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Mol. Cell. Biol. doi:10.1128/MCB.02096-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Association of tyrosine phosphatase epsilon with microtubules inhibits phosphatase activity and is regulated by the EGF receptor

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100

^* To whom correspondence should be addressed. Email: ari.elson{at}weizmann.ac.il.

	Abstract

Protein tyrosine phosphatases (PTPs) are key mediators that link physiological cues with reversible changes in protein structure and function; nevertheless, significant details concerning their regulation in vivo remain unknown. We demonstrate that PTP epsilon (PTP) associates with microtubules in vivo and is inhibited by them in a non-competitive manner. Microtubule Associated Proteins, which interact strongly with microtubules in vivo, significantly increase binding of PTP to tubulin in vitro and further reduce phosphatase activity. Conversely, disruption of microtubule structures in cells reduces their association with PTP, alters the subcellular localization of the phosphatase and increases its specific activity. Activation of the epidermal growth factor receptor (EGFR) increases the PTP-microtubule association in a manner dependent upon EGFR-induced phosphorylation of PTP at Y638 and upon microtubule integrity. These events are transient and occur with rapid kinetics similar to EGFR autophosphorylation, suggesting that activation of the EGFR transiently down-regulates PTP activity near the receptor by promoting the PTP-microtubule association. Tubulin also inhibits the tyrosine phosphatase PTP1B but not RPTPm nor the unrelated alkaline phosphatase. The data suggest that reversible association with microtubules is a novel, physiologically-regulated mechanism for regulation of tyrosine phosphatase activity in cells.