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Hence, the emerging view is that fibrillin-rich microfibrils are molecular integrators of structural and instructive signals, with TGFbeta and BMPs as the nodal points that convert extracellular inputs into discrete and context-dependent cellular responses. Correlative evidence suggests functional coupling of the cell-directed assembly of microfibrils and targeting of TGFbeta and BMP complexes to fibrillins. The majority of mutations affecting FBN1 result in Marfan syndrome (MFS) one of the most common human connective tissue disorders affecting the cardiovascular, skeletal and ocular systems. Forty-three of the EGF domains have a calcium binding (cb) motif and are arranged in. They have also suggested that the relative composition of fibrillin-rich microfibrils imparts contextual specificity to TGFbeta and BMP signaling by concentrating the ligands locally so as to regulate cell differentiation within a spatial context during organ formation (positive regulation) and by restricting their bioavailability so as to modulate cell performance in a timely fashion during tissue remodeling/repair (negative regulation). In humans, three fibrillin isoforms, FBN1, -2 and -3, are expressed from separate genes 8 12. The modular architecture of fibrillin-1 is dominated by EGF and TB domains. Fibrillin-1 is a 350-kDa glycoprotein and has a modular structure comprising 47 epidermal growth factor-like (EGF) domains, seven transforming growth factor 1. More generally, these studies have indicated that fibrillins are integral components of a broader biological network of extracellular, cell surface, and signaling molecules that orchestrate morphogenetic and homeostatic programs in multiple organ systems. Fibrillin-1 is the major constitutive element of extracellular microfibrils encoded by the large FBN1 gene that contains 66 exons spanning 235 kb of genomic DNA on chromosome 15q21.1. Characterization of fibrillin mutations in human patients and in genetically engineered mice has demonstrated that perturbation of either function manifests in disease. The structural role of fibrillins is exerted through the temporal and hierarchical assembly of microfibrils and elastic fibers, whereas the instructive role reflects the ability of fibrillins to sequester transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) complexes in the extracellular matrix. Fibrillin-1 and fibrillin-2 are large cysteine-rich glycoproteins that serve two key physiological functions: as supporting structures that impart tissue integrity and as regulators of signaling events that instruct cell performance.
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