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.

Protein Tyrosine Phosphatase Receptor Type γ Is a JAK Phosphatase and Negatively Regulates Leukocyte Integrin Activation

“…Notably, most of the studies describe proadhesive signaling events, even when antiadhesive signals likely have an equally relevant role in leukocyte recruitment, for example, during the on-off turnover of integrin activation necessary for cell motility and transmigration. To date, few signaling molecules have been shown to negatively regulate leukocyte integrin activation; these include PKA (34), RHOH (35), CDC42 (10,36), SRC (37-39), H-RAS (40), ILK (41), FAM65B (42), and CAPN2 (43), with only CDC42 investigated according to the previously formalized four criteria (2). In the present study, fully compliant with these criteria, we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes.…”

“…A number of protein and lipid kinases have been shown to regulate the proadhesive signaling network triggered by chemoattractants (2). In this context, we have recently shown that protein tyrosine kinases (PTKs) of the JAK family are upstream transducers linking the chemokine receptor CXCR4 to the hierarchical activation of Rho and Rap small GTPases, thus controlling integrin affinity upregulation and homing to secondary lymphoid organs of T lymphocytes (3).…”

A Complement-Optimized EGFR Antibody Improves Cytotoxic Functions of Polymorphonuclear Cells against Tumor Cells

“…The affinity of integrins, such as CR3, to their ligands is controlled by G-protein-coupled receptor-initiated inside-out signaling in leukocytes (45). Hence, one may hypothesize that enhanced CR3 activation triggered by C5a may result from the G-protein-coupled receptor C5aR-mediated inside-out signaling in PMN.…”

Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis

“…In agreement with these functional observations, the expression of the macrophage scavenger receptor CD36 and the major lipid droplet protein ADRP was not modified by Arhgef1 deletion (Supplemental Figure 5) Figure 2B). β 2 Integrin activation results in a conformational change that depends on both RhoA-and Rap-dependent signaling (18)(19)(20). This conversion to a high-affinity open conformation leads to the formation of the epitope for the 24 antibody (mAb 24).…”