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Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.
Mitogen Activated Protein (MAP) kinase kinase kinase, MAPKKK is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:
Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways.
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.
SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 is a highly conserved protein present in all metazoans. It belongs to the SMAD family of transcription factor proteins, which act as mediators of TGF-β signal transduction. The TGFβ family of cytokines regulates critical processes during the lifecycle of metazoans, with important roles during embryo development, tissue homeostasis, regeneration, and immune regulation.
Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the SMAD7 gene.
Smads comprise a family of structurally similar proteins that are the main signal transducers for receptors of the transforming growth factor beta (TGF-B) superfamily, which are critically important for regulating cell development and growth. The abbreviation refers to the homologies to the Caenorhabditis elegans SMA and MAD family of genes in Drosophila.
The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis and other cellular functions. The TGFB signaling pathways are conserved. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.
Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.
Activin receptor type-2A is a protein that in humans is encoded by the ACVR2A gene. ACVR2A is an activin type 2 receptor.
Activin receptor type-2B is a protein that in humans is encoded by the ACVR2B gene. ACVR2B is an activin type 2 receptor.
Transforming growth factor beta (TGFβ) receptors are single pass serine/threonine kinase receptors that belong to TGFβ receptor family. They exist in several different isoforms that can be homo- or heterodimeric. The number of characterized ligands in the TGFβ superfamily far exceeds the number of known receptors, suggesting the promiscuity that exists between the ligand and receptor interactions.
Betaglycan also known as Transforming growth factor beta receptor III (TGFBR3), is a cell-surface chondroitin sulfate / heparan sulfate proteoglycan >300 kDa in molecular weight. Betaglycan binds to various members of the TGF-beta superfamily of ligands via its core protein, and bFGF via its heparan sulfate chains. TGFBR3 is the most widely expressed type of TGF-beta receptor. Its affinity towards all individual isoforms of TGF-beta is similarly high and therefore it plays an important role as a coreceptor mediating the binding of TGF-beta to its other receptors - specifically TGFBR2. The intrinsic kinase activity of this receptor has not yet been described. In regard of TGF-beta signalling it is generally considered a non-signaling receptor or a coreceptor. By binding to various member of the TGF-beta superfamily at the cell surface it acts as a reservoir of TGF-beta.
An Activin receptor is a receptor which binds activin. These proteins are receptor-type kinases of Ser/Thr type, which have a single transmembrane domain and a specific hydrophilic Cys-rich ligand-binding domain.
Serine/threonine-protein kinase receptor R3 is an enzyme that in humans is encoded by the ACVRL1 gene.
The upstream signaling pathway is triggered by the binding of a signaling molecule, a ligand, to a receiving molecule, a receptor. Receptors and ligands exist in many different forms, and only recognize/bond to particular molecules. Upstream extracellular signaling transduce a variety of intracellular cascades.
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.
AKT2, also known as RAC-beta serine/threonine-protein kinase, is an enzyme that in humans is encoded by the AKT2 gene. It influences metabolite storage as part of the insulin signal transduction pathway.
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, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), activin and inhibin, myostatin, anti-Müllerian hormone (AMH), and NODAL.
The DAF-1 gene encodes for a cell surface Enzyme-linked receptor of TGF-beta signaling pathway in the worm Caenorhabditis elegans. DAF-1 is one of the type I receptor of TGF-beta pathway. DAF-1 acts as a receptor protein serine/threonine kinase, is activated by type II receptor Daf-4 phosphorylation after the ligand Daf-7 binds to the receptor heterotetramer, and then phosphorylates Daf-8 or Daf-14, the SMAD proteins in C. elegans.
References
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- Massague J, Chen YG (2000). "Controlling TGF-beta signaling". Genes Dev. 14 (6): 627–44. PMID 10733523.
- Lechleider RJ; Hemmati, P; Larisch-Bloch, S; Ajmera, R; Roberts, AB; Lechleider, RJ (1997). "Characterization of functional domains within Smad4/DPC4". J. Biol. Chem. 272 (21): 13690–6. doi: 10.1074/jbc.272.21.13690 . PMID 9153220.
