Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 459

9.1.2.2 Cell-Matrix Junctions

Focal adhesions are sites of adhesions of endothelial cells to the extracellular
matrix mediated by integrins. Endothelial cells express mainly on their abluminal
surface numerous heterodimeric integrins (

α 1 β 1 , α 2 β 1 , α 3 β 1 , α 5 β 1 , α 6 β 1 , α V β 3 ,

α 1 β 5 ,and α V β 5 )[ 854 ]. These transmembrane glycoproteins interact with matrix

proteins, such as fibronectin, fibrinogen, vitronectin, and collagen. Association
between integrins and extracellular matrix constituents restricts the passage of
macromolecules across the endothelial barrier.
Integrin

cytoplasmic domain connects to actin-binding proteins, such as

α -Actinin that binds

zyxin targets vasoactive stimulatory phosphoprotein and profilin. Filamin links
to small GTPases CDC42, Rac, RhoA, and Ral1, as well as RhoA-associated
kinase, Trio with its 3 enzymatic domains, 14 and caveolin-1. Paxillin interacts with
P21-activated kinase (PAK) and PAK-interacting exchange factors RhoGEF6 and
RhoGEF7, Abelson Tyr kinase (Abl), and Ras GTPase-activating protein RasA1.
Tensin binds multiple phosphotyrosine proteins, such as BCAR1 (or CAS) and
Src kinase. Vinculin interacts with the actin-related proteic ARP2-ARP3 complex
and phosphatidylinositol 4-phosphate 5-kinase. These proteins coordinate signals
between focal adhesions and the actin cytoskeleton.
These proteic interactions define the adhesome, a signaling platform integrator of
many signaling axes. Adhesome regulates actin polymerization and focal adhesion
function. For example, ligation of

-actinin, filamin, paxillin, talin, tensin, vinculin, and zyxin. α

α V β 3 -integrin with matrix proteins causes:
(1) tyrosine phosphorylation of focal adhesion kinase, paxillin, cortactin, and ezrin;
(2) Ca 2 + influx; and (3) activation of phospholipase-A2 and Rac GTPase.
Focal adhesion constituents are recruited into focal adhesions upon tyrosine
phosphorylation by focal adhesion kinase and Src kinases. Integrin clustering
provokes FAK autophosphorylation (activation). Kinase Src further phosphorylates
activated FAK enzyme. Activated FAK phosphorylates various substrates, such as
paxillin, tensin, PI3K, and BCAR1, that aggregate to form focal adhesions.
Paxillin recruits other focal adhesion constituents, as it associates with vinculin,
CRK, C-terminal Src kinase, and Src, as well as ArfGAPs APAP1 and APAP2 [ 854 ].
Activated APAP1 regulates CDC42 and Rac, as it can complex with RhoGEF6 and
RhoGEF7 that serves as CDC42- and Rac1-GEF to maintain or restore endothelial
barrier.
Focal adhesion kinase not only associates with paxillin and talin, but also
with SRC family kinases Src and Fyn, guanine nucleotide-exchange factor Ras-
GRF1, growth factor receptor-bound protein GRB2, adpribosylation factor GAP-
containing, SH3, ankyrin repeats, and PH domain protein ASAP1, BCAR1 adap-
tor, RhoGAP26, and actin-polymerizing proteins ezrin and WASP [ 854 ]. Focal
adhesion kinase is phosphorylated (activated) in response to integrin activation.

14 Molecule Trio contains 2 GEF sites for RhoA and Rac and a Ser-Thr kinase region, hence its
name.