To study the influence of subcellular localization as a determinant of signal transduction specificity, we assessed the effects of wild-type transmembrane and cytoplasmic protein tyrosine phosphatase (PTP) ε on tyrosine kinase signalling in baby hamster kidney (BHK) cells overexpressing the insulin receptor (BHK-IR). The efficiency by which differently localized PTPε and PTPα variants attenuated insulin-induced cell rounding and detachment was determined in a functional clonal-selection assay and in stable cell lines. Compared with the corresponding receptor-type PTPs, the cytoplasmic PTPs (cytPTPs) were considerably less efficient in generating insulin-resistant clones, and exceptionally high compensatory expression levels were required to counteract phosphotyrosine-based signal transduction. Targeting of cytPTPε to the plasma membrane via the Lck-tyrosine kinase dual acylation motif restored high rescue efficiency and abolished the need for high cytPTPε levels. Consistent with these results, expression levels and subcellular localization of PTPε were also found to determine the phosphorylation level of cellular proteins including focal adhesion kinase (FAK). Furthermore, PTPε stabilized binding of phosphorylated FAK to Src, suggesting this complex as a possible mediator of the PTPε inhibitory response to insulin-induced cell rounding and detachment in BHK-IR cells. Taken together, the present localization–function study indicates that transcriptional control of the subcellular localization of PTPε may provide a molecular mechanism that determines PTPε substrate selectivity and isoform-specific function.
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Research Article|
March 08 2001
Comparative study of protein tyrosine phosphatase-ɛ isoforms: membrane localization confers specificity in cellular signalling
Jannik N⊘rgaard ANDERSEN;
Jannik N⊘rgaard ANDERSEN
1
*Signal Transduction, Novo Nordisk, DK-2880 Bagsvaerd, Denmark,
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Ari ELSON;
Ari ELSON
†Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel,
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Reiner LAMMERS;
Reiner LAMMERS
‡Department of Internal Medicine IV, Eberhard-Karls-Universität, Otfried-Müller Strasse10, D-72076 Tübingen, Germany,
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John RØMER;
John RØMER
§Pharmacological Research, Novo Nordisk, DK-2880 Bagsvaerd, Denmark
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Jes Thorn CLAUSEN;
Jes Thorn CLAUSEN
ǁAssay & Cell Technology, Novo Nordisk, DK-2880 Bagsvaerd, Denmark
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Karin Bach MØLLER;
Karin Bach MØLLER
*Signal Transduction, Novo Nordisk, DK-2880 Bagsvaerd, Denmark,
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Niels Peter Hundahl MØLLER
Niels Peter Hundahl MØLLER
2
*Signal Transduction, Novo Nordisk, DK-2880 Bagsvaerd, Denmark,
2To whom correspondence should be addressed (e-mail nphm@novonordisk.com).
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Publisher: Portland Press Ltd
Received:
August 22 2000
Revision Received:
December 04 2000
Accepted:
January 05 2001
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2001
2001
Biochem J (2001) 354 (3): 581–590.
Article history
Received:
August 22 2000
Revision Received:
December 04 2000
Accepted:
January 05 2001
Citation
Jannik N⊘rgaard ANDERSEN, Ari ELSON, Reiner LAMMERS, John RØMER, Jes Thorn CLAUSEN, Karin Bach MØLLER, Niels Peter Hundahl MØLLER; Comparative study of protein tyrosine phosphatase-ɛ isoforms: membrane localization confers specificity in cellular signalling. Biochem J 15 March 2001; 354 (3): 581–590. doi: https://doi.org/10.1042/bj3540581
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