2016 Group Project 6: Difference between revisions
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The Transforming Growth Factor (TGF) beta signalling pathway is required in the regulation for a large number of cellular processes such as cell proliferation, invasion and inflammation. TGF-beta can also activate mitogen activated protein kinase signalling. | The Transforming Growth Factor (TGF) beta signalling pathway is required in the regulation for a large number of cellular processes such as cell proliferation, invasion and inflammation. TGF-beta can also activate mitogen activated protein kinase signalling. | ||
[[File:TGF-B Signalling - Formation of Receptor Hetero-Tetramers.png|frame|caption]] | [[File:TGF-B Signalling - Formation of Receptor Hetero-Tetramers.png|thumb|frame|caption]] | ||
(Diagram) | (Diagram) |
Revision as of 11:36, 23 September 2016
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Signalling: 1 Wnt | 2 Notch | 3 FGF Receptor | 4 Hedgehog | 5 T-box | 6 TGF-Beta | ||||
2016 Group Project Topic - Signaling in Development
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TGF beta Signaling Pathway
Introduction
TGF-beta
Transforming Growth Factor (TGF) beta is a multifunctional peptide/cytokine that controls proliferation, cellular differentiation, angiogenesis and other functions in various cell types. TGF-beta plays a dominant part in the development of the embryo and adult organism, as well as cell growth, immune function and hormone secretion.
TGF-beta superfamily
TGF-beta belongs to the Transforming Growth Factor superfamily, a large group of structurally connected cell regulatory proteins. It consists of TGF-beta 1, 2 and 3, Activins, Inhibins, Lefty, Nodal, Growth Differentiation Factors (GDFs), Bone Morphogenetic Proteins (BMPs), Glial-derived Neurotrophic Factors (GDNFs) and Mullierian Inhibiting Substance (MIS). This site will focus on the TGF-beta family. TGF betas are involved in embryogenesis. During development of the embryo, members of the TGF-beta family are essential for bone and cartilage formation, mesoderm induction and patterning and dorso-ventral patterning.
Process of TGF-beta signalling pathway
The Transforming Growth Factor (TGF) beta signalling pathway is required in the regulation for a large number of cellular processes such as cell proliferation, invasion and inflammation. TGF-beta can also activate mitogen activated protein kinase signalling.
(Diagram)
TGF beta superfamily ligands form dimers that bind to heterodimeric receptor complexes composed of two type I and two type II transmembrane receptor subunits with serine/threonine kinase domains. Following ligand binding, the Type II receptor (TGF-beta RII) phosphorylates and activates the Type I receptor (TGF-beta RI). In most cell types, this leads to recruitment and phosphorylation of SMAD2 and SMAD3. (SMAD is a family of gene regulatory proteins). SMAD1 and SMAD5 can be activated by TGF-beta signalling in some cell types depending on the Type I receptor that is expressed. Activated SMAD proteins associate with SMAD4 and translocate to the nucleus, where they accumulate (and act as transcription factors and participate in the regulation of target gene expression). They recruit additional transcriptional regulators, including DNA-binding transcription factors, co-activators, co-repressors and chromatin remodeling factors, that control the expression of numerous target genes.This initiates a SMAD-dependent signalling cascade that induces or represses transcriptional activity. SMADs are widely expressed in most adult tissue and cell types indicating that the TGF-beta signalling pathway is ubiquitous. Differential expression of these factors may be responsible for some of the cell type-specific responses to TGF-beta.
Note: On one hand, Type I cytokine receptors are also transmembrane receptors expressed on the surface of cells. They recognize and respond to cytokines with four alpha helical strands. On the other hand, Type II cytokine receptors are transmembrane proteins that are expressed on the surface of certain cells. The difference between Type I and Type II receptors is that Type II receptors do not possess the signature sequence WSXWS, which is a characteristic of Type I receptors. (Tabulate how it is involved in the various processes of embryology)
History of TGF-beta signalling pathway
1970s - It was known that the growth of normal cells was mainly controlled by the interaction between various polypeptide hormones and hormone-like growth factors that are found in tissue fluids. It was also stated that malignant cells were not subject to all the same growth as normal cells were, as it was shown that malignant cells required less of these exogenous growth factors for optimal growth and multiplication. The Nobel laureate, Robert Holley, had suggested that "transformed or malignant cells escape from normal growth controls by requiring less of such hormones of growth factors".
http://www.cgfr.co.uk/article/S1359-6101(05)00116-4/fulltext?mobileUi=0
(Place discoveries and findings in a timeline)
Regulation of the pathway and factors affecting it
2
Current Research
Limitations
Mutations in the TGF-beta RII gene have been associated with multiple syndromes. Alterations of this signalling pathway are common in cancer. Accessory proteins such as soluble or membrane-bound regulators or co-receptors can also affect TGF-beta signalling.
Further Reading
Glossary
Apoptosis - Cytokine - a broad and loose category of small proteins that are important in cell signalling Ligands - a molecule that binds to a larger molecule
References
http://wormbook.org/chapters/www_tgfbsignal/tgfbsignal.html https://www.rndsystems.com/research-area/tgf--beta-superfamily https://www.rndsystems.com/pathways/tgf-beta-signaling-pathways - used for the Process