Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 709

inositol 5-phosphatase SHIP1 also regulates PIP 3 levels. Enzymes PI3K c1γ ,PTen,
and SHIP1 cooperatively confine PIP 3 to the leading edge for full polarization and
motility.
Isotypes PI3K

operate in neutrophil migration from blood circulation in
response to brief chemokine stimulation [ 1444 ]. After longer stimulation, migration
depends on PI3K

γ and - δ

.
Different classes of chemoattractants use different signaling pathways. Kinase
PI3K accelerates the initial response to bacterial chemoattractant N formyl methionyl
leucyl phenylalanine (fMLP). Afterward, an alternative pathway replaces the PI3K
axis. Neutrophil migration launched by chemoattractants fMLP and C5a can indeed
rely on P38MAPK [ 1444 ]. On the other hand, chemoattractants IL8 and LTb4
trigger PI3K-dependent migration.

δ

11.5.5.2 Phospholipase-A2

The family of phospholipase-A2 is divided into 4 groups: cytosolic (cPLA2),
calcium-independent (iPLA2), secreted (sPLA2), and a group that includes platelet-
activating factor acetylhydrolase and related PLA2s. Both cPLA2

use
different lipid mediators, arachidonic acid and lipopolysaccharide, respectively, to
provoke migration of monocytes subjected to CCL2 chemokine [ 1444 ].

α and iPLA2 β

11.5.5.3 Guanylate Cyclase

During chemotaxis, cyclic guanosine monophosphate and soluble guanylate cyclase
operate in the pseudopod and uropod, respectively [ 1444 ].

11.5.5.4 Monomeric Guanosine Triphosphatases

During chemotaxis, activated small guanosine triphosphatase Rac organizes mem-
brane protrusions in the direction of migration. In neutrophils, Rac activation
is primarily mediated by DOCK2 guanine nucleotide-exchange factor [ 1455 ].
Phosphatidylinositol (3,4,5)-trisphosphate supports rapid recruitment of DOCK2 to
the plasma membrane. Subsequent accumulation of DOCK2 at the leading edge
requires synthesis by phospholipase-D of phosphatidic acid. Phosphatidic acid
recruits DOCK2 to the pseudopod to initiate chemotaxis.
Monomeric Rap GTPase participates in the regulation of the integrin inside-
out signaling pathway. Activated Rap1 redistributes integrins and promotes their
clustering. Several guanine nucleotide-exchange factors activate Rap GTPases.
Activator RasGRP2 that binds both Ca 2 + and diacylglycerol (DAG) contributes to
integrin-based adhesion regulated by chemokines via Rap GTPases [ 1444 ].