Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 521

Table 9.21. Regulatory enzymes of the contractile state of endothelial cells ( + : activation

or stabilization of cell junctions; : inactivation or inhibition of actin filament formation;

AMPK: AMP-activated protein kinase; ERK: extracellular signal-regulated protein kinase; ERM:
ezrin-radixin-moesin; LIMK: Lin1, Isl1, and Mec3 kinase; MLCK: myosin light chain kinase;
MLCP: myosin light chain phosphatase; PAK: P21-activated kinase; PKA: protein kinase-A;
PKG: protein kinase-G; PP: protein phosphatase; RoCK: Rho-associated, coiled coil-containing
protein kinase; Src: sarcoma-associated Schmidt-Ruppin A2 viral oncogene homolog kinase;
VASP: vasodilator-stimulated phosphoprotein). Endothelial permeability is regulated by myosin
light chain phosphorylation and dephosphorylation that direct endothelial cell contraction and
relaxation.

−

Enzyme Substrates

AMPK VASP ( − )

+

ERK1/2 MLCK ( )

Fyn Vav (RhoGEF)

LIMK Cofilin ( − )

MLCK MLC

MLC P MLCP

PAK MLC, MLCK ( − )

PKA MLCK ( − ), VASP ( + )

PKG VASP ( − )

PP1 Src ( − )

PP2 Src ( − )

RoCK ERM ( + ), LIMK ( + ), MLC, MLCP ( − ), PP1 ( − )

Src MLCK ( + ), FAK, paxillin,

phosphorylation of the myosin-binding protein phosphatase-1 inhibitory subunit
PP1 r12a and subsequent inhibition of myosin light chain phosphatase. At basal
concentrations of intracellular Ca 2 + , phosphorylation level of myosin light chain is
modulated by PP1 r12a subunit. Calcium sensitization of endothelial cell contraction
is initiated by the activation of the small GTPase Rho and RoCK kinase.
Kinases of the SRC family do not change the strength of E-cadherin-mediated
adhesion, but integrin-dependent enhancement of cadherin-mediated adhesion
strength. Establishment of cadherin-based cell adhesion needs myosin-2 and
MLCK and RoCK kinases. The regulation of intercellular adhesion strength by
stimulated integrins requires activated SRC family kinases that target the Rho-
RoCK pathway [ 955 ]. Kinase Src binds to newly formed actomyosin stress fibers
linked to focal adhesions. Phosphorylation by Src kinase modulates endothelial
cell contraction [ 956 ]. Similarly, in thrombocytes, Src is recruited to actin bundles.
Enzyme Src activates PLC γ 2 and causes MLC phosphorylation for clot retraction

α 2B β 3 integrin [ 957 ]. 86 downstream from

86 Activation of

3 -integrin by inside-out signals promotes binding to fibrinogen and platelet
aggregation. In turn, clustering of

α β 2B

3 -integrin, once engaged by fibrinogen, mediates outside-
in signals that elicit phosphorylation of

α β 2B

3 -integrin tail and activation of the SRC cascade that
involves SYK, lymphocyte cytosolic protein LCP2, and PLC

β

γ 2. However, binding of SYK to