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VOL. 74 (4) SIGNALS EMANATING FROM LEUKOCYTE...

calcium-dependent manner. Although selectins and their ligands tend to
interact with a variable affinity, their rapid association and dissociation
rates mediate transient contacts between leukocytes and endothelium
(“tethering”) (5, 6). Tethering results in the slowing of leukocytes in the
bloodstream and their rolling on the surface of endothelium, which favors
subsequent interactions with endothelial cells mediated by integrins and
their ligands, increasing the adhesiveness of leukocytes, that leads to their
final arrest on the vessel wall (7).

It has been demonstrated that L-selectin activates multiple
signaling pathways involved in the reorganization of the actin
cytoskeleton, such as the MAPK cascade (8), the tyrosine kinase p56lck
and Ras (9) or the Rho GTPase Rac2 (10). In this regard, it has been
described that neutrophils from Rac2-/- mice show deficient actin
polymerization and L-selectin-mediated rolling (11). On the other hand,
the best characterized selectin ligand named PSGL-1 (P-selectin
glycoprotein ligand-1) activates the MAPK pathway (12), and acts as a
negative regulator of human hematopoietic progenitor cells (13). In
addition, it has been shown that PSGL-1 induces a rapid synthesis of
uPAR and different cytokines such as TNF-alpha, IL-8 and MCP-1 in
neutrophils, monocytes and T cells (14-17). Moreover, PSGL-1 induces
activation of beta-2 integrins and binding to ICAM-1 in neutrophils (18-
20). Our group has also described the interaction of PSGL-1 with ERM
proteins, which link membrane molecules with the actin cytoskeleton (21,
22). This interaction is of critical importance for the leukocyte activation
that occurs before extravasation, because it allows the recruitment of the
tyrosine kinase Syk by association to ERM proteins through their
phosphorylated ITAM-like motifs. Therefore, after PSGL-1 ligation to P-
selectin or E-selectin, Syk conveys rolling-emanating signals to the
activation of gene expression programs (23). This phenomenon suggests
that the intracellular signals induced through PSGL-1 have a priming
effect on leukocyte activation, up-regulating the expression of different
molecules further involved in extravasation and effector functions (24)
and an unsuspected role inducing tolerogenic functions in dendritic cells
(25). Since it has been demonstrated that the cytoplasmic tail of L-selectin
also interacts with moesin (26), it is very likely that selectins use a similar
strategy to trigger intracellular signaling cascades. In this regard, it has

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