Heparin, Hormones, Immunology, Metals, Reproduction
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The transforming growth factor beta receptors

The TGF-β superfamily. Based on their structural features, the mammalian members of the TGF-β family are subdivided into (i) TGF-βs, (ii) activins/inhibins, and (iii) BMPs/growth and differentiation factors (GDFs). https://www.researchgate.net/publication/329884659_The_Role_of_TGF-b_and_Its_Receptors_in_Gastrointestinal_Cancers

The transforming growth factor beta (TGF-β) superfamily is a large group of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983.

They interact with TGF-beta receptors.

The transforming growth factor beta (TGFβ) receptors are a family of serine/threonine kinase receptors involved in TGF beta signaling pathway. These receptors bind growth factor and cytokine signaling proteins in the TGF-beta family such as TGFβs (TGFβ1, TGFβ2, TGFβ3), bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), activin and inhibin, myostatin, anti-Müllerian hormone (AMH), and NODAL. TGFβ family receptors are grouped into three types, type I, type II, and type III. There are seven type I receptors, termed the activin-like receptors (ALK1–7), five type II receptors, and one type III receptor, for a total of 13 TGFβ superfamily receptors. In the transduction pathway, ligand-bound type II receptors activate type I receptors by phosphorylation, which then autophosphorylate and bind SMAD. The Type I receptors have a glycine-serine (GS, or TTSGSGSG) repeat motif of around 30 AA, a target of type II activity. At least three, and perhaps four to five of the serines and threonines in the GS domain, must be phosphorylated to fully activate TbetaR-1.

Type I

Type II

Type III

Unlike the Type I and II receptors which are kinases, TGFBR3 has a Zona pellucida-like domain. Its core domain binds TGF-beta family ligands and its heparan sulfate chains bind bFGF. It acts as a reservoir of ligand for TGF-beta receptors.

Many proteins have since been described as members of the TGF-β superfamily in a variety of species, including invertebrates as well as vertebrates and categorized into 23 distinct gene types that fall into four major subfamilies.

1. The TGF-β subfamily

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 signaling proteins. TGFB proteins are produced by all white blood cell lineages.

Activated TGF-β complexes with other factors to form a serine/threonine kinase 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 (LTBP) and latency-associated peptide (LAP). Serum proteinases such as plasmin 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 via its ligand, thrombospondin-1 (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.

The primary 3 mammalian types are:

A fourth member, TGF beta 4, has been identified in birds – TGRB4 (synonyms: endometrial bleeding associated factor beta-4 (EBAF)[citation needed], Lefty preproprotein[citation needed], LEFTA[citation needed]; Left-Right Determination Factor 2; LEFTYA; Left-Right Determination Factor A; Transforming Growth Factor Beta-4; Protein Lefty-2; Protein Lefty-A).

A fifth member of the subfamily, TGFB5, has been identified only in frogs.

  • Roberts, Anita B.; Kim, Seong-Jin; Noma, Takafumi; Glick, Adam B.; Lafyatis, Robert; Lechleider, Robert; Jakowlew, Sonia B.; Geiser, Andrew; O’Reilly, Michael A.; Danielpour, David; Sporn, Michael B. (2007). “Multiple Forms of TGF-β: Distinct Promoters and Differential Expression”. Ciba Foundation Symposium 157 – Clinical Applications of TGF-β. Novartis Foundation Symposia. Vol. 157. pp. 7–28. doi:10.1002/9780470514061.ch2. ISBN 978-0-470-51406-1. PMID 1906395.

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 precursors; TGF-β1 contains 390 amino acids and TGF-β2 and TGF-β3 each contain 412 amino acids. They each have an N-terminal signal peptide 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 region that becomes the mature TGF-β molecule following its release from the pro-region by proteolytic cleavage. The mature TGF-β protein dimerizes to produce a 25 KDa active protein with many conserved structural motifs. TGF-β has nine cysteine residues that are conserved among its family. Eight form disulfide bonds within the protein to create a cysteine knot structure characteristic of the TGF-β superfamily. The ninth cysteine forms a disulfide bond 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.

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 and a number of matrix metalloproteinases (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 and MMP-2 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.

Average pH of common solutions
SubstancepH rangeType
Battery acid< 1Acid
Gastric acid1.0 – 1.5
Vinegar4-5
Orange juice3.3 – 4.2
Black coffee5 – 5.03
Milk6.5 – 6.8
Pure water at 25 °C7Neutral
Sea water7.5 – 8.4Base
Ammonia11.0 – 11.5
Bleach12.5
1 M NaOH14

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 (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 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.

Further reading

External links

2. The bone morphogenetic proteins and the growth differentiation factors

Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue architecture throughout the body. The important functioning of BMP signals in physiology is emphasized by the multitude of roles for dysregulated BMP signaling in pathological processes. Cancerous disease often involves misregulation of the BMP signaling system. Absence of BMP signaling is, for instance, an important factor in the progression of colon cancer, and conversely, overactivation of BMP signaling following reflux-induced esophagitis provokes Barrett’s esophagus and is thus instrumental in the development of esophageal adenocarcinoma.

BMPs interact with specific receptors on the cell surface, referred to as bone morphogenetic protein receptors (BMPRs).

Signal transduction through BMPRs results in mobilization of members of the SMAD family of proteins. The signaling pathways involving BMPs, BMPRs and SMADs are important in the development of the heart, central nervous system, and cartilage, as well as post-natal bone development.

They have an important role during embryonic development on the embryonic patterning and early skeletal formation. As such, disruption of BMP signaling can affect the body plan of the developing embryo. For example, BMP4 and its inhibitors noggin and chordin help regulate polarity of the embryo (i.e. back to front patterning). Specifically BMP-4 and its inhibitors play a major role in neurulation and the development of the neural plate. BMP-4 signals ectoderm cells to develop into skin cells, but the secretion of inhibitors by the underlying mesoderm blocks the action of BMP-4 to allow the ectoderm to continue on its normal course of neural cell development. Additionally, secretion of BMPs by the roof plate in the developing spinal cord helps to specify dorsal sensory interneurons.

As a member of the transforming growth factor-beta superfamily, BMP signaling regulates a variety of embryonic patterning during fetal and embryonic development. For example, BMP signaling controls the early formation of the Mullerian duct (MD) which is a tubular structure in early embryonic developmental stage and eventually becomes female reproductive tracts. Chemical inhibiting BMP signals in chicken embryo caused a disruption of MD invagination and blocked the epithelial thickening of the MD-forming region, indicating that the BMP signals play a role in early MD development. Moreover, BMP signaling is involved in the formation of foregut and hindgut, intestinal villus patterning, and endocardial differentiation. Villi contribute to increase the effective absorption of nutrients by extending the surface area in small intestine. Gain or lose function of BMP signaling altered the patterning of clusters and emergence of villi in mouse intestinal model. BMP signal derived from myocardium is also involved in endocardial differentiation during heart development. Inhibited BMP signal in zebrafish embryonic model caused strong reduction of endocardial differentiation, but only had little effect in myocardial development. In addition, Notch-Wnt-Bmp crosstalk is required for radial patterning during mouse cochlea development via antagonizing manner.

Mutations in BMPs and their inhibitors are associated with a number of human disorders which affect the skeleton.

BMPs are also involved in adipogenesis and functional regulation of adipose tissue. BMP4 favors white adipogenesis, whereas BMP7 activates brown fat functionality; BMP inhibitors are also involved in this regulation. 

Types

Originally, seven such proteins were discovered. Of these, six (BMP2 through BMP7) belong to the Transforming growth factor beta superfamily of proteins. BMP1 is a metalloprotease. Since then, thirteen more BMPs, all of which are in the TGF-beta family, have been discovered, bringing the total to twenty.

  • Even J, Eskander M, Kang J (Sep 2012). “Bone morphogenetic protein in spine surgery: current and future uses”. The Journal of the American Academy of Orthopaedic Surgeons. 20 (9): 547–52. doi:10.5435/JAAOS-20-09-547. PMID 22941797.

The current nomenclature only recognizes 13, as many others are put under the growth differentiation factor naming instead.

BMPKnown functionsGene Locus
BMP1*BMP1 does not belong to the TGF-β family of proteins. It is a metalloprotease that acts on procollagen I, II, and III. It is involved in cartilage development.Chromosome: 8; Location: 8p21
BMP2Acts as a disulfide-linked homodimer and induces bone and cartilage formation. It is a candidate as a retinoid mediator. Plays a key role in osteoblast differentiation.Chromosome: 20; Location: 20p12
BMP3Induces bone formation.Chromosome: 14; Location: 14p22
BMP4Regulates the formation of teeth, limbs and bone from mesoderm. It also plays a role in fracture repair, epidermis formation, dorsal-ventral axis formation, and ovarian follical development.Chromosome: 14; Location: 14q22-q23
BMP5Performs functions in cartilage development.Chromosome: 6; Location: 6p12.1
BMP6Plays a role in joint integrity in adults. Controls iron homeostasis via regulation of hepcidin.Chromosome: 6; Location: 6p12.1
BMP7Plays a key role in osteoblast differentiation. It also induces the production of SMAD1. Also key in renal development and repair.Chromosome: 20; Location: 20q13
BMP8aInvolved in bone and cartilage development.Chromosome: 1; Location: 1p35–p32
BMP8bExpressed in the hippocampus.Chromosome: 1; Location: 1p35–p32
BMP10May play a role in the trabeculation of the embryonic heart.Chromosome: 2; Location: 2p14
BMP11Controls anterior-posterior patterning.Chromosome: 12; Location: 12p
BMP15May play a role in oocyte and follicular development.Chromosome: X; Location: Xp11.2

Several BMPs are also named ‘cartilage-derived morphogenetic proteins’ (CDMPs), while others are referred to as ‘growth differentiation factors‘ (GDFs).

Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.

  • Herpin A, Lelong C, Favrel P (2004). “Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans”. Dev Comp Immunol. 28 (5): 461–85. doi:10.1016/j.dci.2003.09.007. PMID 15062644.

Several members of this subfamily have been described, and named GDF1 through GDF15.

3. The activin and inhibin subfamilies

Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle.

Many other functions have been found to be exerted by activin, including roles in cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine function.

Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion.

The existence of inhibin was hypothesized as early as 1916; however, it was not demonstrated to exist until Neena Schwartz and Cornelia Channing‘s work in the mid-1970s, after which both proteins were molecularly characterized ten years later.

Activin is a dimer composed of two identical or very similar beta subunits. Inhibin is also a dimer wherein the first component is a beta subunit similar or identical to the beta subunit in activin. However, in contrast to activin, the second component of the inhibin dimer is a more distantly-related alpha subunit. Activin, inhibin and a number of other structurally related proteins such as anti-Müllerian hormone, bone morphogenetic protein, and growth differentiation factor belong to the TGF-β protein superfamily.

Structure

The activin and inhibin protein complexes are both dimeric in structure, and, in each complex, the two monomers are linked to one another by a single disulfide bond.

In addition, both complexes are derived from the same family of related genes and proteins but differ in their subunit composition.

  • Burger HG, Igarashi M (April 1988). “Inhibin: definition and nomenclature, including related substances”. The Journal of Clinical Endocrinology and Metabolism. 66 (4): 885–6. PMID 3346366.

The alpha and beta subunits share approximately 25% sequence similarity, whereas the similarity between beta subunits is approximately 65%.

In mammals, four beta subunits have been described, called activin βA, activin βB, activin βC and activin βE. Activin βA and βB are identical to the two beta subunits of inhibin. A fifth subunit, activin βD, has been described in Xenopus laevis. Two activin βA subunits give rise to activin A, one βA, and one βB subunit gives rise to activin AB, and so on. Various, but not all theoretically possible, heterodimers have been described.

The subunits are linked by a single covalent disulfide bond.

The βC subunit is able to form activin heterodimers with βA or βB subunits but is unable to dimerize with inhibin α.

Function

Activin

Activin is produced in the gonads, pituitary gland, placenta, and other organs:

Inhibin

In both females and males, inhibin inhibits FSH production. Inhibin does not inhibit the secretion of GnRH from the hypothalamus.

However, the overall mechanism differs between the sexes:

In females

Inhibin is produced in the gonads, pituitary gland, placenta, corpus luteum and other organs.

FSH stimulates the secretion of inhibin from the granulosa cells of the ovarian follicles in the ovaries. In turn, inhibin suppresses FSH.

Inhibin secretion is diminished by GnRH, and enhanced by insulin-like growth factor-1 (IGF-1).

In males

It is secreted from the Sertoli cells, located in the seminiferous tubules inside the testes. 

Androgens stimulate inhibin production; this protein may also help to locally regulate spermatogenesis.

Mechanism of action

Activin

As with other members of the superfamily, activins interact with two types of cell surface transmembrane receptors (Types I and II) which have intrinsic serine/threonine kinase activities in their cytoplasmic domains:

Activin binds to the Type II receptor and initiates a cascade reaction that leads to the recruitment, phosphorylation, and activation of Type I activin receptor. This then interacts with and then phosphorylates SMAD2 and SMAD3, two of the cytoplasmic SMAD proteins.

Smad3 then translocates to the nucleus and interacts with SMAD4 through multimerization, resulting in their modulation as transcription factor complexes responsible for the expression of a large variety of genes.

Inhibin

In contrast to activin, much less is known about the mechanism of action of inhibin, but may involve competing with activin for binding to activin receptors and/or binding to inhibin-specific receptors.

Clinical significance

Activin

Activin A is more plentiful in the adipose tissue of obese, compared to lean persons.

Activin A promotes the proliferation of adipocyte progenitor cells, while inhibiting their differentiation into adipocytes.

Activin A also increases inflammatory cytokines in macrophages.

A mutation in the gene for the activin receptor ACVR1 results in fibrodysplasia ossificans progressiva, a fatal disease that causes muscle and soft tissue to gradually be replaced by bone tissue. This condition is characterized by the formation of an extra skeleton that produces immobilization and eventually death by suffocation. The mutation in ACVR1 causes activin A, which normally acts as an antagonist of the receptor and blocks osteogenesis (bone growth), to behave as an agonist of the receptor and to induce hyperactive bone growth.

  • Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS (May 2006). “A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva”. Nature Genetics. 38 (5): 525–527. doi:10.1038/ng1783. PMID 16642017. S2CID 41579747.

On 2 September 2015, Regeneron Pharmaceuticals announced that they had developed an antibody for activin A that effectively cures the disease in an animal model of the condition.

Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma (DIPG).

Elevated Activin B levels with normal Activin A levels provided a possible biomarker for myalgic encephalomyelitis/chronic fatigue syndrome.

Activin A is overexpressed in many cancers. It was shown to promote tumorigenesis by hampering the adaptive anti-tumor immune response in melanoma.

Inhibin

Quantification of inhibin A is part of the prenatal quad screen that can be administered during pregnancy at a gestational age of 16–18 weeks. An elevated inhibin A (along with an increased beta-hCG, decreased AFP, and a decreased estriol) is suggestive of the presence of a fetus with Down syndrome.

  • Aitken DA, Wallace EM, Crossley JA, Swanston IA, van Pareren Y, van Maarle M, Groome NP, Macri JN, Connor JM (May 1996). “Dimeric inhibin A as a marker for Down’s syndrome in early pregnancy”. The New England Journal of Medicine. 334 (19): 1231–6. doi:10.1056/NEJM199605093341904. PMID 8606718.

As a screening test, abnormal quad screen test results need to be followed up with more definitive tests.

It also has been used as a marker for ovarian cancer.

Inhibin B may be used as a marker of spermatogenesis function and male infertility. The mean serum inhibin B level is significantly higher among fertile men (approximately 140 pg/mL) than in infertile men (approximately 80 pg/mL).

In men with azoospermia, a positive test for inhibin B slightly raises the chances for successfully achieving pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.

External links

4. The left-right determination factors

Lefty (left-right determination factors) are a class of proteins that are closely related members of the TGF-beta superfamily of growth factors. These proteins are secreted and play a role in left-right asymmetry determination of organ systems during development. Mutations of the genes encoding these proteins have been associated with left-right axis malformations, particularly in the heart and lungs.

Lefty, a divergent member of the transforming growth factor-β (TGF beta) superfamily of proteins, was originally discovered in the Hamada lab at the Osaka University using deletion screening of cDNA libraries in P19 embryonic carcinoma cells to find clones that did not differentiate when induced to differentiate using retinoic acid. From these screens, researchers found one gene that was a tentative member of the TGF-beta superfamily that was predominantly expressed on the left side the embryo and aptly named it lefty. 

Like other members of the TGF-beta superfamily, lefty is synthesized as a preproprotein, meaning that the protein is proteolytically cleaved and excreted to produce the active form of the protein. However, lefty has only 20-25% sequence similarity with other members of the TGF-beta superfamily. Lefty is conserved in all vertebrates and many species have more than one homologue. Humans and mice, for instance have two homologues, Lefty 1 and Lefty 2, whose differential expression leads to distinct purposes while the mechanism of action is conserved.

Lefty proteins function as an antagonist of the Nodal Signaling pathway. Nodal is another signaling protein which is responsible for gastrulation, left-right patterning and induction of the primitive node. As NODAL protein diffuse through an embryo, it triggers Nodal Signaling within tissues with the required receptors and coreceptors. Activated nodal signaling leads to the transcription of the lefty gene. The protein is then expressed, proteolytically cleaved, and finally secreted. Secreted lefty binds to EGF-CFC proteins like one-eyed pinhead in zebrafish keeping the essential cofactor from associating with NODAL/ Activin-like receptor complex. This will effectually block Nodal Signaling. During induction of the primitive streak, lefty confines Nodal activity to the posterior end of the embryo, establishing a posterior signaling center and inducing the formation of the primitive streak and mesoderm. (See Nodal Signaling or TGF beta signaling pathway for more information on the nodal signaling pathway.)

There are many differences between the left and right sides, including heart and lung positioning. Mutations in these genes cause incorrect positioning of these organs (e.g., situs inversus), or in the case of constitutively inactive lefty, the embryo becomes entirely mesoderm and fails to pattern or develop. During vertebrate development, lefty proteins regulate left-right asymmetry by controlling the spatiotemporal influence of the NODAL protein. Lefty1 in the ventral midline prevents the Cerberus (paracrine factor or “Caronte”) signal from passing to the right side of the embryo.

This spatiotemporal control is achieved by using two sources of excreted lefty. While lefty is produced in response to activated nodal signaling, it is also produced and secreted in the anterior visceral endoderm (AVE). The balance of lefty from the AVE and from Nodal Signaling results in the patterning of the embryo and left-right asymmetry.

Proper functioning of Lefty is crucial to the proper development of the heart, lungs, spleen, and liver. Mutations in Lefty, called Lefty-A, are associated with left-right patterning defects. This mutation may cause congenital heart defects due to malformation, interrupted inferior vena cava, and lack of lung asymmetry (left pulmonary isomerism).

  • Carlson, Bruce M. “Formation of Germ Layers and Early Derivatives.” Human Embryology and Developmental Biology. Philadelphia, Pennsylvania: Mosby/Elsevier, 2009. 91-95. Print.

Lefty2 may play a role in endometrial bleeding.

Lefty-1 is a regulatory gene that plays a vital role in the determination of the left-right internal asymmetry observed in mammals. The lefty-1 protein works in tandem with two other genes: lefty-2 and nodal. As the primitive node migrates towards the cranial end of the embryo during development, its cilia preferentially sling lefty-2 and nodal towards the left side of the embryo.

  • Hashimoto M, Shinohara K, Wang J, Ikeuchi S, Yoshiba S, Meno C, Nonaka S, Takada S, Hatta K, Wynshaw-Boris A, Hamada H (February 2010). “Planar polarization of node cells determines the rotational axis of node cilia”. Nature Cell Biology. 12 (2): 170–6. doi:10.1038/ncb2020. PMID 20098415. S2CID 6379844.

These two genes encode for “leftness”, and initiate the formation of the heart, spleen, and other internal organs that are found on the left side in a typical human being. Lefty-1 protein can be viewed as a barrier between the left and right portions of the embryo that prevents the diffusion of lefty-2 and nodal to the right side. This ensures that the left-determining molecules are confined to their correct developmental domain. A variety of defects were observed in mice that had lefty-1 deleted, including left pulmonary isomerism, situs inversus, and atrial septal defect.

The high incidence of left pulmonary isomerism in the knockout mice indicates that lefty-1 itself is not involved in encoding for leftness, but simply ensures the correct compartmentation of the left-determining molecules. In the absence of the lefty-1 barrier, lefty-2 and nodal are free to diffuse to the right side and initiate the development of a left lung that was meant to be limited to the left side of the thoracic cavity.

Further reading

  • Carlson BM (2014). “Formation of germ layers and early derivatives.”. Human Embryology and Developmental Biology. Philadelphia, Pennsylvania: Mosby/Elsevier. pp. 75–91. ISBN 978-0-323-08279-2.
  • Sakuma R, Ohnishi Yi Y, Meno C, Fujii H, Juan H, Takeuchi J, Ogura T, Li E, Miyazono K, Hamada H (April 2002). “Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion”. Genes to Cells: Devoted to Molecular & Cellular Mechanisms. 7 (4): 401–12. doi:10.1046/j.1365-2443.2002.00528.x. PMID 11952836. S2CID 19320756.

4. A group encompassing various divergent members?

Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types.

TGF-beta-1 is a peptide of 112 amino acid residues derived by proteolytic cleavage from the C-terminal of a precursor protein. These proteins interact with a conserved family of cell surface serine/threonine-specific protein kinase receptors, and generate intracellular signals using a conserved family of proteins called SMADs. They play fundamental roles in the regulation of basic biological processes such as growth, development, tissue homeostasis and regulation of the immune system.

  • Herpin A, Lelong C, Favrel P (May 2004). “Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans”. Dev. Comp. Immunol. 28 (5): 461–85. doi:10.1016/j.dci.2003.09.007. PMID 15062644.

Structure

Proteins from the TGF-beta superfamily are only active as homo- or heterodimer; the two chains being linked by a single disulfide bond. From X-ray studies of TGF-beta-2, it is known that all the other cysteines are involved in intrachain disulfide bonds.

As shown in the following schematic representation, there are four disulfide bonds in the TGF-beta’s and in inhibin beta chains, while the other members of this superfamily lack the first bond.

                                                     interchain
                                                     |
          +------------------------------------------|+
          |                                          ||
xxxxcxxxxxCcxxxxxxxxxxxxxxxxxxCxxCxxxxxxxxxxxxxxxxxxxCCxxxxxxxxxxxxxxxxxxxCxCx
    |      |                  |  |                                        | |
    +------+                  +--|----------------------------------------+ |
                                 +------------------------------------------+

where ‘C’ denotes a conserved cysteine involved in a disulfide bond.

Examples

Human genes encoding proteins that contain this domain include:

AMH; ARTN; BMP2; BMP3; BMP4; BMP5; BMP6; BMP7; BMP8A; BMP8B; BMP10; BMP15; GDF1; GDF2; GDF3; GDF5; GDF6; GDF7; GDF9; GDF10; GDF11; GDF15; GDNF; INHA; INHBA; INHBB; INHBC; INHBE; LEFTY1; LEFTY2; MSTN; NODAL; NRTN; PSPN; TGFB1; TGFB2; TGFB3;

References

  1. Schlunegger MP, Grütter MG (July 1992). “An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming growth factor-beta 2”. Nature. 358 (6385): 430–4. Bibcode:1992Natur.358..430S. doi:10.1038/358430a0. PMID 1641027. S2CID 4239431.
  2. Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB (June 1983). “Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization”. J. Biol. Chem. 258 (11): 7155–60. doi:10.1016/S0021-9258(18)32345-7. PMID 6602130.
  3. Herpin A, Lelong C, Favrel P (May 2004). “Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans”. Dev. Comp. Immunol. 28 (5): 461–85. doi:10.1016/j.dci.2003.09.007. PMID 15062644.
  4. Burt DW (April 1992). “Evolutionary grouping of the transforming growth factor-beta superfamily”. Biochem. Biophys. Res. Commun. 184 (2): 590–5. doi:10.1016/0006-291X(92)90630-4. PMID 1575734.
  5. Burt DW, Law AS (1994). “Evolution of the transforming growth factor-beta superfamily” (PDF). Prog. Growth Factor Res. 5 (1): 99–118. doi:10.1016/0955-2235(94)90020-5. hdl:20.500.11820/50fc2d69-c411-4835-9cd9-36bf4144bae4. PMID 8199356. S2CID 41326578.
  6. Roberts AB, Sporn MB (1990). Peptide growth factors and their receptors. Berlin: Springer-Verlag. ISBN 3-540-51184-9.
  7. Daopin S, Piez KA, Ogawa Y, Davies DR (July 1992). “Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily”. Science. 257 (5068): 369–73. Bibcode:1992Sci…257..369D. doi:10.1126/science.1631557. PMID 1631557.
  8.  “Prosite Documentation PDOC00223”. Archived from the original on 2011-05-25. Retrieved 2006-07-01.
  9. Fliesler SJ, Kisselev OG (26 December 2007). Signal Transduction in the Retina. CRC Press. pp. 273–. ISBN 978-1-4200-0716-9.
  10. Thiriet M (14 December 2011). Signaling at the Cell Surface in the Circulatory and Ventilatory Systems. Springer Science & Business Media. pp. 666–. ISBN 978-1-4614-1991-4.
  11. Wrana JL, Attisano L, Cárcamo J, et al. (December 1992). “TGF beta signals through a heteromeric protein kinase receptor complex”. Cell. 71 (6): 1003–14. doi:10.1016/0092-8674(92)90395-S. PMID 1333888. S2CID 54397586.
  12. Huse, M; Muir, TW; Xu, L; Chen, YG; Kuriyan, J; Massagué, J (September 2001). “The TGF beta receptor activation process: an inhibitor- to substrate-binding switch”. Molecular Cell. 8 (3): 671–82. doi:10.1016/S1097-2765(01)00332-X. PMID 11583628.
  13. Andres JL, Stanley K, et al. (1989). “Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta”. J. Cell Biol. 109 (6 (Pt 1)): 3137–3145. doi:10.1083/jcb.109.6.3137. PMC 2115961. PMID 2592419.
  14. Andres JL, DeFalcis D, et al. (1992). “Binding of two growth factor families to separate domains of the proteoglycan betaglycan”. J. Biol. Chem. 267 (9): 5927–5930. PMID 1556106.
Intercellular signaling peptides and proteins / ligands
Cell signaling: TGFβ signaling pathway
TGFβ receptor superfamily modulators
Cell signaling / Signal transduction
Receptors: growth factor receptors
Cytokine receptors
Cell surface receptors: enzyme-linked receptors
Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)
Protein, glycoconjugate: glycoproteins and glycopeptides
Hormones
Drugs for treatment of bone diseases (M05)

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