User:SamSenatore/Upstream and downstream (transduction)
TGF-β signaling as a demonstration of upstream signaling
[edit]The upstream signaling pathway is triggered by the binding of a signaling molecule, a Ligand, to a receiving molecule, Receptor (biochemistry). Receptors and ligands exist in many different forms, and they will only recognize/bond particular molecules. Upstream extracellular signaling transduce an endless variety of intracellular cascades. [1] Receptors and ligands are common upstream signaling molecules that dictate the downstream elements of the signal pathway. A plethora of different factors affect which ligands bind to which receptors, and the downstream cellular response that it initiates.
TGF-β
[edit]
Transforming growth factor-β (TGF-β) is a superfamily of cytokines that play a significant upstream role in regulating of Morphogenesis, Homeostasis, cell proliferation, and differentiation.[2] The significance of TGF-β is apparent with the human diseases that occur when TGF-β processes are disrupted, such as cancer, and skeletal, intestinal and cardiovascular diseases.[3] [4] TGF-β is pleiotropic and multifunctional, meaning they are able to act on a wide variety of cell types.[5]
Determinants of TGF-β action
[edit]The effects of transforming growth factor-β (TGF-β) are determined by cellular context. There are three kinds of contextual factors that determine the shape the TGF-β response: the signal transduction components, the transcriptional cofactors and the epigenetic state of the cell. The different ligands and receptors of TGF-β are significant as well in the composition signal transduction pathway.[6][2]
Contextual Factors that determines TGF-β response
[edit]- the signal transduction components: ligand isoforms, ligand traps, co-receptors, receptor sub-types, inhibitory SMAD proteins, crosstalk inputs
- the transcriptional cofactors of SMAD proteins: pluripotency factors, lineage regulators, DNA-binding cofactors, HATs and HDACs, SNF, chromatin readers
- the epigenetic factors: heterochromatin, pluripotency marks, lineage marks, EMT marks, iPS cell marks, oncogenic marks.
Upstream TGF-β Signaling Pathway
[edit]
Signaling is initiated by the binding of TGF-β to its serine/threonine receptors. The serene/threonine receptors are the type II and type I receptors on the cell membrane.[7][2] Binding of a TGF-β members induces assembly of a heterotetrameric complex of two type I and two type II receptors at the plasma membrane. [8] Individual members of the TGF-β family bind to a certain set of characteristic combination of these type I and type II receptors. [9] The type I receptors can be divided into two groups, which depends on the cytoplasmic R-Smads that they bind and phosphorylate. The first group of type I receptors (Alk1/2/3/6) bind and activate the R-Smads, Smad1/5/8. The second group of type I reactors (Alk4/5/7) act on the R-Smads, Smad2/3. The phosphorylated R-Smads then form complexes and the signals are funneled through two regulatory Smad (R-Smad) channels (Smad1/5/8 or Smad2/3).[8][2] After the ligand-receptor complexes phosphorylate the cytoplasmic R-Smads, the signal is then sent through Smad 1/5/8 or Smad 2/3. This leads to the downstream signal cascade and cellular gene targeting.[5][7]
Downstream TGF-β Signaling Pathway
[edit]TGF-β regulates multiple downstream processes and cellular functions. The pathway is highly variable based on cellular context. TGF-β downstream signaling cascade includes regulation of cell growth, cell proliferation, cell differentiation, and apoptosis. [10]
Referances
[edit]- ^ Miller, Daniel S. J.; Schmierer, Bernhard; Hill, Caroline S. (2019-07-15). "TGF-β family ligands exhibit distinct signalling dynamics that are driven by receptor localisation". Journal of Cell Science. 132 (14): jcs234039. doi:10.1242/jcs.234039. ISSN 0021-9533. PMC 6679586. PMID 31217285.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b c d Massagué, Joan (2012-10). "TGFβ signalling in context". Nature Reviews Molecular Cell Biology. 13 (10): 616–630. doi:10.1038/nrm3434. ISSN 1471-0080. PMC 4027049. PMID 22992590.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ Kashima, Risa; Hata, Akiko (2018-01-01). "The role of TGF-β superfamily signaling in neurological disorders". Acta Biochimica et Biophysica Sinica. 50 (1): 106–120. doi:10.1093/abbs/gmx124. ISSN 1672-9145. PMC 5846707. PMID 29190314.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Huang, Tao; Schor, Seth L.; Hinck, Andrew P. (2014-09-16). "Biological Activity Differences between TGF-β1 and TGF-β3 Correlate with Differences in the Rigidity and Arrangement of Their Component Monomers". Biochemistry. 53 (36): 5737–5749. doi:10.1021/bi500647d. ISSN 0006-2960. PMC 4165442. PMID 25153513.
{{cite journal}}: line feed character in|title=at position 47 (help) - ^ a b Letterio, John J.; Roberts, Anita B. (1998-04-01). "REGULATION OF IMMUNE RESPONSES BY TGF-β". Annual Review of Immunology. 16 (1): 137–161. doi:10.1146/annurev.immunol.16.1.137. ISSN 0732-0582.
- ^ Massagué, Joan (2012-10). "TGFβ signalling in context". Nature Reviews Molecular Cell Biology. 13 (10): 616–630. doi:10.1038/nrm3434. ISSN 1471-0080. PMC 4027049. PMID 22992590.
{{cite journal}}: Check date values in:|date=(help)CS1 maint: PMC format (link) - ^ a b Vilar, Jose M. G.; Jansen, Ronald; Sander, Chris (2006-01-27). "Signal Processing in the TGF-β Superfamily Ligand-Receptor Network". PLOS Computational Biology. 2 (1): e3. doi:10.1371/journal.pcbi.0020003. ISSN 1553-7358. PMC 1356091. PMID 16446785.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ a b Vilar, Jose M. G.; Jansen, Ronald; Sander, Chris (2006-01-27). "Signal Processing in the TGF-β Superfamily Ligand-Receptor Network". PLOS Computational Biology. 2 (1): e3. doi:10.1371/journal.pcbi.0020003. ISSN 1553-7358. PMC 1356091. PMID 16446785.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Heldin, Carl-Henrik; Moustakas, Aristidis (2016-08-01). "Signaling Receptors for TGF-β Family Members". Cold Spring Harbor Perspectives in Biology. 8 (8): a022053. doi:10.1101/cshperspect.a022053. ISSN 1943-0264. PMID 27481709.
- ^ Shuang, Li Nian; Chuan, Xie; Hua, Lu nong (2015). "Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis". Frontiers in Cellular and Infection Microbiology. 5. doi:10.3389/fcimb.2015.00077. ISSN 2235-2988. PMC 4632021. PMID 26583078.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)