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

INTEGRIN SIGNALING TRIGGERED BY LIGAND BINDING

Upon interaction with their ligands, integrins activate distinct
myosin contractility effectors, actin-remodeling GTPases and molecules
involved in microtubule network regulation at the leading and trailing
edges of motile leukocytes (52, 53). During cell polarization, Cdc42,
MLCK, Rac, RAPL, Rap1, mDia, Myosin-IIA and chemokine receptors
are redistributed to the cellular front, participating in the formation of
exploratory filopodia and in the extension of lamellipodia. In contrast,
Rho and ROCK (both involved in trailing edge retraction), the
microtubule-organizing center (MTOC) and the adhesion receptors
ICAM-1, ICAM-3, CD44 and CD43 move towards the rear pole (54).
Interestingly, the redistribution of integrin ligands to the uropod seems to
be involved in the recruitment of bystander leukocytes through this
cellular structure (55). Hence, the integration of signals generated in both
cellular poles leads to a coordinate movement of the leukocyte.

The a4 integrins can bind paxillin upon dephosphorylation of
Ser988 in their cytoplasmic domain at the sides and rear pole of the cell,
whereas PKA-mediated phosphorylation of these integrins is confined at
the leading edge of the cell. Paxillin regulates a4 integrin function
(tethering and firm adhesion) in immune cells (56), enhancing their rate
of migration and reducing their spreading. In addition, paxillin/a4
interaction down-regulates the formation of focal adhesions, stress fibers
and lamellipodia by triggering the activation of different tyrosine kinases
such as FAK, Pyk2, Src and Abl (57). The a4/paxillin complex inhibits
stable lamellipodia by recruiting an ADP-ribosylation factor GTPase-
activating protein (Arf-GAP) that decreases Arf activity, thereby
inhibiting Rac, and limiting lamellipodia formation to the cell front (58).

On the other hand, it has been described that LFA-1 and Mac-1
may use the adaptor molecules talin, a-actinin, filamin and 14-3-3 to
properly anchor to the actin cytoskeleton (59, 60). Regarding the
subcellular localization, the pattern of LFA-1 varies from low expression
in the lamellipodia to high expression in the uropod. However, it has been
reported that high affinity clustered LFA-1 is restricted to a mid-cell zone,
termed the “focal zone”, different from focal adhesions and focal
contacts. In addition, talin, properly activated by phosphorylation or PIP2,

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