TGF-beta Background

What is TGF-beta
TGF-beta (Transforming growth factor beta / TGF-β) is a type of cytokine that controls proliferation, cellular differentiation, and other functions in most cells. TGF-beta, is a factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. The TGF-β family is part of a superfamily of proteins known as the transforming growth factor beta superfamily, which includes inhibins, activin, anti-müllerian hormone, bone morphogenetic protein, decapentaplegic and Vg-1. Learn More.

TGF-beta Structure and Function
The genes associated with TGF-beta isoforms encode 390-412 amino acids-long precursor proteins constituting three distinct domains: a N-terminal signal domain which associates the full precursor molecule to the proper cellular secretory pathways; a propeptide domain, which may support folding or dimerization of the mature cytokine; and an approximately 100-114 amino acids-long C-terminal "TGF-beta-like" domain-the functional autocrine signaling molecule-which is highly conserved across the superfamily. TGF-beta family members play central roles in metazoan developmental processes, including initiation of appendage formation in adult flies, establishment of the mammalian left-right body plane, and regulation of nematode morphology. Learn More.

TGF-beta Superfamily
TGF-beta superfamily is comprised of a large group of proteins, including the activin/inhibin family, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), the TGF-beta subfamily, and glial cell line-derived neurotrophic factor (GDNF) family. Learn More.

TGF-beta Receptor
TGF-beta receptors are single pass serine/threonine kinase receptors. They exist in several different isoforms that can be homo-or heterodimeric. TGF-beta signaling is initiated by binding of the growth factor ligand to the small extracellular domains of two homologous, functionally distinct transmembrane receptor kinases: the TGF-beta receptor 1 and TGF-beta receptor 2 (TbetaR1 and TbetaR2, respectively). TGF-beta receptor 1 and TGF-beta receptor 2 have similar ligand-binding affinities and can be distinguished from each other only by peptide mapping. Both TGF-beta receptor 1 and TGF-beta receptor 2 have a high affinity for TGF-beta 1 and low affinity for TGF-beta 2. TGF-beta initiates receptor assembly by binding with high affinity to TGF-beta receptor 2. TGF-beta receptor 1 is subsequently recruited by the TbetaR2−ligand complex, allowing TGF-beta receptor 2 to phosphorylate TGF-beta receptor 1. In turn, TGF-beta receptor 1 phosphorylates cytoplasmic effectors known as SMADs. Learn More.

TGF-beta Signaling
TGF-beta signaling is involved in the regulation of proliferation, differentiation and survival/or apoptosis of many cells, including glioma cells. TGF-beta acts via specific receptors activating multiple intracellular pathways resulting in phosphorylation of receptor-regulated Smad2/3 proteins that associate with the common mediator, Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of many genes. Furthermore, TGF-beta-activated kinase-1 (TAK1) is a component of TGF-beta signaling and activates mitogen-activated protein kinase cascades.Learn More.

TGF-beta Inhibitor
Misregulation of the activity of TGF-beta (Transforming Growth Factor-beta) family members is involved in pathogenesis of cancer, muscular dystrophy, obesity and bone and tooth remodeling. Natural inhibitors for the TGF-beta superfamily regulate fine-tuning of activity of TGF-beta family in vivo . In addition to natural inhibitors for the TGF-beta family, soluble forms of receptors for the TGF-beta family, blocking monoclonal antibodies and small chemical TGF-beta inhibitors have been developed. Members of the TGF-beta superfamily bind to type I and type II serine/threonine kinase receptors and transduce intra-cellular signaling through Smad proteins. TGF-beta /activin/ myostatin activate Smad2/3, whereas the BMP subfamily activates Smad1/5/8. These pathway-restricted Smads asso-ciate with Co-Smad, Smad4 and translocate into the nucleus, and regulate transcription of target genes. Smad6/7 are in-hibitory Smads that serve as negative regulators of signaling of the TGF-beta family. Learn More.

TGF-beta and Cancer
TGF-beta induces tumor-suppressive effects that cancer cells must circumvent in order to develop into malignancies. Cancer cells can take two alternative paths to this end: (1) decapitate the pathway with receptor-inactivating mutations or (2) selectively amputate the tumor-suppressive arm of the pathway. The latter path allows cancer cells to extract additional benefits by co-opting the TGF-beta response for protumorigenic purposes. In both cases, cancer cells can use TGF-beta to modulate the microenvironment to avert immune surveillance or to induce the production of protumorigenic cytokines. Learn More.

TGF-beta References
  1. The TGF-beta system — Nature Reviews Molecular Cell Biology
  2. Joan M, et al. (2008) TGFβ in Cancer. Cell. 134(2): 215–230.
  3. 215–230. Qin J, et al. (2013) COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature. 493(7431):236-40.
  4. Kaminska B, et al. (2013) TGF beta signaling and its role in glioma pathogenesis. Adv Exp Med Biol. 986:171-87.
  5. K. Tsuchida, et al. (2006) Inhibitors of the TGF-beta Superfamily and their Clinical Applications. Mini-Reviews in Medicinal Chemistry. 6, 1255-1261.
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