Article (Scientific journals)
EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway.
Deroanne, Christophe; Vouret-Craviari, Valerie; Wang, Bingcheng et al.
2003In Journal of Cell Science, 116 (Pt 7), p. 1367-76
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Keywords :
Animals; Cell Adhesion/drug effects/physiology; Cell Movement/drug effects/physiology; Cells, Cultured; Enzyme Inhibitors/pharmacology; Ephrin-A1/metabolism/pharmacology; Feedback, Physiological/drug effects/physiology; Integrins/metabolism; Lysophospholipids; Muscle, Smooth, Vascular/cytology/drug effects/enzymology; Neovascularization, Physiologic/physiology; Protein-Serine-Threonine Kinases/metabolism; RNA Interference; Rats; Signal Transduction/drug effects/physiology; Sphingosine/analogs & derivatives/metabolism/pharmacology; cdc42 GTP-Binding Protein/genetics/metabolism; p21-Activated Kinases; rac GTP-Binding Proteins/metabolism; rhoA GTP-Binding Protein/antagonists & inhibitors/metabolism
Abstract :
[en] Interactions between the Eph receptor tyrosine kinase and ephrin ligands transduce short-range signals regulating axon pathfinding, development of the cardiovascular system, as well as migration and spreading of neuronal and non-neuronal cells. Some of these effects are believed to be mediated by alterations in actin dynamics. The members of the small Rho GTPase family elicit various effects on actin structures and are probably involved in Eph receptor-induced actin modulation. EphrinA1 is proposed to contribute to angiogenesis as it is strongly expressed at sites of neovascularization. Moreover, angiogenic factors induce the expression of ephrinA1 in endothelial cells. In this study, using rat vascular smooth muscle cells (VSMCs), we investigated the contribution of the small Rho GTPases in ephrinA1-induced integrin inactivation. EphrinA1 did not significantly affect early adhesion of VSMCs on purified laminin or fibronectin, but strongly impaired cell spreading. The Rho kinase inhibitor Y-27632 partly reversed the ephrinA1 effect, suggesting involvement of Rho in this model. However, inhibition of RhoA synthesis with short interfering (si)RNA had a modest effect, suggesting that RhoA plays a limited role in ephrinA1-mediated inhibition of spreading in VSMCs. The ephrinA1-mediated morphological alterations correlated with inhibition of Rac1 and p21-activated kinase 1 (PAK1) activity, and were antagonized by the expression of a constitutively active Rac mutant. Moreover, repression of Rac1 synthesis with siRNA amplifies the ephrinA1-induced inhibition of spreading. Finally, sphingosine-1-phosphate (S1P), a lipid mediator known to inhibit Rac activation in VSMCs amplifies the ephrinA1 effect. In conclusion, our results emphasize the role of the Rac/PAK pathway in ephrinA1-mediated inhibition of spreading. In this way, ephrinA1, alone or in synergy with S1P, can participate in blood vessel destabilization, a prerequisite for angiogenesis.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Deroanne, Christophe ;  Institute of Signaling, Developmental Biology and Cancer Research > CNRS-UMR 6543,Centre Antoine Lacassagne, Nice
Vouret-Craviari, Valerie;  Institute of Signaling, Developmental Biology and Cancer Research > CNRS-UMR 6543,Centre Antoine Lacassagne, Nice
Wang, Bingcheng;  Case Western Reserve University, School of Medicine, Cleveland-USa > Rammelkamp Center for Research, > R421 and DPt of Pharmacol and Ireland Cancer Center
Pouyssegur, Jacques;  Institute of Signaling, Developmental Biology and Cancer Research > CNRS-UMR 6543,Centre Antoine Lacassagne, Nice
Language :
English
Title :
EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway.
Publication date :
2003
Journal title :
Journal of Cell Science
ISSN :
0021-9533
eISSN :
1477-9137
Publisher :
Company of Biologists, Cambridge, United Kingdom
Volume :
116
Issue :
Pt 7
Pages :
1367-76
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 09 April 2010

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