TGF-beta: from latent to active.
The transforming growth factor-betas (TGF-betas) are synthesized as precursor proteins that are modified intracellularly prior to secretion. One of the most relevant intracellular modifications is the cleavage of the C-terminal pro-region from the N-terminal portion of the protein. The C-terminal pro-region is referred to as the latency-associated peptide (LAP) while the N-terminal region is called the mature TGF-beta or active TGF-beta. However, with some exceptions the LAP noncovalently associates with the mature TGF-beta prior to secretion. When the mature TGF-beta is associated with the LAP it is called L-TGF-beta and cannot interact with its receptor and has no biological effect. The TGF-betas and their receptors are very ubiquitously expressed, suggesting that the regulation of TGF-beta activity is likely to be complex and multifactorial. However, one of the most important means of controlling the biological effects of TGF-beta is the regulation of converting L-TGF-beta to active TGF-beta. The current literature supports two major mechanisms of activation of L-TGF-beta and suggests that the mechanism of activation of L-TGF-beta may be varied and context-dependent. For TGF-beta to become biologically active the LAP has to be either released from its associations with L-TGF-beta or undergo conformational change such that the LAP is not released from the L-TGF-beta complex but exposes the TGF-beta receptor binding site. Since TGF-beta has been associated with the pathogenesis of numerous diseases, the various mechanisms of activation of L-TGF-beta in context offer the possibility of controlling TGF-beta activity localized to the organ of involvement and to a more specific disease process.
Khalil
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Department of Medicine and the Manitoba Institute of Cell Biology, University of Manitoba, 100 Olivia Street, Winnipeg R3E 0V9, Manitoba, Canada.
D005786:Gene Expression Regulation; D006801:Humans; D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D010446:Peptide Fragments; D011498:Protein Precursors; D011506:Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1