Convergence of immunoreceptor and integrin signaling

A common signaling pathway is known to operate downstream of immunoreceptors, such as the T-cell, B-cell, or Fc receptors, following engagement by their respective ligands. This pathway involves Src family kinase-mediated tyrosine phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) that recruit and activate spleen tyrosine kinase (Syk) or Zap70 (zeta-associated protein of 70 kDa) kinases, which in turn activate a variety of downstream signals. Evidence has been building from a variety of sources, particularly mouse models, that molecules involved in the immunoreceptor signaling pathway are also required for signals initiated by integrins. Integrins are the major cell surface receptors that mediate adhesion of leukocytes to a variety of extracellular matrix proteins and counter-receptors expressed on endothelial cells. Integrin ligation is a critical step in the activation of leukocyte effector functions (such as neutrophil degranulation or lymphocyte proliferation). Integrin signaling through pathways common to those utilized by immunoreceptors provides a mechanism by which leukocyte adhesion can regulate activation of cellular responses. In animal models, integrin-mediated signal transduction plays a critical role in inflammatory disease. In this review, we discuss the convergence of immunoreceptor and integrin signaling, focusing on how these pathways modulate leukocyte activation.