TGF-beta Superfamily Proteins
The transforming growth factor beta (TGF-β/TGF-beta) superfamily is a large group of structurally related proteins that are all involved in cell regulation. They all interact with TGF-β receptors to stimulate activation. The family is comprised of over 30 members including Bone Morphogenetic Proteins (BMPs), Activins, Growth Differentiation Factors (GDFs) and Glial cell-Derived-Neurotrophic Factor (GDNFs). TGF-β proteins are found in both vertebrates and invertebrates and are prominently expressed in a variety of tissues. They function during the earliest stages of development in humans and are expressed ubiquitously throughout the lifetime of animals. Their major roles in development are embryonic stem cell self-renewal, gastrulation, differentiation, organ morphogenesis and adult tissue homeostasis.
TGF-beta superfamily ligands signal through cell-surface serine/threonine kinase receptors which stimulate intracellular SMAD proteins to activate. This in turn leads to the activation or repression of transcription factors within the nucleus of the cell thereby leading to the upregulation or downregulation of specific gene expression. The binding of TGF-beta superfamily members to their signalling receptors is regulated by numerous secreted agonists and antagonists and by membrane-associated coreceptors.
SMAD Signalling Proteins
SMADs are a family of intracellular proteins that regulate signalling by members of the TGF-beta superfamily. SMADs are divided into three subgroups based on their varying roles in TGF-beta family signal transduction. The three subgroups are R-SMADs which are receptor regulated, Co-SMAD (SMAD-4), and I-SMADs (SMAD-6 and SMAD-7) which have an inhibitory role. Activation of TGF-beta superfamily kinase receptors leads to the phosphorylation of R-SMADs (SMADs 1, 2, 3, 5, and 8). This leads to the recruitment of the Co-SMAD which forms an R-SMAD/Co-SMAD complex that translocate to the nucleus to regulate gene expression. I-SMADS antagonize this signalling pathway by preventing R-SMADs from interacting with the receptor, or by competing with Co-SMADs to prevent the R-SMAD/Co-SMAD complex from forming.
TGF-beta Family Modulators
TGF-beta is a multifunctional protein, and plays a role in various processes of the cell including cell growth, cell proliferation, cell differentiation and cell death via apoptosis. TGF-beta was first identified in human platelets and was suspected to have a role in wound healing, however through consistent research it was discovered that most immune cells secrete the signalling protein. TGF-beta has a predominately anti-inflammatory effect on immune cells. For example, regulatory T cells (Treg cells) can secrete TGF-beta to inhibit the action of effector T cells such as cytotoxic T cells. Additionally, TGF-beta secretion can inhibit the activation of various pro-inflammatory cytokines such as interferon-gamma, tumour necrosis factor-alpha (TNF-α) and various interleukins. In B cells, this cytokine inhibits proliferation and stimulates apoptosis. It also plays a role in regulating the expression of antibody, transferrin, and MHC Class II proteins on immature and mature B cells. Likewise, TGF-beta also has a suppressive role in macrophages and monocytes. It can inhibit the proliferation of these cells and prevent their production of reactive oxygen species which are pro-inflammatory.
Bone Morphogenetic Proteins (BMPs)
BMPs are also included in the TGF-beta superfamily. They were originally associated with being regulators of cartilage and bone formation. There are around 20 structurally and functionally related bone morphogenic proteins and the majority of them play a role in the embryogenesis and morphogenesis of various organs and tissues. BMPs interact with specific cell surface receptors called bone morphogenetic protein receptors (BMPRs) which results in a signal transduction cascade involving the SMAD proteins. This cascade is essential for the development of the central nervous system, the heart and cartilage, as well as post-natal bone development.
Activins are also members of the TGF-beta superfamily. They are secreted disulphide-linked dimeric proteins and were originally identified with a reproductive function by acting as endocrine-derived regulators of the pituitary follicle stimulating hormone (FSH). However, after thorough research it was found that activins have a broader range of functions including a regulatory role during essential phases of growth, differentiation and development such as tissue repair, would healing and regulation of branching morphogenesis. Activins are homodimers or heterodimers of the various beta subunit isoforms. There are five beta subunits including beta A, beta B, beta C and beta E.
Glial cell-Derived-Neurotrophic Factor Family (GDNFs)
The GDNF family (Glial cell-Derived Neurotrophic Factor) is another member of the TGF-beta superfamily. Artemin, neurturin, persephin and GDNF are all members of the GDNF family of ligands. This family plays a role in a number of processes such as cell survival, neuronal outgrowth, cell differentiation and cell migration. In addition, signalling by the ligand GDNF promotes the survival of dopaminergic neurons.
ELISA Genie provides an extensive range of ELISA kits for research into the TGF-beta superfamily of ligands, receptors and signalling molecules.