Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 424

addition to extracellular matrix components [ 784 ]. 50 Multiple migration regulators
can intervene simultaneously, such as sphingosine-1 phosphate and platelet-derived
growth factor. 51
Intracellular molecules that contribute to SMC migration comprise kinases,
especially calcium-dependent and Rho-activated protein kinases, phosphatidylino-
sitol 3-kinase, 52 its antagonist PTen, 53 SRC family kinases, such as Fyn, Lyn,

Src, and Yes, 54 P21-activated protein kinases, 55 LIM kinases, 56 mitogen-activated

protein kinases, 57 and integrin-linked kinase, 58

as well as their main targets, such

50 Collagen-1 and -4 as well as laminin participate in SMC displacements. Osteopontin is a matrix
glycoprotein that enhances SMC migration via α V β 3 -integrins. Conversely, heparin and tissue
inhibitors of metallopeptidases inhibit cell motility.
51 Activated S1P 1 and S1P 5 receptors foster and impede cell migration, respectively. In airway
smooth myocytes, activated PDGFR provokes release of sphingosine kinase. Synthesized S1P then
activates S1P 1 -PDGFR β complexes. In addition, a transactivation of S1P receptors by PDGF can

occur [ 784 ].
52 Activated PDGFR

, thereby caus-
ing PIP 2 hydrolysis, Ca 2 + influx, and activation of mitogen-activated protein kinases, such as ERKs
and P38MAPKs. Kinase PI3K also participates in microtubule remodeling via PKB, GSK3

β targets phosphatidylinositol 3-kinase and phospholipase-C γ

β ,and

adenomatous polyposis coli protein [ 784 ].
53 Phosphatase and tensin homolog deleted on chromosome 10 dephosphorylates PIP 3 into PIP 2 .
During cell migration, it contributes to disassembly of focal adhesions at the trailing cell edge via
ILK inactivation and FAK1 dephosphorylation.
54 Kinase Src is stimulated by PDGF during SMC migration. It can then target ERK, FAK, BCAR,
and paxillin.
55 Cyclin-dependent kinase inhibitor CKI1a (or P21)-activated protein kinase phosphorylates
LIM kinase that, in turn, phosphorylates cofilin, cortactin, caldesmon, and myosin light chain for
SMC contraction. Activated PAK by the small GTPase Rac1 stabilizes microtubules, as it precludes
activity of microtubule-destabilizing stathmin [ 784 ]. Kinase PAK also phosphorylates desmin and
vimentin to enhance intermediate filament turnover [ 784 ].
56 LIM kinase activated by small GTPase RhoA and its effector RoCK as well as small GTPase
Rac and p21-activated protein kinase PAK1 phosphorylates and inhibits cofilin to enhance actin
polymerization.
57 In response to growth factors, ERK activation leads to 2 sequential distinct effects: an early and
later stimulation that elicit cell migration and proliferation, respectively. In addition, a signaling
cascade with MAP2K3, P38MAPK, MK2, and HSP27 that can be activated by PDGF, angiotensin-
2, S1P, and thrombin contributes to cell migration [ 784 ]. Overexpressed JNKs can also participate
in cell migration induced by PDGFbb, but prevent angiotensin-2-induced migration. The JNK
kinases can be activated by PKC, FAK2, and RoCK kinases. They can phosphorylate microtubule-
associated proteins and paxillin.
58 Integrin-linked kinase binds several integrin-actin linkers, such as affixin and paxillin, and
adaptor.