1 (LAP: pink and magenta, TGFβ1: light and dark green). Enlargement shows the binding of the RGD peptide (N atoms blue, O atoms red) of LAP / TGFβ1 to the αV integrin subunit using arginine and to the β6 intgrin subunit using aspartate. Aspartate binds directly to the central MIDAS metal ion of β6 integrin. Based on PDB ID 5FFO.

At the beginning of the discovery of TGFβ it was unclear that it is only secreted inactive by cells. The biochemical protocols for the purification and concentration of TGFβ contained acids that are able to dissolve TGFβ from the complex with LAP. The importance of the activation of TGFβ was therefore not recognized at the beginning, since one was only working with TGFβ that was unknowingly already activated.

Over the years, more and more processes have become known that are in principle able to activate TGFβ. Based on various studies with knockout mice , it currently appears that certain integrins are most important for the activation of TGFβ1 and TGFβ3. However, no integrin was found that binds to TGFβ2. This means either that TGFβ2 is activated exclusively integrin-independently, or that TGFβ2-integrin binding has not yet been discovered. Also for TGFβ1 and TGFβ3 there is still the possibility that integrin-independent activation mechanisms dominate at least in certain situations.

Integrin dependent

Both TGFβ1 and TGFβ3 have an RGD peptide sequence in their LAP protein . This amino acid sequence is recognized by many integrins. The importance of the RGD-integrin binding for the activation of TGFβ1 can be seen in knockin mice in which TGFβ1-RGD is replaced by RGE (the RGE sequence reduces integrin binding or prevents it completely). These TGFβ1-RGE mice show effects similar to those of mice completely lacking TGFβ1. This means that a lack of activation of TGFβ1 by an integrin is synonymous with the complete absence of TGFβ1.

Two integrins, αVβ6 and αVβ8 integrin, are currently being discussed as the most important integrins for the activation of TGFβ1 and TGFβ3 in organisms. However, recent publications also suggest that αVβ1 integrin is of great importance. At least in cell culture, αVβ3, αVβ5 and α8β1 integrins have also shown binding to TGFβ1. However, structural considerations so far suggest that at least αVβ3 and αVβ5 integrin cannot easily bind to RGD in TGFβ1 and could therefore activate TGFβ1 more in exceptional situations.

While both αVβ6 and αVβ8 integrin bind to the RGD sequence in TGFβ1 and TGFβ3, the respective activation mechanism by the two integrins is different.

Activation by means of αVβ6 integrin

The activation of TGFβ by means of integrin is based on a conformational change in the LAP protein through traction. For this to be possible, the LAP / TGFβ homodimer must be stably anchored at one end, while at the other end cells must pull on a LAP protein by means of αVβ6 integrin. Stable anchoring takes place through a link to EZM proteins using LTBP or to the surface of a neighboring cell using GARP. The tensile force through the cell is given by binding through αVβ6 integrin, since this integrin is linked to contractile actin filaments by means of focal adhesions . Molecular simulations based on an αVβ6-LAP / TGFβ1 structure show how mechanical pulling leads to conformational changes in the LAP area, which ultimately release TGFβ1 from the LAP bracket. It can be demonstrated experimentally that free, active TGFβ1 is released from binding to EZM proteins by this process and is soluble in the medium.

Other integrins like αVβ1, αVβ3, αVβ5 and α8β1 are like αVβ6 able to transmit tensile forces into the ECM through actin filaments. If these integrins play a role in TGFβ activation in organisms, they will probably also use the mechanism described here for TGFβ activation.

Activation by means of αVβ8 integrin

β8 integrin has a cytoplasmic amino acid sequence that is very different from that of all other β integrins. As a result, αVβ8 integrin is not able to develop focal adhesions and to bind to contractile actin filaments via adapter proteins. Activation of TGFβ via tensile force is therefore very probably out of the question for αVβ8 integrin. It was previously assumed that the binding of TGFβ to αVβ8 integrin rather enables the recruitment of proteases, which then open the LAP clamp so that TGFβ can be released and diffuse to TGFβ receptors. In the meantime, however, it has been shown that αVβ8 integrin enables activation of TGFβ1 in which TGFβ1 is not released, but is nevertheless able to bind to TGFβ receptors.

Integrin independent

Different integrin-independent activation mechanisms of TGFβ are also discussed:

Compared to activation by integrins, the evidence for TGFβ activation by the factors mentioned here is less consistent. This is also supported by an evolutionary biological argument: Integrins were already present when TGFβ arose. Plasmin, the aforementioned proteases and thrombospondin, on the other hand, did not develop until later. However, this does not mean that integrin-independent activation mechanisms cannot decide on TGFβ activation in certain situations.

Signaling pathways

The TGFβ signaling pathway consists of the binding of growth factor to the receptor complex on the cell surface. This activates signal molecules of the Smad family intracellularly , which in turn influence gene regulation .

Side view of a TGFβ1 homodimer (light and dark green) with the extracellular domains of two TbR-I (light and dark blue) and two TbR-II (light and dark pink). Disulfide bridges are shown in yellow. Based on PDB ID 3KFD.


The canonical TGFβ signaling pathway occurs through activation of TGFβ receptors, which belong to the serine / threonine kinases . To do this, a TGFβ homodimer binds to two TGFβ receptor type II (TbR-II). This precomplex then in turn recruits two TGFβ receptor type I (TbR-I). TGFβ1 and TGFβ3 have a higher affinity for TbR-II than for TbR-I, which explains the sequence of binding of TGFβ to the receptor subunits. In contrast, TGFβ2 has approximately equal affinities for TbR-I and TbR-II. Additional coreceptors (beta glycan) can ensure that TGFβ2 first binds TbR-II and then TbR-I in a similar sequence.

In general, the affinity between TGFβ and the TbR-I / TbR-II receptor complex is higher than between receptor tyrosine kinases and the growth factors that bind to them, such as EGF. At the same time, the number of TbR-I and TbR-II on the cell surface, at 5,000 or less, is very low compared to receptor tyrosine kinases. This enables cells to potentially adjust their TGFβ signaling capacities very dynamically, since adding or removing a comparatively small number of receptors on the cell surface already makes a big difference in percentage terms.

Smad-regulated gene expression

After TbR-I is recruited by the TGFβ-TbR-II complex, TbR-I is phosphorylated by TbR-II and thus activated. In this state, TbR-I is able to recruit and activate receptor-regulated Smad proteins (R-Smads: Smad2, 3, 5, 8). A complex of two of these Smads formed with Smad4 a complex which binds to DNA in the nucleus and other transcription factors , the gene expression influenced. Other signaling pathways can influence this process on several levels. This regulation by other signaling pathways, as well as the context-dependent cofactors of gene expression, make it difficult to predict exactly which genes of the TGFβ-Smad signaling pathway are influenced. In the context of the above-described effect of TGFβ on EMT and wound healing, however, the recruitment of transcription factors such as Snail (regulate EMT) and increased production and secretion of several EZM proteins such as collagens are typical effects of the TGFβ-Smad signaling pathway.

Clinical relevance

The inhibition of the TGFβ signaling pathway has received increased clinical interest in recent years. On the one hand, this is due to the immune-suppressing effect of TGFβ. Tumors can lead to an increased activation of TGFβ and protect themselves against an attack by the immune system through the action of TGFβ.

On the other hand, persistent TGFβ activation, as occurs with inflammations or wounds, leads to fibrosis, which can lead to organ failure. It is estimated that more than 40% of all deaths in developed countries are related to fibrotic disease.

The Camurati-Engelmann disease is caused by a gene mutation in chromosome 19 locus caused q13.1-13.3. The β-1 chain of transforming growth factor (TGF β1) is affected.

It is believed that TGF-β plays a key role in the pathogenesis of radiation-induced pulmonary fibrosis , and antagonizing TGF-β may prevent such an inflammation. However, little or no research results are available to date on this question.

TGF-β also appears to be involved in the development of diabetic kidney damage. In diabetic nephropathy there is an enlargement of cells (hypertrophy) and an increased formation of collagen in the kidney corpuscle . Increased blood sugar stimulates the release of TGF-β. If TGF-β is inhibited by ACE inhibitors , specific antibodies or hepatocyte growth factor , this leads to an improvement in diabetic kidney damage.

In patients with vascular type of Ehlers-Danlos syndrome , and in patients with Loeys-Dietz syndrome have mutations in the genes of the receptors for TGF-β ( TGFBR detected 1 and TGFBR2).

The Marfan syndrome is caused by a mutation in the gene for fibrillin caused. Fibrillin is an integral part of the microfibrils of the connective tissue . The mutation leads to a reduced strength of the connective tissue. However, fibrillin is also homologous to the family of latent TGF-β binding proteins ( LTBP ), which bind TGF-β in an inactive complex. The mutation in the fibrillin gene leads to a reduced binding of TGF-β. The resulting surplus of active TGF-β in the connective tissue is blamed for some complications of Marfan syndrome, such as emphysema , mitral valve prolapse and aneurysms of the aortic root .

Ciclosporin is an important drug in transplant medicine . Serious side effects are high blood pressure and kidney damage . One possible cause of these complications is that the transcription of TGF-β is stimulated by ciclosporin.

See also

Individual evidence

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