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.de Bruyn et al. [1xThe small GTPase Rap1 is required for Mn2+- and antibody-induced LFA-1- and VLA-4-mediated cell adhesion. de Bruyn, K.M. et al. J. Biol. Chem. 2002; 277: 29468–29476Crossref | PubMed | Scopus (92)See all References][1] extend the analysis of Rap1 and its role in regulating integrin function by examining potential requirements for Rap1 in adhesion induced by the divalent cation manganese (Mn2+) and integrin-specific antibodies that directly activate integrins. Just like adhesion induced by signals, such as TCR stimulation, integrin function induced by Mn2+ and these antibodies was inhibited by the expression of proteins that block Rap1 function. This is an intriguing result because integrin activation induced by Mn2+ and activating integrin-specific antibodies are believed to bypass requirements for intracellular signaling. In fact, unlike Rap1, disruption of the function of other molecules implicated in ‘inside-out’ signaling from the TCR and other receptors does not inhibit Mn2+ and antibody-induced activation of integrins. Integrin ligation itself does not appear to enhance Rap1 activity, suggesting that integrins require some basal level of Rap1 function in order to respond to activating signals. Together with results obtained with transgenic mice expressing active Rap1, this study suggests that the activity of Rap1 in unstimulated lymphocytes could be crucial to how adhesive these cells are in the absence of stimulation. Changes in adhesiveness during T-cell activation and differentiation might therefore be related to changes in Rap1 expression and/or activity. In addition, this study suggests that Rap1 is required for ‘inside-out’ signaling but in a rather unexpected way. Rather than directly transmitting signals from receptors, such as the TCR, to integrins, Rap1 might work to regulate integrin function in a more global manner, perhaps by regulating factors that are required for integrins to work.