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J. Biol. Chem., Vol. 278, Issue 19, 17509-17514, May 9, 2003
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From the Voltage-gated potassium (Kv) channels are a
complex and heterogeneous family of proteins that play major roles in
brain and cardiac excitability. Although Kv channels are activated by
changes in cell membrane potential, tyrosine phosphorylation of channel subunits can modulate the extent of channel activation by
depolarization. We have previously shown that dephosphorylation of
Kv2.1 by the nonreceptor-type tyrosine phosphatase PTP
Phosphorylation-dependent Regulation of Kv2.1 Channel
Activity at Tyrosine 124 by Src and by Protein-tyrosine Phosphatase
*
,
Department of Molecular Genetics, The
Weizmann Institute of Science, Rehovot 76100, Israel and the
§ Department of Physiology, Sackler Medical School, Tel Aviv
University, Tel Aviv 69978, Israel
(cyt-PTP) down-regulates channel activity and counters its
phosphorylation and up-regulation by Src or Fyn. In the present study,
we identify tyrosine 124 within the T1 cytosolic domain of Kv2.1 as a
target site for the activities of Src and cyt-PTP.
Tyr124 is phosphorylated by Src in vitro;
in whole cells, Y124F Kv2.1 is significantly less phosphorylated by Src
and loses most of its ability to bind the D245A substrate-trapping
mutant of cyt-PTP. Phosphorylation of Tyr124 is critical
for Src-mediated up-regulation of Kv2.1 channel activity, since Y124F
Kv2.1-mediated K+ currents are only marginally up-regulated
by Src, in contrast with a 3-fold up-regulation of wild-type Kv2.1
channels by the kinase. Other properties of Kv2.1, such as expression
levels, subcellular localization, and voltage dependence of channel
activation, are unchanged in Y124F Kv2.1, indicating that the effects
of the Y124F mutation are specific. Together, these results indicate that Tyr124 is a significant site at which the mutually
antagonistic activities of Src and cyt-PTP affect Kv2.1
phosphorylation and activity.
*
This study was supported by the Israel Science Foundation,
founded by The Israel Academy of Sciences and Humanities (to A. E. and
B. A.) and the AFIRST (to B. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed. Tel.: 972-8-934-2331;
Fax: 972-8-934-4108; E-mail: ari.elson@weizmann.ac.il.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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