The activation of neuronal NO synthase is mediated by G-protein βγ subunit and the tyrosine phosphatase SHP-2

被引:26
作者
Cordelier, P
Esteve, JP
Rivard, N
Marletta, M
Vaysse, N
Susini, C
Buscail, L
机构
[1] CHU Rangueil, INSERM U151, Inst Louis Bugnard, F-31403 Toulouse 4, France
[2] Univ Sherbrooke, Fac Med, Dept Anat & Biol Cellulaire, Sherbrooke, PQ J1K 2R1, Canada
[3] Univ Michigan, Howard Hughes Med Inst, Sch Med, Ann Arbor, MI 48109 USA
关键词
cholecystokinin; nitric oxide; cell growth; G beta gamma complex;
D O I
10.1096/fasebj.13.14.2037
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
In CHO cells we had found that CCK positively regulated cell proliferation via the activation of a soluble guanylate cyclase, Here we demonstrate that CCK stimulated a nitric oxide synthase (NOS) activity. The production of NO was involved in the proliferative response elicited by CCK regarding the inhibitory effect of NOS inhibitors L-NAME and alpha-guanidinoglutaric acid. We identified the NOS activated by the peptide as the neuronal isoform: the expression of the C415A neuronal NOS mutant inhibited both CCK-induced stimulation of NOS activity and cell proliferation, These two effects were also inhibited after expression of the C459S tyrosine phosphatase SHP-2 mutant and the beta ARK1 (495-689) sequestrant peptide, indicating the requirement of activated SHP-2 and G-beta gamma subunit, Kinetic analysis (Western blot after coimmunoprecipitation and specific SHP-2 activity) revealed that in response to CCK-treatment, SHP-2 associated to G-beta 1 subunit, became activated, and then dephosphorylated the neuronal NOS through a direct association, These data demonstrate that the neuronal NOS is implicated in proliferative effect evoked by CCK, A novel growth signaling pathway is described, involving the activation of neuronal NOS by dephosphorylation of tyrosyl residues.-Cordelier P., Esteve, J.-P., Rivard, N., Marletta, M., Vaysse, N., Susini, C., Buscail, L. The activation of neuronal no synthase is mediated by G-protein beta gamma subunit and the tyrosine phosphatase SHP-2.
引用
收藏
页码:2037 / 2050
页数:14
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