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MBC in Press, published online ahead of print July 26, 2006
Mol. Biol. Cell 10.1091/mbc.E06-02-0151

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Submitted on February 24, 2006
Revised on June 20, 2006
Accepted on July 17, 2006

Tyrosine Phosphatases Epsilon and Alpha Perform Specific and Overlapping Functions in Regulation of Voltage-gated Potassium Channels in Schwann Cells

Zohar Tiran,* Asher Peretz,{dagger} Tal Sines,* Vera Shinder,{ddagger} Jan Sap,{sect}|| Bernard Attali,{dagger} and Ari Elson*

Departments of *Molecular Genetics and {ddagger}Chemical Research Support, The Weizmann Institute of Science, Rehovot 76100, Israel; {dagger}Department of Physiology and Pharmacology, Tel Aviv University Medical School, Tel Aviv 69978, Israel; {sect}Department of Pharmacology, New York University Medical School, New York, NY 10016

Monitoring Editor: Carl-Henrik Heldin

Tyrosine phosphatases Epsilon (PTP{varepsilon}) and Alpha (PTP{alpha}) are closely related and share several molecular functions, such as regulation of Src family kinases and voltage-gated potassium (Kv) channels. Functional interrelationships between PTP{varepsilon} and PTP{alpha} and the mechanisms by which they regulate K+ channels and Src were analyzed in vivo in mice lacking either or both PTPs. Lack of either PTP increases Kv channel activity and phosphorylation in Schwann cells, indicating these PTPs inhibit Kv current amplitude in vivo. Open probability and unitary conductance of Kv channels are unchanged, suggesting an effect on channel number or organization. PTP{alpha} inhibits Kv channels more strongly than PTP{varepsilon}; this correlates with constitutive association of PTP{alpha} with Kv2.1, driven by membranal localization of PTP{alpha}. PTP{alpha}, but not PTP{varepsilon}, activates Src in sciatic nerve extracts, suggesting Src deregulation is not responsible exclusively for the observed phenotypes and highlighting an unexpected difference between both PTPs. Developmentally, sciatic nerve myelination is reduced transiently in mice lacking either PTP and more so in mice lacking both PTPs, suggesting both PTPs support myelination but are not fully redundant. We conclude that PTP{varepsilon} and PTP{alpha} differ significantly in their regulation of Kv channels and Src in the system examined, and that similarity between PTPs does not necessarily result in full functional redundancy in vivo.


||Present address: Department of Molecular Pathology, The University of Copenhagen, Frederik V vej 11, 6. sal, 2100-København Ø, Denmark.

Address correspondence to: Ari Elson (ari.elson{at}weizmann.ac.il)




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