Transactivation of vascular endothelial growth factor (VEGF) receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS)

被引:177
作者
Tanimoto, T [1 ]
Jin, ZG [1 ]
Berk, BC [1 ]
机构
[1] Univ Rochester, Cardiovasc Res Ctr, Rochester, NY 14642 USA
关键词
D O I
10.1074/jbc.M204764200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sphingosine 1-phosphate (S1P) and vascular endothelial growth factor (VEGF) elicit numerous biological responses including cell survival, growth, migration, and differentiation in endothelial cells mediated by the endothelial differentiation gene, a family of G-protein-coupled receptors, and fetal liver kinase-1/kinase-insert domain-containing receptor (Flk-1/KDR), one of VEGF receptors, respectively. Recently, it was reported that SIP or VEGF treatment of endothelial cells leads to phosphorylation at Ser-1179 in bovine endothelial nitric oxide synthase (eNOS), and this phosphorylation is critical for eNOS activation. SIP stimulation of eNOS phosphorylation was shown to involve G(i) protein, phosphoinositide 3-kinase, and Akt. VEGF also activates eNOS through Flk-1/KDR, phosphoinositide 3-kinase, and Akt, which suggested that SIP and VEGF may share upstream signaling mediators. We now report that SIP treatment of bovine aortic endothelial cells acutely increases the tyrosine phosphorylation of Flk-1/KDR, similar to VEGF treatment. S1P-mediated phosphorylation of Flk-1/KDR, Akt, and eNOS were all inhibited by VEGF receptor tyrosine kinase inhibitors and by antisense Flk-1/KDR oligonucleotides. Our study suggests that SIP activation of eNOS involves Gi, calcium, and Src family kinase-dependent transactivation of Flk-1/KDR. These data are the first to establish a critical role of Flk-1/KDR in S1P-stimulated eNOS phosphorylation and activation.
引用
收藏
页码:42997 / 43001
页数:5
相关论文
共 41 条
[1]   Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependent [J].
Bernatchez, PN ;
Soker, S ;
Sirois, MG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (43) :31047-31054
[2]   Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors [J].
Daub, H ;
Weiss, FU ;
Wallasch, C ;
Ullrich, A .
NATURE, 1996, 379 (6565) :557-560
[3]   Signal characteristics of G protein-transactivated EGF receptor [J].
Daub, H ;
Wallasch, C ;
Lankenau, A ;
Herrlich, A ;
Ullrich, A .
EMBO JOURNAL, 1997, 16 (23) :7032-7044
[4]   Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation [J].
Dimmeler, S ;
Fleming, I ;
Fisslthaler, B ;
Hermann, C ;
Busse, R ;
Zeiher, AM .
NATURE, 1999, 399 (6736) :601-605
[5]   Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells [J].
Eguchi, S ;
Numaguchi, K ;
Iwasaki, H ;
Matsumoto, T ;
Yamakawa, T ;
Utsunomiya, H ;
Motley, ED ;
Kawakatsu, H ;
Owada, KM ;
Hirata, Y ;
Marumo, F ;
Inagami, T .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (15) :8890-8896
[6]   VEGF induces nuclear translocation of Flk-1/KDR, endothelial nitric oxide synthase, and caveolin-1 in vascular endothelial cells [J].
Feng, YY ;
Venema, VJ ;
Venema, RC ;
Tsai, N ;
Caldwell, RB .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 256 (01) :192-197
[7]  
Fulton D, 2001, J PHARMACOL EXP THER, V299, P818
[8]   Regulation of endothelium-derived nitric oxide production by the protein kinase Akt [J].
Fulton, D ;
Gratton, JP ;
McCabe, TJ ;
Fontana, J ;
Fujio, Y ;
Walsh, K ;
Franke, TF ;
Papapetropoulos, A ;
Sessa, WC .
NATURE, 1999, 399 (6736) :597-601
[9]   Dynamic activation of endothelial nitric oxide synthase by Hsp90 [J].
García-Cardeña, G ;
Fan, R ;
Shah, V ;
Sorrentino, R ;
Cirino, G ;
Papapetropoulos, A ;
Sessa, WC .
NATURE, 1998, 392 (6678) :821-824
[10]   Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase Akt signal transduction pathway -: Requirement for Flk-1/KDR activation [J].
Gerber, HP ;
McMurtrey, A ;
Kowalski, J ;
Yan, MH ;
Keyt, BA ;
Dixit, V ;
Ferrara, N .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (46) :30336-30343