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Molecular Endocrinology 16 (1): 58-69
Copyright © 2002 by The Endocrine Society

A Nuclear Protein Tyrosine Phosphatase TC-PTP Is a Potential Negative Regulator of the PRL-Mediated Signaling Pathway: Dephosphorylation and Deactivation of Signal Transducer and Activator of Transcription 5a and 5b by TC-PTP in Nucleus

Naohito Aoki and Tsukasa Matsuda

Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan

Address all correspondence and requests for reprints to: Dr. Naohito Aoki, Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail: naoki{at}agr

In the present study we examined involvement of nuclear protein tyrosine phosphatase TC-PTP in PRL-mediated signaling. TC-PTP could dephosphorylate signal transducer and activator of transcription 5a (STAT5a) and STAT5b, but the apparent dephosphorylation activity of TC-PTP was weaker than that of cytosolic PTP1B 30 min after PRL stimulation in transfected COS-7 cells, whereas both STAT5a and STAT5b were dephosphorylated to the same extent by recombinant TC-PTP and PTP1B in vitro. Tyrosine-phosphorylated STAT5 was coimmunoprecipitated with substrate trapping mutants of TC-PTP, suggesting that STAT5 is a specific substrate of TC-PTP. These observations were further extended in mammary epithelial COMMA-1D cells stably expressing TC-PTP. A time-course study revealed that dephosphorylation of STAT5 by TC-PTP was delayed compared with that by cytosolic PTP1B due to nuclear localization of TC-PTP throughout PRL stimulation in mammary epithelial cells. Endogenous ß-casein gene expression and ß-casein gene promoter activation in COS-7 cells were largely suppressed by TC-PTP wild type as well as catalytically inactive mutants, suggesting that stable complexes formed between STAT5 and TC-PTP in the nucleus. Taken together, we conclude that TC-PTP is catalytically competent with respect to dephosphorylation and deactivation of PRL-activated STAT5 in the nucleus.




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