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O. BARREIRO AND F. SÁNCHEZ-MADRID AN. R. ACAD. NAC. FARM

phosphorylation of cortactin (73, 74). ICAM-1 is also able to activate
RhoA inducing stress fiber formation (75) and phosphorylation of FAK,
paxillin and p130Cas, which in turn trigger different signaling pathways
involving JNK or p38 (76-78). Moreover, ICAM-1 cross-linking
stimulate c-fos and rhoA transcription (75). ICAM-1 cross-linking can
also induce its own expression as well as that of VCAM-1, as a regulatory
mechanism to facilitate leukocyte transendothelial migration (TEM) (79).
More recently, it has been described the ICAM-1-mediated tyrosine
phosphorylation of VE-cadherin dependent on Src and Pyk-2 activity and
required for neutrophil transmigration (80).

INTEGRINS DURING TRANSENDOTHELIAL MIGRATION
(TEM)

Once the leukocyte finds a proper site for transmigration, mostly
at intercellular junctions, it extends exploratory pseudopodia in between
the two adjacent endothelial cells. Subsequently, pseudopodia evolve into
a lamella squeezed into the monolayer gap. During this process, LFA-1 is
the integrin with a more prominent role. This molecule is rapidly
relocalized, forming a ring-like cluster at the leukocyte-endothelial
interface, where it interacts with ICAM-1 and, in some cellular models,
with JAM-A. When the transmigration process is over, LFA-1 is finally
concentrated at the uropod (81, 82). Interestingly, the NADase/ADP-
ribosyl cyclase CD157 is localized at endothelial junctions and can
associate with ß2-integrins, playing an important role in TEM (83).

ENDOTHELIAL SIGNALS CONTRIBUTING TO THE
LEUKOCYTE TRANSMIGRATION

Several molecules specifically localized at endothelial intercellular
contacts induce signaling pathways to facilitate leukocyte transmigration.
This is the case for CD99 that activates in leukocytes and probably in
endothelial cells the ERK, JNK and MAPK pathways (84). In addition,

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