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TGF-β Superfamily

Overview

Transforming growth factor-β(TGF-β) is the founding member of a large superfamily of secreted polypeptide growth factors, which additionally includes activins, nodal, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and others. From early development and continuously throughout adult life, TGF-β members carry out pivotal functions by regulating biological events ranging from gastrulation and organ morphogenesis to homeostatic tissue turnover.

TGF-β superfamily proteins

Figure 1. TGF-β superfamily proteins

Major subfamilies

Activins, members of the TGF-beta superfamily, are disulfide-linked dimeric proteins originally purified from gonadal fluids as proteins that stimulated pituitary follicle stimulating hormone (FSH) release. 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.

Activin is produced in the gonads, pituitary gland, placenta, and other organs. In the ovarian follicle, activin increases FSH binding and FSH-induced aromatization. Activin is strongly expressed in wounded skin, and overexpression of activin in epidermis of transgenic mice improves wound healing and enhances scar formation. Activin also regulates the morphogenesis of branching organs such as the prostate, lung, and especially kidney.

Bone Morphogenetic Proteins (BMPs) are secreted signaling molecules that comprise a subfamily of the TGF-beta superfamily. 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.

BMP1 BMP1 is 202 residues in length. Its secondary structure is made up of 30% helices, or 10 helices, 61 residues in length, and 15% beta sheets, or 11 strands, 32 residues in length. It contains ligands of an acetyl group and a Zinc ion.
BMP2 BMP2 has been demonstrated to potently induce osteoblast differentiation in a variety of cell types. It is involved in the hedgehog pathway, TGF beta signaling pathway, and in cytokine-cytokine receptor interaction.
BMP3 BMP3 is known for its ability to induce bone and cartilage development. It is a disulfide-linked homodimer. It negatively regulates bone density. BMP3 is an antagonist to other BMP's in the differentiation of osteogenic progenitors. It is highly expressed in fractured tissues.
BMP4 BMP4 is found on chromosome 14q22-q23. Yielding an active carboxy-terminal peptide of 116 residues, human bmp4 is initially synthesized as a forty percent residue preproprotein which is cleaved post translationally. BMP4 has seven residues which are conserved and glycosylated.
BMP5 BMP5 may play a role in certain cancers. It is expressed in the trabecular meshwork and optic nerve head and may have a role in the development and normal function.
BMP6 BMP6 is able to induce all osteogenic markers in mesenchymal stem cells. BMPs were originally identified by an ability of demineralized bone extract to induce endochondral osteogenesis in vivo in an extraskeletal site.
BMP7 BMP7 may be involved in bone homeostasis. It is expressed in the brain, kidneys and bladder. BMP7 induces the phosphorylation of SMAD1 and SMAD5, which in turn induce transcription of numerous osteogenic genes.
BMP8A BMP8A may be involved in epithelial osteogenesis. It also plays a role in bone homeostasis. It is a disulfide-linked homodimer.
BMP8B BMP8B is believed to play a role in bone and cartilage development. It has been shown to be expressed in the hippocampus of murine embryos.
BMP10 BMP10 is a polypeptide belonging to the TGF-β superfamily of proteins. It is a novel protein that, unlike most other BMP's, is likely to be involved in the trabeculation of the heart.
BMP11 BMP11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin, including stopping the progenitor cell-cycle during G-phase.
BMP15 BMP15 has been shown to be exclusively expressed in the ovaries. It is thought that this protein may be involved in oocyte maturation and follicular development as a homodimer or by forming heterodimers with a related protein, Gdf9.

Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development. They are produced as inactive preproproteins which are then cleaved and assembled into active secreted homodimers. GDF dimers are disulfide-linked with the exception of GDF3 and GDF9. GDF proteins are important during embryonic development, particularly in the skeletal, nervous, and muscular systems.

GDF1 GDF1 has a role in left-right patterning and mesoderm induction during embryonic development. It is found in the brain, spinal cord and peripheral nerves of embryos.
GDF2 GDF2 contains an N-terminal TGF-beta-like pro-peptide (prodomain) (residues 56–257) and a C-terminal transforming growth factor beta superfamily domain (325–428).
GDF3 Expression of GDF3 occurs in ossifying bone during embryonic development and in the brain, thymus, spleen, bone marrow and adipose tissue of adults.
GDF5 GDF5 increases the survival of neurones that respond to the neurotransmitter dopamine, and is a potential therapeutic molecule associated with Parkinson's disease.
GDF6 GDF6 may regulate patterning of the ectoderm by interacting with bone morphogenetic proteins, and control eye development.
GDF9 GDF9 is expressed in oocytes and is thought to be required for ovarian folliculogenesis. It is highly expressed in the oocyte and has a pivotal influence on the surrounding somatic cells, particularly granulosa, cumulus and theca cells.
GDF10 GDF10 plays a role in head formation and may have multiple roles in skeletal morphogenesis. Human GDF10 mRNA is found in the cochlea and lung of foetuses, and in testis, retina, pineal gland, and other neural tissues of adults.
GDF11 GDF11 is a myostatin(GDF8)-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin, including stopping the progenitor cell-cycle during G-phase.
GDF15 GDF15 is expressed in low concentrations in most organs and upregulated because of injury of organs such as such as liver, kidney, heart and lung.

GDNF, neurturin, persephin and artemin are a class of secretory proteins with similar structure and function. They all have 7 conserved cysteine residues, with similar spatial structure, nucleotide sequence and amino acid sequence with high homology. They constitute a subfamily of the transforming growth factor beta (TGF-beta) superfamily, which are similar in physiological functions, receptors, signal transduction pathways, and so on.

GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particularly GFRα1. Persephin promotes the survival and growth of central dopaminergic and motor neurons, and is also involved in kidney development. Artemin promotes the survival and growth of various peripheral and central neurons, including sympathetic and dopaminergic neurons. Neurturin exerts a positive effect on the survival of a variety of neurons and possibly other cell types.

Smads are a family of intracellular proteins that mediate signaling by members of the TGF-beta superfamily. Smads are divided into three distinct subgroups based on their different roles in TGF-beta family signal transduction. There are three distinct sub-types of Smads: receptor-regulated Smads (R-Smads), common partner Smads (Co-Smads), and inhibitory Smads (I-Smads). The eight members of the Smad family are divided among these three groups. Trimers of two receptor-regulated SMADs and one co-SMAD act as transcription factors that regulate the expression of certain genes.

SMAD1 SMAD1 is a receptor regulated SMAD (R-SMAD) and is activated by bone morphogenetic protein type 1 receptor kinase.
SMAD2 SMAD2 mediates the signal of the transforming growth factor (TGF)-beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation.
SMAD3 SMAD3 is recruited by SARA (SMAD Anchor for Receptor Activation) to the membrane, where the TGF-β receptor is located. SMAD3 has been related with tumor growth in cancer development.
SMAD4 SMAD4 belongs to the co-SMAD group, the second class of the SMAD family. SMAD4 is the only known co-SMAD in most metazoans.
SMAD5 SMAD5 is a receptor regulated SMAD (R-SMAD) and is activated by bone morphogenetic protein type 1 receptor kinase. It may play a role in the pathway where TGF-β is an inhibitor of hematopoietic progenitor cells.
SMAD6 SMAD6 is involved in cell signalling. It acts as a regulator of TGFβ family (such as bone morphogenetic proteins) activity by competing with SMAD4 and preventing the transcription of SMAD4's gene products.
SMAD7 SMAD7 is involved in cell signalling. It is a TGF-β type 1 receptor antagonist. It blocks TGF-β1 and activin associating with the receptor, blocking access to SMAD2.
SMAD9 SMAD9 is a receptor regulated SMAD (R-SMAD) and is activated by bone morphogenetic protein type 1 receptor kinase. There are two isoforms of the protein.

Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes four different isoforms (TGF-β 1 to 4) and many other signaling proteins 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, which is 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-β1 TGF-β1 was first identified in human platelets as a protein with a molecular mass of 25 kilodaltons with a potential role in wound healing. TGF-β1 plays an important role in controlling the immune system, and shows different activities on different types of cell, or cells at different developmental stages.
TGF-β2 TGF-β2 is a secreted protein known as a cytokine that performs many cellular functions and has a vital role during embryonic development. It is an extracellular glycosylated protein. It is known to suppress the effects of interleukin dependent T-cell tumors.
TGF-β3 TGF-β3 is believed to regulate molecules involved in cellular adhesion and extracellular matrix (ECM) formation during the process of palate development. Without TGF-β3, mammals develop a deformity known as a cleft palate.

References:

1. Sulyok S, Wankell M, Alzheimer C, et, al. "Activin: an important regulator of wound repair, fibrosis, and neuroprotection". Molecular and Cellular Endocrinology. October 2004; 225 (1–2): 127–32.
2. Reddi AH, Reddi A. "Bone morphogenetic proteins (BMPs): from morphogens to metabologens". Cytokine & Growth Factor Reviews. 2009; 20 (5-6): 341–2.
3. Ago T, Sadoshima J. "GDF15, a cardioprotective TGF-beta superfamily protein". Circ Res. 2006; 98 (3): 294–7.
4. Airaksinen M, Saarma M. "The GDNF family: signalling, biological functions and therapeutic value". Nat Rev Neurosci. 2002; 3 (5): 383–94.
5. Derynck R, Zhang Y, Feng XH. "Smads: transcriptional activators of TGF-beta responses". Cell. 1998; 95 (6): 737–40.
6. Letterio JJ, Roberts AB. "Regulation of immune responses by TGF-beta". Annual Review of Immunology. 1998; 16 (1): 137–61.
7. Herpin A, Lelong C, Favrel P. "Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans". Dev. Comp. Immunol. May 2004; 28 (5): 461–85.

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