TGF beta

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The SMAD Pathway
The SMAD Pathway
The DAXX Pathway
The DAXX Pathway

Transforming growth factor beta (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. TGF beta controls proliferation, cellular differentiation, and other functions in most cell types. It can also act as a negative autocrine growth factor.

Contents

[edit] 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.[1] The mature TGF-β protein dimerizes to produce a 25 KDa active molecule with many conserved structural motifs.[2] 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.[3] 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.

[edit] Functions

[edit] Role in apoptosis

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

[edit] SMAD 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.

[edit] 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.

[edit] Role in cell cycle

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

[edit] 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-ß, thus helping prevent the development of atherosclerosis and heart disease. [1]

[edit] Types

The primary three are:

[edit] See also

[edit] References

  1. ^ Khalil N (1999). "TGF-beta: from latent to active". Microbes Infect 1 (15): 1255–63. doi:10.1016/S1286-4579(99)00259-2. PMID 10611753. 
  2. ^ Herpin A, Lelong C, Favrel P (2004). "Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans". Dev Comp Immunol 28 (5): 461–85. doi:10.1016/j.dci.2003.09.007. PMID 15062644. 
  3. ^ Daopin S, Piez K, Ogawa Y, Davies D (1992). "Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily". Science 257 (5068): 369–73. doi:10.1126/science.1631557. PMID 1631557. 

[edit] External links

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