Protein tyrosine phosphatase ε inhibits signaling by mitogen-activated protein kinases

被引:0
作者
Toledano-Katchalski, H
Kraut, J
Sines, T
Granot-Attas, S
Shohat, G
Gil-Henn, H
Yung, Y
Elson, A [1 ]
机构
[1] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel
[2] Weizmann Inst Sci, Dept Biol Regulat, IL-76100 Rehovot, Israel
关键词
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中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Mitogen-activated protein kinases (MAPKs) mediate signaling from the cell membrane to the nucleus following their phosphorylation at conserved threonine and tyrosine residues within their activation loops. We show that protein tyrosine phosphatase epsilon (PTPepsilon) inhibits ERK1 and ERK2 kinase activity and reduces their phosphorylation; in agreement, ERK phosphorylation is increased in fibroblasts and in mammary tumor cells from mice genetically lacking PTPepsilon. PTPepsilon inhibits events downstream of ERKs, such as transcriptional activation mediated by Elk1 or by the serum response element. PTPepsilon also inhibits transcriptional activation mediated by c-Jun and C/EBP binding protein (CHOP) but not that mediated by the unrelated NFkB, attesting that it is broadly active within the MAPK family but otherwise specific. The effect of PTPepsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTPepsilon. Nonetheless, PTPE is present in a molecular complex with ERK, providing PTPepsilon with opportunity to act on ERK proteins also directly. We conclude that PTPepsilon is a physiological inhibitor of ERK signaling. Slow induction of PTPE and its lack of nuclear translocation following mitogenic stimulation suggest that PTPepsilon functions to prevent inappropriate activation and to terminate prolonged, rather than acute, activation of ERK in the cytosol.
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页码:541 / 550
页数:10
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