Transforming growth factor beta

The SMAD Pathway

The DAXX Pathway

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. TGF-beta acts as an antiproliferative factor in normal epithelial cells and at early stages of oncogenesis.

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. The mature TGF-β protein dimerizes to produce a 25 KDa active molecule with many conserved structural motifs. 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. 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.

Function

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.

SMAD pathway

The SMAD pathway is the canonical 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.

Cell cycle

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

Immune System

TGF-β is believed to be important in regulation of the immune system by CD25+ Regulatory T cell. TGF-β appears to block the activation of lymphocytes and monocyte derived phagocytes.

Clinical significance

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. 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.

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.

Marfan Syndrome

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

Types

The primary three are:

• TGF beta 1 - TGFB1 Online Mendelian Inheritance in Man (OMIM): 190180
• TGF beta 2 - TGFB2 Online Mendelian Inheritance in Man (OMIM): 190220
• TGF beta 3 - TGFB3 Online Mendelian Inheritance in Man (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).

See also

• Anita Roberts

External links

• Description of the TGF beta producing genes at ncbi.nlm.nih.gov
• Diagram of the TGF beta signaling pathway at genome.ad.jp
• TGF-beta at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• TGF Israeli Forum