tyrosine phosphatase;
breast cancer;
mammary tumor;
Src;
Neu;
D O I:
10.1038/sj.onc.1210505
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:
The receptor-type protein tyrosine phosphatase epsilon (RPTPe) activates c-Src in mammary tumor cells induced in vivo by Neu. Tumor cells lacking RPTPe exhibit reduced c-Src activity, appear less transformed morphologically and proliferate slower in vitro and in vivo. Expression of Src rescues most of these phenotypes, indicating that c-Src activity is important for maintaining the transformed phenotype. However, the molecular mechanisms that control activation of c-Src by RPTPe are unknown. We show that Neu induces phosphorylation of RPTPe exclusively at its C-terminal Y695, and that this phosphorylation is required for activation of c-Src by RPTPe. Phosphorylation of RPTPe does not affect its activity toward another substrate, the voltage-gated potassium channel Kv2.1, suggesting that phosphorylation directs RPTPe activity toward c-Src. Phosphorylation of RPTPe reduces its dimerization at the cell membrane, although this does not affect its activity significantly. RPTPe is subject to strong auto-and trans-dephosphorylation, suggesting that dephosphorylation limits the activation of c-Src downstream of Neu. We conclude that an Neu-RPTP epsilon-Src signaling pathway exists in mammary tumor cells, in which phosphorylation of RPTPe by Neu directs RPTPe to activate c-Src. Reversible phosphorylation of RPTPe at Y695 may thus function as a 'molecular switch', which affects the substrate specificity of the phosphatase.
机构:
Univ Buenos Aires, Fac Med, Dept Bioquim, Sch Med, Buenos Aires, DF, ArgentinaUniv Buenos Aires, Fac Med, Dept Bioquim, Sch Med, Buenos Aires, DF, Argentina
Paz, C
Maciel, FC
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机构:
Univ Buenos Aires, Fac Med, Dept Bioquim, Sch Med, Buenos Aires, DF, ArgentinaUniv Buenos Aires, Fac Med, Dept Bioquim, Sch Med, Buenos Aires, DF, Argentina
Maciel, FC
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h-index:
机构:
Poderoso, C
Gorostizaga, A
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机构:
Univ Buenos Aires, Fac Med, Dept Bioquim, Sch Med, Buenos Aires, DF, ArgentinaUniv Buenos Aires, Fac Med, Dept Bioquim, Sch Med, Buenos Aires, DF, Argentina
Gorostizaga, A
Podestá, EJ
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机构:
Univ Buenos Aires, Fac Med, Dept Bioquim, Sch Med, Buenos Aires, DF, ArgentinaUniv Buenos Aires, Fac Med, Dept Bioquim, Sch Med, Buenos Aires, DF, Argentina