John G. Harpel

TGF‐β Latency: Biological Significance and Mechanisms of Activation

Transforming growth factor (TGF‐)β is secreted as a latent complex in which the mature growth factor remains associated with its propeptide. In order to elicit a biological response, the cytokine must be released from the latent complex, a process termed latent TGF‐β activation or TGF‐β formation. Although latent TGF‐β activation is a critical step in the regulation of its activity, little is known about the molecular mechanisms that lead to the production of active TGF‐β. In this article, we present an overview of the data available on this topic, and we propose a tentative model for the mechanism of TGF‐β formation based upon the observations with different cell systems and on recent findings on the structure of the latent TGF‐β complex.

Control of transforming growth factor-β activity: latency vs. activation

Transforming growth factor-β is a pluripotent regulator of cell growth and differentiation. The growth factor is expressed as a latent complex that must be converted to an active form before interacting with its ubiquitous high affinity receptors. This conversion involves the release of the mature growth factor through disruption of the non-covalent interactions with its pro-peptide or latency associated peptide. The mechanisms for this release in vivo have not been fully characterized but appear to be cell specific and might involve processes such as acidification or proteolysis. Although several factors including transcriptional regulation, receptor modulation and scavenging of the active growth factor have been implicated, the critical step controlling the biological effects of transforming growth factor-β may be the activation of the latent molecule.