Integrin Signaling in Vascular Biology and Beyond
Integrin adhesion receptors transfer biochemical and mechanical information between the extracellular and intracellular environments of cells at plasma membrane adhesion sites. Integrin signaling encompasses “inside-out” signals that regulate integrin affinity and avidity for extracellular ligands and "outside-in" signals that regulate anchorage-dependent cellular responses, such as motility and changes in gene expression. Integrin signaling promotes normal processes as diverse as embryonic development and vascular cell function, while abnormal integrin signaling plays a role in diseases such as atherothrombosis, bleeding disorders and cancer. Recent work has demonstrated the importance of integrin cytoplasmic domains in integrin signaling in vivo. Knock-in mice with certain integrin β3 cytoplasmic domain mutations demonstrate selective defects in either inside-out or outside-in integrin αIIbβ3 signaling in platelets. These mice do not exhibit a bleeding diathesis, but they are resistant to arterial thrombosis. Primary endothelial cells from some of these mice express mutant αVβ3 and exhibit defective migration and angiogenesis. Certain other α3 integrin cytoplasmic domain mutations or deletions in mice and humans cause global defects in bidirectional αIIbβ3 signaling and a bleeding diathesis. In zebrafish embryos, knockdown of an αVintegrin by morpholino oligonucleotides causes gastrulation defects, developmental abnormalities in the cardiovascular system and unanticipated defects in laterality specification, likely due in part to a disruption of integrin signaling. A future challenge is to integrate the wealth of information being obtained from studies of purified proteins, model cell systems, animal models and humans to yield a complete understanding of the protein-protein interactions involved in adhesive signaling, with implications for the diagnosis and therapy of cardiovascular diseases.
- © 2010 by American Heart Association, Inc.