p38 Mitogen-activated Protein Kinase Regulation of Endothelial Cell Migration Depends on Urokinase Plasminogen Activator Expression

Abstract

The migration of endothelial cells in response to various stimulating factors plays an essential role in angiogenesis. The p38 MAPK pathway has been implicated to play an important role in endothelial cell migration because inhibiting p38 MAPK activity down-regulates vascular endothelial growth factor (VEGF)-stimulated migration. Currently, the signaling components in the p38 MAPK activation pathway and especially the mechanisms responsible for p38 MAPK-regulated endothelial cell migration are not well understood. In the present study, we found that p38 MAPK activity is required for endothelial cell migration stimulated by both VEGF and nongrowth factor stimulants, sphingosine 1-phosphate and soluble vascular cell adhesion molecule. By using dominant negative forms of signaling components in the p38 MAPK pathway, we identified that a regulatory pathway consisting of MKK3-p38␣/␥-MAPK-activated protein kinase 2 participated in VEGF-stimulated migration. In further studies, we showed that a minimum of a 10-h treatment with SB203580 (specific p38 MAPK inhibitor) was needed to block VEGF-stimulated migration, suggesting an indirect role of p38 MAPK in this cellular event. Most interestingly, the occurrence of SB203580-induced migratory inhibition coincided with a reduction of urokinase plasminogen activator (uPA) expression. Furthermore, agents disrupting uPA and uPA receptor interaction abrogated VEGF-stimulated cell migration. These results suggest a possible association between cell migration and uPA expression. Indeed, VEGF-stimulated migration was not compromised by SB203580 in endothelial cells expressing the uPA transgene; however, VEGF-stimulated migration was inhibited by agents disrupting uPA-uPA receptor interaction. These results thus suggest that the p38 MAPK pathway participates in endothelial cell migration by regulating uPA expression.

Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts

“…Our studies are also in agreement with the previous studies demonstrating that Ang-(1-7) decreases the ERK signal transduction pathway in lung and prostate cancer cell growth arrest (10,16). A growing number of studies have shown that p38 MAPK-mediated cell migration and invasion (38)(39)(40)(41) pathways are involved in Ang II-stimulated migration of vascular adventitial fibroblasts in spontaneously hypertensive rats (42). A recent study demonstrated that the antimigration and anti-invasion effect of Ang-(1-7) was mediated through inactivation of the PI3K-Akt, p38 MAPK, and JNK signaling pathways (43).…”

Distinct Roles of Nonmuscle Myosin II Isoforms in the Regulation of MDA-MB-231 Breast Cancer Cell Spreading and Migration

“…Figure 3C and D also indicates that p38-MAPK blockade with SB202190 potently blocks spreading. We suggest that inhibition of spreading indirectly reduces matrix-induced RLC phosphorylation, but that the primary positive role of p38-MAPK during spreading is mediated via targets other than activation of RLC phosphorylation or myosin II contractility, possibly related to paxillin (35,36) or Plates were incubated in 37jC incubator for 1 hour and fixed with paraformaldehyde before photos were taken. B, quantification of spread area per cell, quantified via staining with Alexa 595-conjugated WGA and DAPI as described in Materials and Methods.…”

Selective Activation of Mitogen-Activated Protein (MAP) Kinase Kinase 3 and p38α MAP Kinase Is Essential for Cyclic AMP-Dependent UCP1 Expression in Adipocytes

“…The pyridinyl imidazole-sensitive p38 MAPK isoforms are often considered to be redundant enzymes, as their substrate specificities overlap significantly. However, in some cases these two isoforms have been shown to be able to discriminate between substrates, at least under conditions of forced overexpression of dominant-negative mutants (67,73).…”