Transforming growth factor beta
Transforming growth factor beta (TGF-
Activated TGF-
TGF-
Because of its role in immune and stem cell regulation and differentiation, it is a highly researched cytokine in the fields of cancer, auto-immune diseases, and infectious disease.
The TGF-
Structure
[edit]The primary 3 mammalian types are:
- TGF beta 1 – TGFB1[10][11]
- TGF beta 2 – TGFB2[12][13]
- TGF beta 3 – TGFB3[14][15]
A fourth member, TGF beta 4, has been identified in birds[16] – TGRB4 (synonyms: endometrial bleeding associated factor beta-4 (EBAF)[citation needed], Lefty preproprotein[citation needed], LEFTA[citation needed]; Left-Right Determination Factor 2; LEFTYA; Left-Right Determination Factor A; Transforming Growth Factor Beta-4; Protein Lefty-2; Protein Lefty-A[17][18][19][20]).[21]
A fourth member of the subfamily, TGFB4, has been identified in birds and a fifth, TGFB5, only in frogs.[16]
The peptide structures of the TGF-
Latent TGF-β complex
[edit]All three TGF-
In most cases, before the LLC is secreted, the TGF-
There are four different LTBP isoforms known, LTBP-1, LTBP-2, LTBP-3 and LTBP-4.[29] Mutation or alteration of LAP or LTBP can result in improper TGF-
Activation
[edit]Although TGF-
Integrin-independent activation
[edit]Activation by protease and metalloprotease
[edit]Plasmin and a number of matrix metalloproteinases (MMP) play a key role in promoting tumor invasion and tissue remodeling by inducing proteolysis of several ECM components.[33] The TGF-
Activation by pH
[edit]Acidic conditions can denature the LAP. Treatment of the medium with extremes of pH (1.5 or 12) resulted in significant activation of TGF-
Activation by reactive oxygen species (ROS)
[edit]The structure of LAP is important in maintaining its function. Structure modification of LAP can lead to disturb the interaction between LAP and TGF-
Activation by thrombospondin-1
[edit]Thrombospondin-1 (TSP-1) is a matricellular glycoprotein found in plasma of healthy patients with levels in the range of 50–250 ng/ml.[39] TSP-1 levels are known to increase in response to injury and during development.[40] TSP-1 activates latent TGF-beta[41] by forming direct interactions with the latent TGF-
Activation by Alpha(V) containing integrins
[edit]The general theme of integrins participating in latent TGF-
Conformation change mechanism pathway (without proteolysis)
[edit]Integrin protease-dependent activation mechanism
[edit]Because MMP-2 and MMP-9 can activate TGF-
Signaling pathways
[edit]Canonical signaling: The SMAD pathway
[edit]Smads are a class of intracellular signalling proteins and transcription factors for the TGF-
More specifically, activated TGF-
The Smads are not the only TGF-
Apoptosis via the DAXX pathway
[edit]TGF-
TGFβ receptor inhibitors
[edit]Galunisertib is the selective and potent TGF
TGF-β mimic
[edit]The parasitic roundworm Heligmosomoides polygyrus secretes a molecule that mimics the ability of mammalian TGF-
Effects on immune cells
[edit]T lymphocytes
[edit]TGF-
TGF-
Studies show that neutralization of TGF-
B lymphocytes
[edit]TGF-
TGF-
Macrophages
[edit]The general consensus in the literature is that TGF-
TGF-
Cell cycle
[edit]TGF-
Clinical significance
[edit]Cancer
[edit]In normal cells, TGF-
Furthermore, forkhead box protein 3 (FOXP3) as a transcription factor is an essential molecular marker of regulatory T (Treg) cells. FOXP3 polymorphism (rs3761548) might be involved in cancer progression like gastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-
Tuberculosis
[edit]Mycobacterium tuberculosis infection, or tuberculosis, has been shown to result in increased levels of active TGF-
Heart disease
[edit]One animal study suggests that cholesterol suppresses the responsiveness of cardiovascular cells to TGF-
TGF-
Marfan syndrome
[edit]TGF-
Loeys–Dietz syndrome
[edit]TGF-
Obesity and diabetes
[edit]TGF-
As noted above in the section about macrophages, loss of TGF-
Multiple Sclerosis
[edit]Induced T regulatory cells (iTreg), stimulated by TGF-
Decreased levels of TGF-
Neurological
[edit]Higher concentrations of TGF-
Other
[edit]Overactive TGF-
There is substantial evidence in animal and some human studies that TGF-
Skin aging is caused in part by TGF-
See also
[edit]- Anita Roberts, a molecular biologist who made pioneering observations of TGF-
β - Ziad Mallat, identified a major atheroprotective role of regulatory T cells and associated anti-inflammatory cytokines, IL-10 and TGF-
β
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Further reading
[edit]- Moses HL, Roberts AB, Derynck R (July 2016). "The Discovery and Early Days of TGF-
β : A Historical Perspective". Cold Spring Harbor Perspectives in Biology. 8 (7): a021865. doi:10.1101/cshperspect.a021865. PMC 4930926. PMID 27328871.
External links
[edit]- Description of the TGF beta producing genes at ncbi.nlm.nih.gov
- Diagram of the TGF beta signaling pathway at genome.ad.jp
- The TGF-beta system—Nature Reviews Molecular Cell Biology
- SMART:TGFB domain annotation—European Molecular Biology Laboratory Heidelberg
- TGF-beta at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Biochemists Solve Structure Of TGF-Beta And Its Receptor. 2008 – shows TGF-
β 3 dimer in TGFB-receptor - Measurement of Human Latent TGF-
β 1 - TGF beta pathway diagram
- IntroPro Entry - IPR016319