ABSTRACT
The transforming growth factor ß (TGFß) superfamily consists of multipotential secreting cytokines that mediate many key events in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGFßs act as ligand for 3 classes of cell surface receptors, the transmembrane serine-threonine kinase receptors, TGFß receptor type I (TGFßRI) and type 2 (TGFßRII), and TGFßRIII receptors which include an ubiquitous extracellular ß-glycan and the membrane glycoprotein endoglin (CD105). Binding of TGFßs to their receptors initiates diverse cellular responses resulting in the phosphorilation of Smad proteins, which then translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGFß signaling has been implicated in various human disorders including cancer, fibrosis and auto-immune diseases. Recently, mutations in TGFßR1 and TGFßR2 genes have been found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity is represented by the Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by hypertelorism, bifid uvula, and/or cleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular aneurysms and dissections. Elastin disarray, loss of elastic fibre architecture and increased collagen expression in the arterial wall are the pathologic hallmark of LDS. In the present review article we will provide details on the activation of TGFß cascade, on the clinical features of LDS, as well as on the mechanisms of TGFß signaling perturbation leading to this condition and the potential role of the antagonism of TGFß activity in disease management.
