TGF beta

Transforming growth factor beta (TGF-β) controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease and Marfan syndrome.

Some cells secrete TGF-β, and also have receptors for TGF-β. This is known as autocrine signalling. Cancerous cells increase their production of TGF-β, which also acts on surrounding cells.

TGF-β is a secreted protein that exists in three isoforms called TGF-β1, TGF-β2 and TGF-β3. It was also the original name for TGF-β1, which was the founding member of this family. The TGF-β family is part of a superfamily of proteins known as the transforming growth factor beta superfamily, which includes inhibins, activin, anti-müllerian hormone, bone morphogenetic protein, decapentaplegic and Vg-1.

The Structure of TGF-β

The peptide structures of the three members of the TGF-β family are highly similar. They are all encoded as large protein precursors; TGF-β1 contains 390 amino acids and TGF-β2 and TGF-β3 each contain 412 amino acids. They each have an N-terminal signal peptide of 20-30 amino acids that they require for secretion from a cell, a pro-region (called latency associated peptide or LAP), and a 112-114 amino acid C-terminal region that becomes the "mature" TGF-β molecule following its release from the pro-region by proteolytic cleavage. [cite journal |author=Khalil N |title=TGF-beta: from latent to active |journal=Microbes Infect |volume=1 |issue=15 |pages=1255–63 |year=1999 |pmid=10611753 |doi=10.1016/S1286-4579(99)00259-2] The mature TGF-β protein dimerizes to produce a 25 KDa active molecule with many conserved structural motifs. [cite journal |author=Herpin A, Lelong C, Favrel P |title=Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans |journal=Dev Comp Immunol |volume=28 |issue=5 |pages=461–85 |year=2004 |pmid=15062644 |doi=10.1016/j.dci.2003.09.007] TGF-β has nine cysteine residues that are conserved among its family; eight form disulfide bonds within the molecule to create a cysteine knot structure characteristic of the TGF-β superfamily while the ninth cysteine forms a bond with the ninth cysteine of another TGF-β molecule to produce the dimer. [cite journal |author=Daopin S, Piez K, Ogawa Y, Davies D |title=Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily |journal=Science |volume=257 |issue=5068 |pages=369–73 |year=1992 |pmid=1631557 |doi=10.1126/science.1631557] Many other conserved residues in TGF-β are thought to form secondary structure through hydrophobic interactions. The region between the fifth and sixth conserved cysteines houses the most divergent area of TGF-β molecules that is exposed at the surface of the molecule and is implicated in receptor binding and specificity of TGF-β.

Functions

Role in apoptosis

Cells can die in two ways: Through apoptosis, when the cell self-destructs through programmed cell death as a result of "death signals", and through necrosis, which is death from other causes, such as lack of oxygen or toxins.

TGF-β induces apoptosis in numerous cell types. TGF-β can induce apoptosis in two ways: through the SMAD pathway or the DAXX pathway.

MAD pathway

The SMAD pathway is the classical signaling pathway that TGF-β family members signal through. In this pathway, TGF-β dimers bind to a type II receptor which recruits and phosphorylates a type I receptor. The type I receptor then recruits and phosphorylates a receptor regulated SMAD (R-SMAD). SMAD3, an R-SMAD, has been implicated in inducing apoptosis. The R-SMAD then binds to the common SMAD (coSMAD) SMAD4 and forms a heterodimeric complex. This complex then enters the cell nucleus where it acts as a transcription factor for various genes, including those to activate the mitogen-activated protein kinase 8 pathway, which triggers apoptosis.

DAXX pathway

TGF-β may also trigger apoptosis via the death associated protein 6 (DAXX adapter protein).

DAXX has been shown to associate with and bind to the type II TGF-β receptor kinase.

Role in cell cycle

TGF-β plays a crucial role in the regulation of the cell cycle.

Role in cancer

In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive. [ [http://content.nejm.org/cgi/content/full/342/18/1350 Blobe, GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000 May 4;342(18):1350-8.] ] TGF-β also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction.

Role in heart disease

A study at the Saint Louis University School of Medicine has found that cholesterol suppresses the responsiveness of cardiovascular cells to TGF-β and its protective qualities, thus allowing atherosclerosis to develop. It was also found that statins, drugs that lower cholesterol levels, enhance the responsiveness of cardiovascular cells to the protective actions of TGF-β, thus helping prevent the development of atherosclerosis and heart disease. [http://www.slu.edu/x17685.xml]

Role in Marfan Syndrome

TGF-β plays an important role in the progress of Marfan syndrome.

Types

The primary three are:
* TGF beta 1 - TGFB1 OMIM|190180
* TGF beta 2 - TGFB2 OMIM|190220
* TGF beta 3 - TGFB3 OMIM|190230
* TGFβ4 precursor was discovered as a gene upregulated during pre-menstrual phase in the endometrail stroma(Kothapalli et al. 1997) and called EBAF (endometrial bleeding associated factor). Later independently discovered to be involved in vertebrate embryonic left right asymmetry determination, and given the name lefty2 (also called "Lefty A").

ee also

* Anita Roberts

References

External links

* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=7040 Description of the TGF beta producing genes at ncbi.nlm.nih.gov]
* [http://www.genome.ad.jp/dbget-bin/get_pathway?org_name=hsa&mapno=04350 Diagram of the TGF beta signaling pathway at genome.ad.jp]
*MeshName|TGF-beta