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

Hila Toledano-Katchalski, Judith Kraut, Tal Sines, Shira Granot-Attas, Galit Shohat, Hava Gil-Henn, Yuval Yung, Ari Elson

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

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 ε (PTPε) 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 PTPε. PTPε inhibits events downstream of ERKs, such as transcriptional activation mediated by Elk1 or by the serum response element. PTPε 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 PTPε 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 PTPε. Nonetheless, PTPε is present in a molecular complex with ERK, providing PTPε with opportunity to act on ERK proteins also directly. We conclude that PTPε is a physiological inhibitor of ERK signaling. Slow induction of PTPε and its lack of nuclear translocation following mitogenic stimulation suggest that PTPε functions to prevent inappropriate activation and to terminate prolonged, rather than acute, activation of ERK in the cytosol.

Original languageEnglish
Pages (from-to)541-550
Number of pages10
JournalMolecular Cancer Research
Volume1
Issue number7
StatePublished - 1 May 2003
Externally publishedYes

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