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

the selective recruitment of leukocyte subsets to inflammation foci or
secondary lymphoid organs (26). In addition, chemokines may exert a
differential effect on specific integrins within the same
microenvironment. Accordingly, it has been described that chemokines
can only mediate lymphocyte arrest dependent on VLA-4/VCAM-1 when
binding their GPCRs with high affinity and with high relative occupancy,
but this signal threshold-dependent effect is not observed with

chemokine-stimulated ß2 integrins (37).
Small GTPases play a central regulatory role in the integrin

activation induced by chemokines, mainly through RhoA activation
or/and RhoH inactivation (37-39). It has been also suggested that Rac1
and its GDP/GTP exchanging factors (GEFs) Vav-1 and DOCK2 are
involved in the chemokine-mediated activation of integrins in T and B
cells (40-42). However, other authors propose that DOCK2 is mainly
involved in microvilli collapse, lamellipodium formation, and lateral
mobility induced by chemokines (43). On the other hand, the ras-like
small GTPase Rap1 can regulate integrin activation through RAPL that

binds to the cytoplasmic tail of LFA-1 a chain (44, 45). The important
role of Rap1 in integrin activation has been recently underscored by a
deficiency in lymphocyte adhesiveness (LAD III), that correlates with a
selective impairment in the activation of Rap1 induced by chemokines via
CalDAG-GEFI (46, 47). Furthermore, the activation of

phosphatidylinositol 3-OH kinase (PI3K) and PKC? by chemokines is
involved in LFA-1 clustering at areas of low ICAM-1 density (33, 37,
38). In addition, the ARF-guanine-nucleotide exchange factor Cytohesin-

1 induces LFA-1 activation by direct interaction with its ß2 cytoplasmic
domain (48, 49). However, there are also negative regulators of integrin
activation, such as PKA, H-ras and ILK (integrin-linked kinase) (37, 50,
51). Due to the complexity and timeframes of the signaling mechanisms
controlling integrin activation, it is conceivable the existence of
preformed compartmentalized protein networks (“signalosomes”) in
leukocytes encountering endothelial chemokines (37).

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