Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 706

and CD34; E-selectin ligands ESL1 and PSGL1) and -lipids (sialyl Lewis x -carrying
glycolipids)

and proteoglycans participate in the activation of leukocyte

integrins [ 1450 ].
L-selectin can prime signaling cascades that involve lymphocyte-specific protein
Tyr kinase (LCK), GRB2 adaptor, SOS GEF, Ras and Rac2 GTPases, MAPK
kinases, and O 2 [ 1450 ]. E-selectin can stimulate focal adhesion kinase. P-selectin
sensitizes cells for PAF-triggered secretion of CCL2 and TNF

α as well as CCL5-

stimulated secretion of CCL2 and IL8 (CXCL8) [ 1450 ].

Firm Leukocyte Adhesion on Endothelium

Stimulated guanine nucleotide-exchange factors by clustered integrin ligands such
as ICAM1 activates a subset of Rho GTPases. Monomeric RhoA GTPase promotes
additional clustering of ICAM1 and VCAM1 [ 1452 ]. Adhesion-induced clustering
of ICAM1 or VCAM1 on the surface of endothelial cells launches intracellular sig-
naling. Subsequently activated GTPase RhoA provokes bundling of existing F actin
filaments into stress fibers. Small GTPases RhoG and Rac1 mediate membrane
ruffling and the formation of the apical docking structure. The DOCK-ELMO
complex allows crosstalk between RhoG and Rac1 GTPases.
Crosslinking of ICAM1 molecules causes the production of inositol phosphate
and phosphorylation of phospholipase-C

[ 1452 ]. In addition, ICAM1 clustering
rapidly triggers calcium influx. Calcium-dependent activation of protein kinase-C
regulates the phosphorylation of Src kinase and its substrate cortactin. Clustering of
ICAM1 molecules also provokes RhoA-dependent phosphorylation of cytoskeletal
and regulatory proteins, such as paxillin, FAK, and BCAR1 (or P130CAS), as well
as interaction of CRK adaptor with paxillin and BCAR1 adaptor.

γ

Crawling

Crawling of leukocytes on the wetted surface of the vascular endothelium is gov-
erned by 2-integrins. The Rho/Rac guanine nucleotide-exchange factor Vav1 par-

ticipates in the control of location and activity of

β

2-integrins [ 1444 ]. Mechanore-
ceptors activate signaling mediators such as Vav1 protein.
Small GTPase RhoG that is activated upon ICAM1 clustering mediates the
formation of docking structures, actin-rich membrane protrusions that are formed
by endothelial cells around adhered leukocytes upon adhesion of leukocytes to
ICAM1 and/or VCAM1 [ 1452 ]. Small GTPase Rac1 is also activated upon ICAM1
clustering. Activated RhoG and Rac1 generate dorsal and lateral membrane ruffles,
respectively. Besides, RhoG can activate Rac1 via the DOCK1-ElMo complex
and CRK adaptor. Tetraspanins (Tspan24, Tspan28, and Tspan29) are involved in
ICAM1 and VCAM1 functioning and clustering.

β