Print this page 
TGF-β signalling pathway disorders
Summary
Transforming growth factor-β2 (TGF-β2), a member of the TGF-β superfamily, plays important roles in diverse developmental and homeostatic processes. Targeted disruption of TGF-β2 results in perinatal lethality and a wide range of developmental defects. In this project, we are focusing on the molecular interactions that mediate the assembly, secretion, ECM localisation and activation of TGF-β2.
Description
Targeted disruption of TGF-β2 results in perinatal lethality and a wide range of developmental defects including, cardiac, lung, craniofacial, limb, eye, ear and urogenital abnormalities. Significantly, increased TGF-β2 signalling, as observed in Marfan and Loeys-Dietz syndromes, also contributes to cardiac and skeletal malformation. Thus, the bioavailability of active TGF-β2 must be strictly controlled.
It is recognised that TGF-β2 is secreted as part of an inactive complex consisting of the mature growth factor, the TGF-β2 propeptide (latency-associated peptide; LAP) and a molecule of latent TGF-β binding protein (LTBP).
The interaction of TGF-β2 with LAP renders the growth factor latent, whereas binding of LAP to LTBP targets TGF-β2 to the extracellular matrix (ECM). In order for TGF-β2 to interact with its receptors and signal, the mature growth factor must be liberated from LAP and the ECM; a process termed latent TGF-β activation.
Subversion of the extracellular control of TGF-β signalling has been implicated in many human diseases, including a range of hereditary disorders. These disorders are related in that they cause congenital malformation or dysfunction of the skeletal, muscular and cardiovascular systems.
Thus, there is a clear need to improve our understanding of the extracellular regulation of TGF-β2 activity and the context dependence of cellular responses. In this project, we are focusing on the molecular interactions that mediate the assembly, secretion, ECM localisation and activation of TGF-β2, and we will consider the consequence of disruptions across this regulatory network.