![Computer graphic of tgf-beta](https://upload.wikimedia.org/wikipedia/commons/1/1c/Computer_graphic_of_tgf-beta.jpg)
Transforming growth factor beta (TGF-β) is a multifunctional
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
belonging to the
transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3,
HGNC
The HUGO Gene Nomenclature Committee (HGNC) is a committee of the Human Genome Organisation (HUGO) that sets the standards for human gene nomenclature. The HGNC approves a ''unique'' and ''meaningful'' name for every known human gene, based on a q ...
symbols
TGFB1,
TGFB2
Transforming growth factor-beta 2 (TGF-β2) is a secreted protein known as a cytokine that performs many cellular functions and has a vital role during embryonic development (alternative names: Glioblastoma-derived T-cell suppressor factor, G-TSF ...
,
TGFB3
Transforming growth factor beta-3 is a protein that in humans is encoded by the gene.
It is a type of protein, known as a cytokine, which is involved in cell differentiation, embryogenesis and development. It belongs to a large family of cytokine ...
) and many other
signaling proteins
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
. TGFB proteins are produced by all
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...
lineages.
Activated TGF-β complexes with other factors to form a
serine/threonine kinase
A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human protei ...
complex that binds to
TGF-β receptors. TGF-β receptors are composed of both type 1 and type 2 receptor subunits. After the binding of TGF-β, the type 2 receptor kinase phosphorylates and activates the type 1 receptor kinase that activates a signaling cascade.
This leads to the activation of different downstream substrates and regulatory proteins, inducing transcription of different target genes that function in differentiation, chemotaxis, proliferation, and activation of many immune cells.
TGF-β is secreted by many cell types, including macrophages, in a latent form in which it is complexed with two other polypeptides,
latent TGF-beta binding protein
The latent TGF-beta binding proteins (LTBP) are a family of carrier proteins.
LTBP is a family of secreted multidomain proteins that were originally identified by their association with the latent form of transforming growth factor Transforming g ...
(LTBP) and latency-associated peptide (LAP). Serum
proteinase
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the for ...
s such as
plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encoded ...
catalyze the release of active TGF-β from the complex. This often occurs on the surface of macrophages where the latent TGF-β complex is bound to
CD36
CD36 (cluster of differentiation 36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is enco ...
via its ligand,
thrombospondin-1
Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the ''THBS1'' gene.
Thrombospondin 1 is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein that mediates cell-to-cell and ...
(TSP-1). Inflammatory stimuli that activate macrophages enhance the release of active TGF-β by promoting the activation of plasmin. Macrophages can also endocytose IgG-bound latent TGF-β complexes that are secreted by plasma cells and then release active TGF-β into the extracellular fluid. Among its key functions is
regulation of inflammatory processes, particularly in the gut.
TGF-β also plays a crucial role in stem cell differentiation as well as T-cell regulation and differentiation.
Because of its role in immune and stem cell regulation and differentiation, it is a highly researched cytokine in the fields of cancer, auto-immune diseases, and infectious disease.
The
TGF-β superfamily includes endogenous growth inhibiting proteins; an increase in expression of TGF-β often correlates with the malignancy of many cancers and a defect in the cellular growth inhibition response to TGF-β. Its immunosuppressive functions then come to dominate, contributing to oncogenesis. The dysregulation of its immunosuppressive functions is also implicated in the pathogenesis of autoimmune diseases, although their effect is mediated by the environment of other cytokines present.
Structure
The primary 3 mammalian types are:
*
TGF beta 1
TGF may refer to:
Medicine
* Tubuloglomerular feedback, a reflex of the nephrons in the kidney
* Transforming growth factor, either of two classes of polypeptide growth factors (TGF-α and TGF-β)
Science
* Terrestrial gamma-ray flash, a burst o ...
– TGFB1
*
TGF beta 2
Transforming growth factor-beta 2 (TGF-β2) is a secreted protein known as a cytokine that performs many cellular functions and has a vital role during embryonic development (alternative names: Glioblastoma-derived T-cell suppressor factor, G-TSF ...
– TGFB2
*
TGF beta 3
Transforming growth factor beta-3 is a protein that in humans is encoded by the gene.
It is a type of protein, known as a cytokine, which is involved in cell differentiation, embryogenesis and development. It belongs to a large family of cytokine ...
– TGFB3
A fourth member, TGF beta 4, has been identified in birds
– TGRB4 (synonyms: endometrial bleeding associated factor beta-4 (EBAF), Lefty preproprotein, LEFTA; Left-Right Determination Factor 2; LEFTYA; Left-Right Determination Factor A; Transforming Growth Factor Beta-4; Protein Lefty-2; Protein Lefty-A).
A fourth member of the subfamily, TGFB4, has been identified in birds and a fifth, TGFB5, only in frogs.
The peptide structures of the TGF-β isoforms are highly similar (homologies on the order of 70–80%). They are all encoded as large
protein precursor
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein (or peptide) that can be turned into an active form by post-translational modification, such as breaking off a piece of the molecule or adding on another molecule ...
s; TGF-β1 contains 390
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s and TGF-β2 and TGF-β3 each contain 412 amino acids. They each have an N-terminal
signal peptide
A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-ter ...
of 20–30 amino acids that they require for secretion from a cell, a pro-region called latency-associated peptide (LAP - Alias: Pro-TGF beta 1, LAP/TGF beta 1), and a 112-114 amino acid
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
region that becomes the mature TGF-β molecule following its release from the pro-region by
proteolytic
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
cleavage. The mature TGF-β protein dimerizes to produce a 25 KDa active protein with many conserved structural motifs. TGF-β has nine
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
residues that are conserved among its family. Eight form
disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
s within the protein to create a
cysteine knot
A cystine knot is a protein structural motif containing three disulfide bridges (formed from pairs of cysteine residues). The sections of polypeptide that occur between two of them form a loop through which a third disulfide bond passes, forming ...
structure characteristic of the TGF-β superfamily. The ninth cysteine forms a
disulfide bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
with the ninth cysteine of another TGF-β protein to produce a dimer. Many other conserved residues in TGF-β are thought to form secondary structure through hydrophobic interactions. The region between the fifth and sixth conserved cysteines houses the most divergent area of TGF-β proteins that is exposed at the surface of the protein and is implicated in receptor binding and specificity of TGF-β.
Latent TGF-β complex
All three TGF-βs are synthesized as precursor molecules containing a propeptide region in addition to the TGF-β homodimer. After it is synthesized, the TGF-β homodimer interacts with a Latency-Associated Peptide (LAP), a protein derived from the N-terminal region of the TGF-β gene product, forming a complex called Small Latent Complex (SLC). This complex remains in the cell until it is bound by another protein called Latent TGF-β-Binding Protein (LTBP), forming a larger complex called Large Latent Complex (LLC). It is this LLC that gets secreted to the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
(ECM).
In most cases, before the LLC is secreted, the TGF-β precursor is cleaved from the propeptide but remains attached to it by noncovalent bonds. After its secretion, it remains in the extracellular matrix as an inactivated complex containing both the LTBP and the LAP which need to be further processed in order to release active TGF-β.
The attachment of TGF-β to the LTBP is by disulfide bond which allows it to remain inactive by preventing it from binding to its receptors . Because different cellular mechanisms require distinct levels of TGF-β signaling, the inactive complex of this cytokine gives opportunity for a proper mediation of TGF-β signaling.
There are four different LTBP isoforms known, LTBP-1, LTBP-2, LTBP-3 and LTBP-4. Mutation or alteration of LAP or LTBP can result in improper TGF-β signaling. Mice lacking LTBP-3 or LTBP-4 demonstrate phenotypes consistent to phenotypes seen in mice with altered TGF-β signaling. Furthermore, specific LTBP isoforms have a propensity to associate with specific LAP•TGF-β isoforms. For example, LTBP-4 is reported to bind only to TGF-β1, thus, mutation in LTBP-4 can lead to TGF-β associated complications which are specific to tissues that predominantly involves TGF-β1. Moreover, the structural differences within the LAP's provide different latent TGF-β complexes which are selective but to specific stimuli generated by specific activators.
Activation
Although TGF-β is important in regulating crucial cellular activities, only a few TGF-β activating pathways are currently known, and the full mechanism behind the suggested activation pathways is not yet well understood. Some of the known activating pathways are cell or tissue specific, while some are seen in multiple cell types and tissues.
Proteases, integrins, pH, and reactive oxygen species are just few of the currently known factors that can activate TGF-β, as discussed below.
It is well known that perturbations of these activating factors can lead to unregulated TGF-β signaling levels that may cause several complications including inflammation, autoimmune disorders, fibrosis, cancer and cataracts.
In most cases, an activated TGF-β ligand will initiate the TGF-β signaling cascade as long as TGF-β receptors I and II are available for binding. This is due to a high affinity between TGF-β and its receptors, suggesting why the TGF-β signaling recruits a latency system to mediate its signaling.
Integrin-independent activation
Activation by protease and metalloprotease
Plasmin
Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encoded ...
and a number of
matrix metalloproteinase
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs b ...
s (MMP) play a key role in promoting tumor invasion and tissue remodeling by inducing proteolysis of several ECM components.
The TGF-β activation process involves the release of the LLC from the matrix, followed by further proteolysis of the LAP to release TGF-β to its receptors.
MMP-9
Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracel ...
and
MMP-2
72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the ''MMP2'' gene. The ''MMP2'' gene is located on chromosome 16 at position 12.2.
Function
Proteins of the ...
are known to cleave latent TGF-β.
The LAP complex contains a protease-sensitive hinge region which can be the potential target for this liberation of TGF-β.
Despite the fact that MMPs have been proven to play a key role in activating TGF-β, mice with mutations in MMP-9 and MMP-2 genes can still activate TGF-β and do not show any TGF-β deficiency phenotypes, this may reflect redundancy among the activating enzymes
suggesting that other unknown proteases might be involved.
Activation by pH
Acidic conditions can denature the LAP. Treatment of the medium with extremes of pH (1.5 or 12) resulted in significant activation of TGF-β as shown by radio-receptor assays, while mild acid treatment (pH 4.5) yielded only 20-30% of the activation achieved by pH 1.5.
Activation by reactive oxygen species (ROS)
The structure of LAP is important in maintaining its function. Structure modification of LAP can lead to disturb the interaction between LAP and TGF-β and thus activating it. Factors that may cause such modification may include hydroxyl radicals from reactive oxygen species (ROS). TGF-β was rapidly activated after ''in vivo'' radiation exposure ROS.
Activation by thrombospondin-1
Thrombospondin-1
Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the ''THBS1'' gene.
Thrombospondin 1 is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein that mediates cell-to-cell and ...
(TSP-1) is a matricellular glycoprotein found in plasma of healthy patients with levels in the range of 50–250 ng/ml. TSP-1 levels are known to increase in response to injury and during development. TSP-1 activates latent TGF-beta by forming direct interactions with the latent TGF-β complex and induces a conformational rearrangement preventing it from binding to the matured TGF-β.
Activation by Alpha(V) containing integrins
The general theme of integrins participating in latent TGF-β1 activation arose from studies that examined mutations/knockouts of β6 integrin, αV integrin, β8 integrin and in LAP. These mutations produced phenotypes that were similar to phenotypes seen in TGF-β1 knockout mice. Currently there are two proposed models of how αV containing integrins can activate latent TGF-β1; the first proposed model is by inducing conformational change to the latent TGF-β1 complex and hence releasing the active TGF-β1 and the second model is by a protease-dependent mechanism.
Conformation change mechanism pathway (without proteolysis)
αVβ6 integrin was the first integrin to be identified as TGF-β1 activator.
LAPs contain an RGD motif which is recognized by vast majority of αV containing integrins, and αVβ6 integrin can activate TGF-β1 by binding to the RGD motif present in LAP-β1 and LAP-β3. Upon binding, it induces adhesion-mediated cell forces that are translated into biochemical signals which can lead to liberation/activation of TGFb from its latent complex.
This pathway has been demonstrated for activation of TGF-β in epithelial cells and does not associate MMPs.
Integrin protease-dependent activation mechanism
Because MMP-2 and MMP-9 can activate TGF-β through
proteolytic degradation
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
of the latent TGF beta complex,
αV containing integrins activate TGF-β1 by creating a close connection between the latent TGF-β complex and MMPs. Integrins αVβ6 and αVβ3 are suggested to simultaneously bind the latent TGF-β1 complex and proteinases, simultaneous inducing conformational changes of the LAP and sequestering proteases to close proximity. Regardless of involving MMPs, this mechanism still necessitate the association of integrins and that makes it a non proteolytic pathway.
Signaling pathways
Canonical signaling: The SMAD pathway
Smads are a class of intracellular signalling proteins and transcription factors for the TGF-β family of signalling molecules. This pathway conceptually resembles the
Jak-STAT signal transduction pathway characterized in the activation of cytokine receptors implicated, for example, in the B cell isotype switching pathway. As previously stated, the binding of the TGF-β ligand to the TGF-β receptor, the type 2 receptor kinase phosphorylates and activates the type 1 receptor kinase that activates a signaling cascade. In the case of Smad, receptor-activated Smads are phosphorylated by the type 1 TGF-β receptor kinase, and these go on to complex with other Smads, which is able to translocate into the cell nucleus to induce transcription of different effectors.
More specifically, activated TGF-β complexes bind to the type 2 domain of the TGF-β receptor which then recruits and phosphorylates a type 1 receptor. The type 1 receptor then recruits and phosphorylates a
receptor regulated SMAD (R-SMAD). The R-SMAD then binds to the common SMAD (coSMAD)
SMAD4
SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 (Deleted in Pancreatic Cancer-4) is a highly conserved protein present in all metazoans. It belongs to the SMAD family of transcription factor proteins, ...
and forms a heterodimeric complex. This complex then enters the
cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
where it acts as a transcription factor for various genes, including those to activate the
mitogen-activated protein kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
8 pathway, which triggers
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. The SMAD pathway is regulated by feedback inhibition. SMAD6 and SMAD7 may block type I receptors. There is also substantial evidence that TGF-β-dependent signaling via the SMAD-3 pathway is responsible for many of the inhibitory functions of TGF-β discussed in later sections and thus it is implicated in oncogenesis.
The Smads are not the only TGF-β-regulated signaling pathways. Non-Smad signaling proteins can initiate parallel signaling that eventually cooperate with the Smads or crosstalk with other major signaling pathways. Among them, the mitogen-activated protein kinase (MAPK) family that include the extracellular-regulated kinases (ERK1 and 2), Jun N-terminal kinases (JNKs) and p38 MAPK play an important role in the TGF-β signaling.
ERK 1 and 2 are activated via the Raf-Ras-MEK1/2 pathway induced by mitogenic stimuli such as epidermal growth factor,
whereas the JNK and p38 MAPK are activated by the MAPK kinase, activated themselves by the TGF-β-activated kinase-1 (TAK1) upon stress stimuli.
Apoptosis via the DAXX pathway
TGF-β induces apoptosis, or programmed cell death, in human lymphocytes and hepatocytes. The importance of this function is clear in TGF-β deficient mice which experience hyperproliferation and unregulated autoimmunity.
In a separate apoptotic pathway from the association of
death-associated protein 6
Death-associated protein 6 also known as Daxx is a protein that in humans is encoded by the ''DAXX'' gene.
Function
Daxx, a Death domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death rece ...
(DAXX) with the death receptor
Fas, there is evidence of association and binding between DAXX and type 2 TGF-β receptor kinase, wherein DAXX binds to the C-terminal region of the type 2 TGF-β receptor. The exact molecular mechanism is unknown, but as a general overview, DAXX is then phosphorylated by homeodomain-interacting protein kinase 2 (HIPK2), which then activates
apoptosis signal-inducing kinase 1 (ASK1), which goes on to activate the
Jun amino-terminal kinase (JNK) pathway and thus apoptosis as seen in the left panel of the adjacent image.
TGFβ receptor inhibitors
RepSox is a selective
TGFβRI/ALK5 inhibitor that inhibits the binding of ATP to TGFβRI and subsequent TGFβRI phosphorylation, thus inhibiting TGF-β signaling.
Also
SB-431542
SB-431542 is a drug candidate developed by GlaxoSmithKline (GSK) as an inhibitor of the activin receptor-like kinase (ALK) receptors, ALK5, ALK4 and ALK7. However, it is ''not'' an inhibitor of anaplastic lymphoma kinase (which are commonly kno ...
and A83-01 inhibit TGFβRI/ALK5 and the type I receptor ALK4/7.
Galunisertib
Galunisertib (LY2157299) is a small molecular experimental cancer drug previously in development by Eli Lilly. It is a TGF-b inhibitor. Development of galunisertib by Eli Lilly was discontinued in January 2020.
Galunisertib was investigated in a ...
is the selective and potent TGFβRI kinase inhibitor.
TGF-β mimic
The parasitic roundworm ''
Heligmosomoides polygyrus
''Heligmosomoides polygyrus'', previously named ''Nematospiroides dubius'', is a naturally occurring intestinal roundworm of rodents. It belongs to the family Trychostrongylidae, and male and female worms are morphologically distinguishable. The ...
'' secretes a molecule that mimics the ability of mammalian TGF-β to bind to the TGFβR complex and trigger downstream signalling pathways. This molecule, termed ''Hp''-TGM, shares no sequence homology to TGF-β and is secreted by ''H. polygyrus'' in a biologically active form. ''Hp''-TGM consists of 5 domains, with the first three shown to crucial for interaction with the TGFβR complex, with functions for domains 4 and 5 not yet known. Importantly, ''Hp''-TGM shows promise as a novel therapeutic as it induces less fibrosis than TGF-β ''in vivo'' in mice and can be used to induce populations of human
FOXP3+ regulatory T cells that had much greater stability than those induced by TGF-β.
Effects on immune cells
T lymphocytes
TGF-β1 plays a role in the induction from CD4
+ T cells of both
induced Treg cells (iT
reg cells), which have a regulatory function, and
Th17 cells, which secrete pro-inflammatory cytokines.
TGF-β1 alone precipitates the expression of FOXP3 and T
reg differentiation from activated T helper cells, and the mechanism for this differentiation is unknown for both induced T regulatory cells as well as natural T regulatory cells. In mouse models, the effect of TGF-β1 appears to be age-dependent.
Studies show that neutralization of TGF-β1 in vitro inhibits the differentiation of helper T cells into T
h17 cells. The role of TGF-β1 in the generation of T
h17 cells goes against its dominant conceptualization as an anti-inflammatory cytokine; however, the shared requirement between inflammatory and anti-inflammatory immune cells suggests that an imbalance between these two cell types can be an important link to autoimmunity.
Co-activation by IL-6 from activated dendritic cells, which serves to activate the transcription factor
STAT3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family.
Function
STAT3 is a member of the STAT protein family. In respons ...
, is required in addition to TGF-β1 for the differentiation of T
h17 cells. However, the molecular mechanism of T
h17 differentiation is not well understood.
Because T
h17 cells are distinct from T
h1 and T
h2 lineages in that they have been shown to be capable of regulatory functions, this is further evidence of TGF-β1's regulatory function in the immune system.
B lymphocytes
TGF-β has mainly inhibitory effects on B lymphocytes. TGF-β inhibits B cell proliferation. The exact mechanism is unknown, but there is evidence that TGF-β inhibits B cell proliferation by inducing the transcription factor Id3, inducing expression of cyclin-dependent kinase inhibitor 21 (a regulator of cell cycle progression through the G1 and S phase), and repressing other key regulatory genes such as c-myc and ATM.
CD40, a key surface molecule in the activation of the innate immune response, can induce Smad7 expression to reverse the growth inhibition of B cells induced by TGF-β. TGF-β also blocks B cell activation and promotes class switching
IgA Iga may refer to:
Arts and entertainment
* Ambush at Iga Pass, a 1958 Japanese film
* Iga no Kagemaru, Japanese manga series
* Iga, a set of characters from the Japanese novel '' The Kouga Ninja Scrolls''
Biology
* ''Iga'' (beetle), a gen ...
in both human and mouse B cells and has an otherwise inhibitory function for antibody production.
TGF-β also induces apoptosis of immature or resting B cells; the mechanism is unknown, but may overlap with its anti-proliferation pathway. TGF-β has been shown to downregulate c-myc as it does in the inhibition of B cell proliferation. It is also known to induce NF-κB inhibitor IKBa, inhibiting NF-κB activation. NF-κB is a transcription factor that regulates the production of cytokines like IL-1, TNF-a, and defensins, although its function in apoptosis may be separate from this function.
Macrophages
The general consensus in the literature is that TGF-β stimulates resting monocytes and inhibits activated macrophages. For monocytes, TGF-β has been shown to function as a chemoattractant as well as an upregulator of inflammatory response. However, TGF-β has also been shown to downregulate inflammatory cytokine production in monocytes and macrophages, likely by the aforementioned inhibition of NF-κB. This contradiction may be due to the fact that the effect of TGF-β has been shown to be highly context-dependent.
TGF-β is thought to play a role in alternative macrophage activation seen in lean mice, and these macrophages maintain an anti-inflammatory phenotype. This phenotype is lost in obese mice, who have not only more macrophages than lean mice but also classically activated macrophages which release TNF-α and other pro-inflammatory cytokines that contribute to a chronically pro-inflammatory milieu.
Cell cycle
TGF-β plays a crucial role in the regulation of the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
by blocking progress through
G1 phase. TGF-β causes synthesis of p15 and p21 proteins, which block the cyclin:CDK complex responsible for
retinoblastoma protein
The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
(Rb) phosphorylation. Thus, TGF-β blocks advancement through the G
1 phase of the cycle.
In doing so, TGF-β suppresses expression of
c-myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes referre ...
, a gene which is involved in G
1 cell cycle progression.
Clinical significance
Cancer
In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. In many cancer cells, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells. It causes
immunosuppression
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
and
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, which makes the cancer more invasive. TGF-β1 has been implicated in the process of activating Hepatic Stellate Cells (HSCs) with the magnitude of hepatic fibrosis being in proportion to increase in TGF β levels. Studies have shown that ACTA2 is associated with TGF β pathway that enhances contractile properties of HSCs leading to Liver fibrosis. TGF-β also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction.
Normal tissue integrity is preserved by feedback interactions between different cell types that express adhesion molecules and secrete cytokines. Disruption of these feedback mechanisms in cancer damages a tissue. When TGF-β signaling fails to control NF-κB activity in cancer cells, this has at least two potential effects: first, it enables the malignant tumor to persist in the presence of activated immune cells, and second, the cancer cell outlasts immune cells because it survives in the presence of apoptotic, and anti-inflammatory mediators.
Furthermore,
forkhead box protein 3 (FOXP3) as a transcription factor is an essential molecular marker of regulatory T (
Treg) cells.
FOXP3
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of reg ...
polymorphism (rs3761548) might be involved in cancer progression like
gastric cancer
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
through influencing Tregs function and the secretion of immunomodulatory cytokines such as
IL-10,
IL-35
Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the develo ...
, and
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
.
Tuberculosis
''
Mycobacterium tuberculosis
''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...
'' infection, or tuberculosis, has been shown to result in increased levels of active TGF-β within the lung. Due to the broad range of suppressive effects of TGF-β on immune cells, computer modeling has predicted that TGF-β blockade may improve immune responses and infection outcome. Research in animal models has further shown that TGF-β impairs immune responses and elimination of TGF-β signaling results in and enhanced T cell response and lower bacterial burdens. Thus, therapies which block TGF-β may have the potential to improve therapy for tuberculosis.
Heart disease
One animal study suggests that
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
suppresses the responsiveness of cardiovascular cells to TGF-β and its protective qualities, thus allowing
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
and
heart disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
to develop, while
statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
Low- ...
s, drugs that lower cholesterol levels, may enhance the responsiveness of cardiovascular cells to the protective actions of TGF-β.
TGF-β is involved in regeneration of zebrafish heart.
Marfan syndrome
TGF-β signaling also likely plays a major role in the pathogenesis of
Marfan syndrome
Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have exceptionally flexible joints a ...
,
a disease characterized by disproportionate height,
arachnodactyly
Arachnodactyly ("spider fingers") is a medical condition that is characterized by fingers and toes that are abnormally long and slender, in comparison to the palm of the hand and arch of the foot. In some cases, the thumbs of an individual with the ...
,
ectopia lentis
Ectopia lentis is a displacement or malposition of the eye's crystalline lens from its normal location. A partial dislocation of a lens is termed lens subluxation or subluxated lens; a complete dislocation of a lens is termed lens luxation or lu ...
and heart complications such as
mitral valve prolapse
Mitral valve prolapse (MVP) is a valvular heart disease characterized by the displacement of an abnormally thickened mitral valve leaflet into the left atrium during systole. It is the primary form of myxomatous degeneration of the valve. There ar ...
and aortic enlargement increasing the likelihood of
aortic dissection
Aortic dissection (AD) occurs when an injury to the innermost layer of the aorta allows blood to flow between the layers of the aortic wall, forcing the layers apart. In most cases, this is associated with a sudden onset of severe chest or ...
. While the underlying defect in Marfan syndrome is faulty synthesis of the
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
fibrillin
Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers found in connective tissue.
Fibrillin is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which ...
I, normally an important component of
elastic fibers
Elastic fibers (or yellow fibers) are an essential component of the extracellular matrix composed of bundles of proteins (elastin) which are produced by a number of different cell types including fibroblasts, endothelial, smooth muscle, and air ...
, it has been shown that the Marfan syndrome phenotype can be relieved by addition of a TGF-β antagonist in affected mice. This suggests that while the symptoms of Marfan syndrome may seem consistent with a connective tissue disorder, the mechanism is more likely related to reduced sequestration of TGF-β by fibrillin.
Loeys–Dietz syndrome
TGF-β signaling is also disturbed in
Loeys–Dietz syndrome
Loeys–Dietz syndrome (LDS) is an autosomal dominant genetic connective tissue disorder. It has features similar to Marfan syndrome and Ehlers–Danlos syndrome. The disorder is marked by aneurysms in the aorta, often in children, and the aorta ...
which is caused by mutations in the TGF-β receptor.
Obesity and diabetes
TGF-β/SMAD3 signaling pathway is important in regulating glucose and energy homeostasis and might play a role in
diabetic nephropathy
Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease ...
.
As noted above in the section about macrophages, loss of TGF-β signaling in obesity is one contributor to the inflammatory milieu generated in the case of obesity.
Multiple Sclerosis
Induced T regulatory cells (iTreg), stimulated by TGF-β in the presence of
IL-2
The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...
, suppressed the development of
experimental autoimmune encephalomyelitis
Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with ro ...
(EAE), an animal model of
multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
(MS) via a
FOXP3
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of reg ...
and
IL-10 mediated response. This suggests a possible role for TGF-β and iTreg in the regulation and treatment of MS.
Decreased levels of TGF-β have been observed in patients diagnosed with multiple sclerosis.
Its role in multiple sclerosis can be explained due to TGF-β role in regulating apoptosis of
Th17 cells.
When TGF-β levels decrease, they are unable to induce T
h17 cells apoptosis.
T
h17 cells secretes TNF-α, which induces demyelination of the oligodendroglial via TNF receptor 1.
The decreased TGF-β levels lead to increased T
h17 cells and subsequently increased TNFα levels.
As a result, demyelination of neurons occurs.
TGF-β have also been observed to induce
oligodendrocyte
Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...
(
myelin sheath
Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
producing cells) growth.
Hence, the decreased TGF-β levels during MS may also prevent remyelination of neurons.
Neurological
Higher concentrations of TGF-β are found in the blood and cerebrospinal fluid of patients with
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
as compared to control subjects, suggesting a possible role in the neurodegenerative cascade leading to Alzheimer's disease symptoms and pathology.
The role of TGF-β in neuronal dysfunction remains an active area of research.
Other
Overactive TGF-β pathway, with an increase of TGF-β2,
was reported in the studies of patients with
keratoconus
Keratoconus (KC) is a disorder of the eye that results in progressive thinning of the cornea. This may result in blurry vision, double vision, nearsightedness, irregular astigmatism, and light sensitivity leading to poor quality-of-life. Usu ...
.
There is substantial evidence in animal and some human studies that TGF-β in breast milk may be a key immunoregulatory factor in the development of infant immune response, moderating the risk of atopic disease or autoimmunity.
Skin aging is caused in part by
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
, which reduces the subcutaneous fat that gives skin a pleasant appearance and texture.
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
does this by blocking the conversion of
dermal fibroblasts into
fat cells
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
; with fewer fat cells underneath to provide support, the skin becomes saggy and wrinkled. Subcutaneous fat also produces
cathelicidin
Cathelicidin antimicrobial peptide (CAMP) is a polypeptide that is primarily stored in the lysosomes of macrophages and Granulocyte, polymorphonuclear leukocytes (PMNs); in humans, the ''CAMP'' gene encodes the peptide precursor CAP-18 (18 kDa), w ...
, which is a
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
that fights bacterial infections.
See also
*
Anita Roberts
Anita Bauer Roberts (April 3, 1942 – May 26, 2006) was an American molecular biologist who made pioneering observations of a protein, TGF-β, that is critical in healing wounds and bone fractures and that has a dual role in blocking or stimu ...
, a molecular biologist who made pioneering observations of TGF-β
References
Further reading
*
External links
Description of the TGF beta producing genes at ncbi.nlm.nih.govDiagram of the TGF beta signaling pathway at genome.ad.jpThe TGF-beta systemNature Reviews Molecular Cell Biology
*
SMART
Smart or SMART may refer to:
Arts and entertainment
* ''Smart'' (Hey! Say! JUMP album), 2014
* Smart (Hotels.com), former mascot of Hotels.com
* ''Smart'' (Sleeper album), 1995 debut album by Sleeper
* ''SMart'', a children's television ser ...
br>
TGFB domain annotationEuropean Molecular Biology Laboratory
The European Molecular Biology Laboratory (EMBL) is an intergovernmental organization dedicated to molecular biology research and is supported by 27 member states, two prospect states, and one associate member state. EMBL was created in 1974 and ...
Heidelberg
*
Biochemists Solve Structure Of TGF-Beta And Its Receptor. 2008– shows TGF-β3 dimer in TGFB-receptor
Measurement of Human Latent TGF-β1IntroPro Entry- IPR016319
{{DEFAULTSORT:Transforming Growth Factor Beta
TGFβ domain