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Molecular and Cellular Biology, August 2003, p. 5460-5471, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5460-5471.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Dimerization In Vivo and Inhibition of the Nonreceptor Form of Protein Tyrosine Phosphatase Epsilon

Hila Toledano-Katchalski,1 Zohar Tiran,1 Tal Sines,1 Gidi Shani,1 Shira Granot-Attas,1 Jeroen den Hertog,2 and Ari Elson1*

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel,1 Hubrecht Laboratory, Netherlands Institute for Developmental Biology, NL-3584 CT Utrecht, The Netherlands2

Received 18 October 2002/ Returned for modification 26 November 2002/ Accepted 8 May 2003

cyt-PTP{varepsilon} is a naturally occurring nonreceptor form of the receptor-type protein tyrosine phosphatase (PTP) epsilon. As such, cyt-PTP{varepsilon} enables analysis of phosphatase regulation in the absence of extracellular domains, which participate in dimerization and inactivation of the receptor-type phosphatases receptor-type protein tyrosine phosphatase alpha (RPTP{alpha}) and CD45. Using immunoprecipitation and gel filtration, we show that cyt-PTP{varepsilon} forms dimers and higher-order associations in vivo, the first such demonstration among nonreceptor phosphatases. Although cyt-PTP{varepsilon} readily dimerizes in the absence of exogenous stabilization, dimerization is increased by oxidative stress. Epidermal growth factor receptor stimulation can affect cyt-PTP{varepsilon} dimerization and tyrosine phosphorylation in either direction, suggesting that cell surface receptors can relay extracellular signals to cyt-PTP{varepsilon}, which lacks extracellular domains of its own. The inactive, membrane-distal (D2) phosphatase domain of cyt-PTP{varepsilon} is a major contributor to intermolecular binding and strongly interacts in a homotypic manner; the presence of D2 and the interactions that it mediates inhibit cyt-PTP{varepsilon} activity. Intermolecular binding is inhibited by the extreme C and N termini of D2. cyt-PTP{varepsilon} lacking these regions constitutively dimerizes, and its activities in vitro towards para-nitrophenylphosphate and in vivo towards the Kv2.1 potassium channel are markedly reduced. We conclude that physiological signals can regulate dimerization and phosphorylation of cyt-PTP{varepsilon} in the absence of direct interaction between the PTP and extracellular molecules. Furthermore, dimerization can be mediated by the D2 domain and does not strictly require the presence of PTP extracellular domains.

* Corresponding author. Mailing address: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972-8-934-2331. Fax: 972-8-934-4108. E-mail: ari.elson{at}weizmann.ac.il.

Molecular and Cellular Biology, August 2003, p. 5460-5471, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5460-5471.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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