Chemokines and the signaling modules regulating integrin affinity

Abstract

Integrin-mediated adhesion is a general concept referring to a series of adhesive phenomena including tethering-rolling, affinity, valency, and binding stabilization altogether controlling cell avidity (adhesiveness) for the substrate. Arrest chemokines modulate each aspect of integrin activation, although integrin affinity regulation has been recognized as the prominent event in rapid leukocyte arrest induced by chemokines. A variety of inside-out and outside-in signaling mechanisms have been related to the process of integrin-mediated adhesion in different cellular models, but only few of them have been clearly contextualized to rapid integrin affinity modulation by arrest chemokines in primary leukocytes. Complex signaling processes triggered by arrest chemokines and controlling leukocyte integrin activation have been described for ras-related rap and for rho-related small GTPases. We summarize the role of rap and rho small GTPases in the regulation of rapid integrin affinity in primary leukocytes and provide a modular view of these pro-adhesive signaling events. A potential, albeit still speculative, mechanism of rho-mediated regulation of cytoskeletal proteins controlling the last step of integrin activation is also discussed. We also discuss data suggesting a functional integration between the rho- and rap-modules of integrin activation. Finally we examine the universality of signaling mechanisms regulating integrin triggering by arrest chemokines.

Keywords: adhesion; chemokine; integrin activation; integrin affinity; leukocyte recruitment; rap small GTPases; rho small GTPases; signal transduction.

Figure 1

Integrin affinity triggering. The diagram refers to the LFA-1 affinity-triggering model. Shown is the dynamic equilibrium between three conformers displaying low-, low/intermediate-, and high-affinity for ICAM-1. The progressive extension of the heterodimer is accompanied by increasing topological availability of the I-domain and I-like domain (in yellow), which are involved in ligand binding with increasing affinity.

Figure 2

The rap- and rho-modules of integrin affinity modulation by chemokines. The diagram mainly reports data regarding LFA-1 affinity triggering. Dotted lines refer to hypothetic effects. Red lines emphasize the functional relationships between rap and rho modules. Arrowed lines indicate activation. Flat ending lines indicate inhibition. Circle ending lines indicate docking activity. Positive regulators of adhesion are represented as red elliptic shapes; negative regulators are in blue. Notably, although the physical and functional interactions between the different signaling molecules have been demonstrated, the functional role of these interactions in the specific context of integrin affinity regulation under experimental conditions satisfying the four criteria is still not always validated.