Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 457

Permeability-increasing factors, such as thrombin and VEGF, induce

phosphorylation 1 to disrupt adherens

junctions [ 854 ]. Phosphorylation by Src or PKC of adherens junction constituents
can modify affinity of catenins for cadherin-5, as well as Cdh5-actin interactions.
Conversely,

of cadherin, β -catenin, and catenin- δ

phosphatases stabilize adherens junctions. PTPn11 Phosphatase

associates with and protect the cadherin-catenin complex.

Tight Junctions

Tight junctions contain occludin, junctional adhesion molecules, and claudins that
interact directly or indirectly with cytoplasmic partners, such as cingulin and zonula
occludens adaptors. Zonula occludens proteins (ZO1-ZO3) are members of the
family of membrane-associated guanylate kinases (MAGUK). Zonula occludens
proteins and cingulin contribute to interaction of tight junction with the actin
cytoskeleton.
Occludins form homotypic bonds. Their cytoplasmic C-terminus associates with
zonula occludens protein ZO1, hence with the actin cytoskeleton to stabilize tight
junction. Arterial and blood-brain endothelial barriers that are the least permeable
of the vasculature contain a much greater number of occludins than do other
compartments.
Among 24 known members of the claudin family, only claudin-5 is specifically
expressed by endothelial cells. Yet, several claudins are synthesized in endothelial
cells (claudin-1, -3, -5, and -12). Claudin-5 that is particularly produced by cerebral
endothelial cells is a major regulator of the blood-brain barrier function. Claudin
extracellular regions form homo- and heterotypic bonds. Its cytoplasmic part also
binds to zonula occludens protein ZO1, and therefore indirectly to ZO1 partners.
Junctional adhesion molecules, endothelial cell-selective adhesion transmem-
brane glycoproteins, and coxsackievirus and adenovirus receptors associate with
tight junctions, but do not build strands per se [ 853 ]. However, they modulate
leukocyte diapedesis across the endothelium.
Junctional adhesion molecules comprise 3 main types: JAM1 (or JAMa), JAM2
(or JAMb), and JAM3 (a.k.a. JAMc and veJAM). Isotype JAM1 resides in epithelial
and endothelial cells; JAM2 in high endothelial venular cells, i.e., endothelial cells
of postcapillary venules of lymphoid tissues that form the leakiest endothelium
of lymphatic vessels; JAM3 exclusively in endothelial cells. Junctional adhesion
molecules are able to bind partitioning-defective protein Par6, small GTPase
CDC42, and PKC , thereby recruiting these signaling mediators to tight junctions.

Zonula occludens proteins interact directly or indirectly via bridging proteins
with claudins, occludins, and junctional adhesion molecules. They intervene in
spatial organization of tight junction constituents, particularly occludins. Zonula
occludens proteins link tight junction proteins to the actin cytoskeleton and recruit
signaling molecules. In addition, ZO1 also binds to adherens junction protein
α

ζ

-catenin, gap-junction component connexin-43, and actin-polymerizing proteins