Understanding TGF beta activation in health and disease

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The TGF ( transforming growth factor) beta signalling pathway plays an essential role in many aspects of biology, including development of the embryo and maintenance of adult tissues. There are three different forms of TGF beta, each of which is secreted from cells in the form of an inactive or latent complex, and this complex is itself often bound to a much larger protein called latent transforming growth factor beta binding protein (LTBP). This large protein ensures that TGF beta is sequestered in the extracellular matrix, an insoluble collection of proteins and carbohydrates which surround cells, where it can be activated in response to specific signals and delivered to its receptor in a carefully regulated manner. Subsequent binding of TGFbeta to its receptor leads to many different cellular effects in tissues. This signalling pathway is disrupted in many different genetic and acquired diseases, such as cancer, autoimmune and inflammatory disorders and heritable diseases of the connective tissues including Marfan syndrome. We have recently identified one of the ways in which LTBP is localised to the extracellular matrix, by its interaction with a protein called fibrillin-1. We believe that studying this interaction in detail will provide insight into how TGF beta is released in an active form from the matrix, and how various diseases associated with excessive levels of TGF beta activation arise. Furthermore this basic science may provide new ways of designing drugs such as monoclonal antibodies or small molecule activators or inhibitors which will be invaluable in a research or clinical setting to manipulate the TGF beta signal.