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J. Biol. Chem., Vol. 278, Issue 20, 18360-18367, May 16, 2003
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From the Endothelial cells approaching confluence exhibit
marked decreases in tyrosine phosphorylation of receptor tyrosine
kinases and adherens junctions proteins, required for cell cycle arrest and adherens junctions stability. Recently, we demonstrated a close
correlation in endothelial cells between membrane cholesterol and
tyrosine phosphorylation of adherens junctions proteins. Here, we probe
the mechanistic basis for this correlation. We find that as endothelial
cells reach confluence, the tyrosine phosphatase SHP-2 is recruited to
a low-density membrane fraction in a cholesterol-dependent manner. Binding of SHP-2 to this fraction was not abolished by phenyl
phosphate, strongly suggesting that this binding was mediated by other
regions of SHP-2 beside its SH2 domains. Annexin II, previously
implicated in cholesterol trafficking, was associated in a complex with
SHP-2, and both proteins localized to adhesion bands in confluent
endothelial monolayers. These studies reveal a novel,
cholesterol-dependent mechanism for the recruitment of signaling proteins to specific plasma membrane domains via their interactions with annexin II.
Regulation of the SHP-2 Tyrosine Phosphatase by a Novel
Cholesterol- and Cell Confluence-dependent
Mechanism*,
§¶,§¶,, and
Department of Molecular Medicine, University
of Massachusetts Medical School, Worcester, Massachusetts 01605 and the
§ Department of Biotechnology, Worcester Polytechnical
Institute, Worcester, Massachusetts 01609
*
This work was supported in part by Grant IRG 93-033 from the
American Cancer Society (to H. S. S.).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.
The on-line version of this article (available at
http://www.jbc.org) contains a supplementary figure.
¶
Both authors contributed equally to this work.
To whom correspondence should be addressed: Dept. of Molecular
Medicine, 373 Plantation St., Suite 107, University of
Massachusetts Medical Center, Worcester, MA 01605. Tel.: 508-856-6866;
Fax: 508-856-4289; E-mail: howard.shpetner@umassmed.edu.
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