Integrin signal transduction in myeloid leukocytes

Integrin-mediated adhesion serves as a powerful costimulus for neutrophil a ctivation, Clustering of integrins at the leukocyte membrane by interaction with surface-bound ligands (extracellular matrix proteins or endothelial c ell counterreceptors) leads to a number of signaling events that culminate in actin cytoskeletal rearrangement and neutrophil functional responses suc h as migration, degranulation, and respiratory burst. Although the signalin g reactions elicited by integrin Ligation are complex and the relative cont ribution of each pathway to neutrophil function is unclear, a large body of evidence suggests that activation of tyrosine kinases is a very proximal e vent in these signaling cascades. This review summarizes the role of adhesi on in activating neutrophil functional properties and the contribution of l eukocyte tyrosine kinases to regulation of integrin signaling in myeloid ce lls. Significant advances in our understanding of leukocyte integrin signal ing have been afforded by studies using knockout mice lacking members of th e Src-family of tyrosine kinases normally expressed in myeloid cells. These studies have demonstrated that these kinases (Hck, Fgr, and Lyn) are not r equired for myeloid cell development or for many of the functional properti es of myeloid cells but are critical in controlling integrin-mediated signa ling events. Absence of these kinases results hi impaired adhesion-dependen t neutrophil activation both in vivo and in vitro. These studies suggest th at leukocyte-specific tyrosine kinases may be good therapeutic targets for controlling myeloid cell-dependent inflammatory disease.