Unchaining the beast; insights from structural and evolutionary studies on TGFβ secretion, sequestration, and activation

TGF beta is secreted in a latent state and must be "activated" by molecules that facilitate its release from a latent complex and allow binding to high affinity cell surface receptors. Numerous molecules have been implicated as potential mediators of this activation process, but only a limited number of these activators have been demonstrated to play a role in TGF beta mobilisation in vivo. Here we review the process of TGF beta secretion and activation using evolutionary data, sequence conservation and structural information to examine the molecular mechanisms by which TGF beta is secreted, sequestered and released. This allows the separation of more ancient TGF beta activators from those factors that emerged more recently, and helps to define a potential hierarchy of activation mechanisms. (C) 2013 Elsevier Ltd. All rights reserved.