Fibulin‐1 is a matricellular regulator of the RAS/mitogen activated protein kinase (MAPK)‐mediated signal transduction pathway

Abstract

Fibulin‐1 (Fbln1) is a glycoprotein found in extracellular matrices of the embryo and adult. In tissues of vertebrate embryos, Fbln1 is found associated with fibronectin and versican. In postembryonic vertebrate tissues, Fbln1 is found associated with elastin‐containing fibers including those in blood vessels, lungs and skin. Targeted deletion of the Fbln1 gene in mice reveals a critical developmental role for Fbln1 in the directed migration and growth of cranial neural crest cells contributing to the development of pharyngeal glands, craniofacial skeleton, cranial nerves, aortic arch arteries, cardiac outflow tract and cephalic blood vessels. However, Fbln1 deficiency does not lead to overt abnormalities in the formation of elastin‐containing fibers. Therefore, the elastin fiber association of Fbln1 may not be reflective of a role for Fbln1 in the assembly and maintenance of elastin fibers, but of a matricellular function in which it serves to modulate cell functions. Findings from several avenues of investigation point to Fbln1 as being a regulator of the RAS/MAPK‐mediated signal transduction pathway. Many of developmental defects observed in Fbln1‐deficient mouse embryos are consistent with disorders associated with mutations in molecules in the RAS/MAPK cascade. Indeed, we find that Fbln1 influences the activity of several growth factors that stimulate the RAS/MAPK pathway.