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= TGF-β signaling as a demonstration of upstream signaling =
= TGF-β signaling as a demonstration of upstream signaling =
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.  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.
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.<ref>{{Cite journal|last=Miller|first=Daniel S. J.|last2=Schmierer|first2=Bernhard|last3=Hill|first3=Caroline S.|date=2019-07-15|title=TGF-β family ligands exhibit distinct signalling dynamics that are driven by receptor localisation|url=https://jcs.biologists.org/content/132/14/jcs234039|journal=Journal of Cell Science|language=en|volume=132|issue=14|doi=10.1242/jcs.234039|issn=0021-9533|pmc=PMC6679586|pmid=31217285}}</ref>  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 ==
== TGF-β ==
The extracellular type II and type I kinase receptors binding to the TGF-β ligands. 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.<ref name=":0">{{Cite journal|last=Massagué|first=Joan|date=October 2012|title=TGFβ signalling in context|url=https://www.nature.com/articles/nrm3434|journal=Nature Reviews Molecular Cell Biology|language=en|volume=13|issue=10|pages=616–630|doi=10.1038/nrm3434|issn=1471-0080|pmc=PMC4027049|pmid=22992590|via=}}</ref> 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.<ref>{{Cite journal|last=Kashima|first=Risa|last2=Hata|first2=Akiko|date=2018-01-01|title=The role of TGF-β superfamily signaling in neurological disorders|url=https://academic.oup.com/abbs/article/50/1/106/4670796|journal=Acta Biochimica et Biophysica Sinica|language=en|volume=50|issue=1|pages=106–120|doi=10.1093/abbs/gmx124|issn=1672-9145|pmc=PMC5846707|pmid=29190314}}</ref><ref>{{Cite journal|last=Huang|first=Tao|last2=Schor|first2=Seth L.|last3=Hinck|first3=Andrew P.|date=2014-09-05|title=Biological Activity Differences between TGF-β1 and TGF-β3 Correlate with Differences in the Rigidity and Arrangement of Their Component Monomers|url=https://doi.org/10.1021/bi500647d|journal=Biochemistry|volume=53|issue=36|pages=5737–5749|doi=10.1021/bi500647d|issn=0006-2960|pmc=PMC4165442|pmid=25153513}}</ref>  TGF-β is [[Pleiotropy|pleiotropic]] and multifunctional, meaning they are able to act on a wide variety of cell types.<ref name=":1">{{Cite journal|last=Letterio|first=John J.|last2=Roberts|first2=Anita B.|date=1998-04-01|title=REGULATION OF IMMUNE RESPONSES BY TGF-β|url=https://www.annualreviews.org/doi/10.1146/annurev.immunol.16.1.137|journal=Annual Review of Immunology|volume=16|issue=1|pages=137–161|doi=10.1146/annurev.immunol.16.1.137|issn=0732-0582}}</ref>
The extracellular type II and type I kinase receptors binding to the TGF-β ligands.
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. 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.  TGF-β is [[Pleiotropy|pleiotropic]] and multifunctional, meaning they are able to act on a wide variety of cell types.


=== Determinants of TGF-β action ===
=== Determinants of TGF-β action ===
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 [[Transcription (biology)|transcriptional]] cofactors and the [[Epigenetics|epigenetic]] state of the cell. The different ligands and receptors of TGF-β are significant as well in the composition signal transduction pathway.
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 [[Transcription (biology)|transcriptional]] cofactors and the [[Epigenetics|epigenetic]] state of the cell. The different ligands and receptors of TGF-β are significant as well in the composition signal transduction pathway.<ref>{{Cite journal|last=Massagué|first=Joan|date=October 2012|title=TGFβ signalling in context|url=https://www.nature.com/articles/nrm3434|journal=Nature Reviews Molecular Cell Biology|language=en|volume=13|issue=10|pages=616–630|doi=10.1038/nrm3434|issn=1471-0080|pmc=PMC4027049|pmid=22992590|via=}}</ref><ref name=":0" />


==== Contextual Factors that determines TGF-β response ====
==== Contextual Factors that determines TGF-β response ====
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=== Upstream TGF-β Signaling Pathway ===
=== Upstream TGF-β Signaling Pathway ===
⚫
The type II receptors phosphorylate the type I receptors; the type I receptors are then enabled to phosphorylate cytoplasmic R-Smads, which then act as transcriptional regulators.<ref name=":2">{{Cite journal|last=Vilar|first=Jose M. G.|last2=Jansen|first2=Ronald|last3=Sander|first3=Chris|date=2006-01-27|title=Signal Processing in the TGF-β Superfamily Ligand-Receptor Network|url=https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.0020003|journal=PLOS Computational Biology|language=en|volume=2|issue=1|pages=e3|doi=10.1371/journal.pcbi.0020003|issn=1553-7358|pmc=PMC1356091|pmid=16446785}}</ref><ref name=":0" /> 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. Binding of a TGF-β members induces assembly of a heterotetrameric complex of two type I and two type II receptors at the [[Cell membrane|plasma membrane]].<ref name=":3">{{Cite journal|last=Vilar|first=Jose M. G.|last2=Jansen|first2=Ronald|last3=Sander|first3=Chris|date=2006-01-27|title=Signal Processing in the TGF-β Superfamily Ligand-Receptor Network|url=https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.0020003|journal=PLOS Computational Biology|language=en|volume=2|issue=1|pages=e3|doi=10.1371/journal.pcbi.0020003|issn=1553-7358|pmc=PMC1356091|pmid=16446785}}</ref>  Individual members of the TGF-β family bind to a certain set of characteristic combination of these type I and type II receptors<ref>{{Cite journal|last=Heldin|first=Carl-Henrik|last2=Moustakas|first2=Aristidis|date=2016-08-01|title=Signaling Receptors for TGF-β Family Members|url=http://cshperspectives.cshlp.org/content/8/8/a022053|journal=Cold Spring Harbor Perspectives in Biology|language=en|volume=8|issue=8|pages=a022053|doi=10.1101/cshperspect.a022053|issn=1943-0264|pmc=PMC4968163|pmid=27481709}}</ref>.  The type I receptors can be divided into two groups, which depends on the cytoplasmic [[R-SMAD|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).<ref name=":3" /><ref name=":0" /> 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.<ref name=":2" /><ref name=":1" />
The type II receptors phosphorylate the type I receptors; the type I receptors are then enabled to phosphorylate cytoplasmic R-Smads, which then act as transcriptional regulators.
⚫
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. Binding of a TGF-β members induces assembly of a heterotetrameric complex of two type I and two type II receptors at the [[Cell membrane|plasma membrane]].  Individual members of the TGF-β family bind to a certain set of characteristic combination of these type I and type II receptors.  The type I receptors can be divided into two groups, which depends on the cytoplasmic [[R-SMAD|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). 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.


=== Downstream TGF-β Signaling Pathway ===
=== Downstream TGF-β Signaling Pathway ===
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, [[Proliferation|cell proliferation]], [[Cellular differentiation|cell differentiation]], and [[apoptosis]].
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, [[Proliferation|cell proliferation]], [[Cellular differentiation|cell differentiation]], and [[apoptosis]].<ref>{{Cite journal|last=Shuang|first=Li Nian|last2=Chuan|first2=Xie|last3=Hua|first3=Lu nong|date=2015|title=Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis|url=https://www.frontiersin.org/articles/10.3389/fcimb.2015.00077/full|journal=Frontiers in Cellular and Infection Microbiology|language=English|volume=5|doi=10.3389/fcimb.2015.00077|issn=2235-2988|pmc=PMC4632021|pmid=26583078}}</ref><br />
<br />


== Referances ==
== Referances ==

Revision as of 18:35, 10 April 2020

The extracellular type II and type I kinase receptors binding to the TGF-β ligands.
The type II receptors phosphorylate the type I receptors; the type I receptors are then enabled to phosphorylate cytoplasmic R-Smads, which then act as tra nscriptional regulators.

TGF-β signaling as a demonstration of upstream signaling

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

The extracellular type II and type I kinase receptors binding to the TGF-β ligands. 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

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

Upstream TGF-β Signaling Pathway

The type II receptors phosphorylate the type I receptors; the type I receptors are then enabled to phosphorylate cytoplasmic R-Smads, which then act as transcriptional regulators.[7][2] 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. 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.[7][5]

Downstream TGF-β Signaling Pathway

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

  1. ^ 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). doi:10.1242/jcs.234039. ISSN 0021-9533. PMC 6679586. PMID 31217285.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ a b c d Massagué, Joan (October 2012). "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}}: CS1 maint: PMC format (link)
  3. ^ 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)
  4. ^ Huang, Tao; Schor, Seth L.; Hinck, Andrew P. (2014-09-05). "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}}: CS1 maint: PMC format (link)
  5. ^ 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.
  6. ^ Massagué, Joan (October 2012). "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}}: CS1 maint: PMC format (link)
  7. ^ 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)
  8. ^ 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)
  9. ^ 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. PMC 4968163. PMID 27481709.{{cite journal}}: CS1 maint: PMC format (link)
  10. ^ 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)
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