Overview-studying integrins in vivo

Integrins are adhesive proteins that have evolved to allow cell-cell and cell-matrix communication that is indispensable for development and post-natal physiology. Despite their widespread expression, the genetic deletion of specific integrin family members in lower organisms as well as mammals leads to relatively distinct abnormalities. Many processes in which integrins participate, have in common a requirement for strong adhesion coincident with times of mechanical stress. As an example in Drosophila, the absence of specific integrins leads to detachment of muscle from the gut and body wall and separation of the two epithelial layers in the wing. In mice and humans, a deletion of either subunit of the laminin binding integrin, α6β4 leads to severe skin blistering and defects in other epithelial layers due to problems in formation and stabilization of hemidesmosomes, which anchor epithelial cells to the basement membrane and are necessary for the skin to withstand frictional forces. However, integrins have also evolved to serve more subspecialized roles. These range from the establishment of a stem cell niche in Drosophila and mammals, to the regulation of pathogenic tumor vascularization, platelet adhesion and leukocyte transmigration in mammalian systems. On the other hand, some cells seem to function normally in the absence of all integrins, as revealed by the very surprising finding that deletion of all the major integrin types on dendritic cells of mice has no effect on the ability of these cells to migrate within the interstitium of the skin and enter into lymphatics. In addition to serving as transmembrane mechanical links, integrins in vertebrates synergize with other receptors including growth factor receptors. This leads to the activation of a large signaling network that affects cell proliferation and differentiation, cell shape and migration. The ability of integrins to directly bind and activate growth factors and interact with their receptors as is the case for VEGF, or modulate growth factor activity as is the case for TGFβ, has major implications for adult homeostasis. In the latter case, the results from knockout mice may aid in the interpretation of observations in patients. That is, β6 deletion in mice leads to a failure in activation of TGFβ, which provides tonic suppression of inflammatory cells, and this may provide an explanation for the observed inflammation in patients with β6 deficiency. These types of in vivo studies, in lower organisms, knock-out models as well as in human conditions together have provided important insights into how this major, primordial family of adhesion receptors have remained true to their name “integrins” as their diverse functions have in common the ability to integrate extracellular stimuli and transmit signals into cells that affect cell behavior. Some of the challenges in the next decade are to understand how these receptors signal their diverse functions, how the same integrin can specialize to promote specific functions that are dependent on the environment (cell and tissue in which it exists) and how integrins collaborate with other integrins and receptors within a network to deliver cues responsible for cell processes that range from migration to differentiation. This type of knowledge will allow integrin-targeted therapeutic modalities that inhibit pathologic processes in which integrins have been heavily implicated including tumor angiogenesis, inflammation and thrombosis.