Let's Rap: making a functional integrin

Abstract

Lymphocytes are called into action on the initiation of intracellular signaling events by antigen-specific receptors and other cell-surface co-receptors. An early and rapid functional consequence of this activation is a transient increase in adhesion mediated by integrin receptors. For T cells, such ‘inside-out’ signaling enhances the interaction of T cells with antigen-presenting cells and promotes the retention of activated T cells in lymphoid organs and peripheral tissue sites. Defects in ‘inside-out’ signaling have dire consequences, illustrated by rare immunodeficiency syndromes in which leukocytes express integrins but are unable to respond to signals that normally result in integrin activation. Recent human and murine studies implicate several intracellular signaling proteins in integrin activation, including adapter proteins, such as ADAP (adhesion and degranulation promoting adaptor protein) and guanine-nucleotide exchange factors, such as Vav. GTPases can also be added to this list, and several recent studies have suggested a particularly prominent role for the small GTPase Rap1 in regulating integrin activation induced by receptors, such as the CD3–T-cell receptor (TCR) complex. These studies demonstrate that overexpression of proteins that inhibit Rap1 activity, such as a putative dominant-negative Rap1 construct or Rap1 GTPase activating proteins, block TCR-induced activation of β1 and β2 integrins. In addition, thymocytes from transgenic mice expressing an active form of Rap1 in T cells show enhanced integrin-mediated adhesion, even in the absence of additional stimulatory signals.