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J. Biol. Chem., Vol. 275, Issue 21, 15665-15668, May 26, 2000
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From the Department of Molecular Medicine, Veterinary Medical
Center, Field of Biochemistry, Molecular, and Cell Biology, Cornell
University, Ithaca, New York 14853
Members of the Rho subfamily of GTP-binding
proteins are implicated in the regulation of phospholipase D (PLD). In
the present study, we demonstrate a physical association between a Rho
family member, Cdc42, and PLD1. Binding of Cdc42 to PLD1 and subsequent activation are GTP-dependent. Although binding of Cdc42 to
PLD1 does not require geranylgeranylation, activation of PLD1 is
dependent on this lipid modification of Cdc42. Specific point mutations in the switch I region of Cdc42 abolish binding to and, therefore, activation of PLD1 by Cdc42. Deletion of the Rho insert region, which
consists of residues 120-139, from Cdc42 does not interfere with
binding to PLD1 but inhibits Cdc42 stimulated PLD1 activity. Interestingly, deletion of the insert region from Cdc42 also inhibits activation of PLD1 by Arf and protein kinase C. With the lack of
specific inhibitors of PLD activity, the insert deletion mutant of
Cdc42 (designated (
Activation of Phospholipase D1 by Cdc42 Requires the Rho
Insert Region*
,
L8)Cdc42) is a novel reagent for in
vitro studies of PLD1 regulation, as well as for in
vivo studies of Cdc42-mediated signaling pathways leading to PLD1
activation. Because the insert region is required for the transforming
activity of Cdc42, regulation of PLD1 by this region on Cdc42 is of
major interest.
*
This work was supported by Grant-in-Aid 970168 from the New
York State American Heart Association and National Institutes of Health
Grant GM58516 (to H. A. B.).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.
Pharmaceutical Research and Manufacturers Association of America
Foundation Predoctoral Fellow.
§
Sidney Kimmel Foundation for Cancer Research Scholar. To whom
correspondence should be addressed. Tel.: 607-253-3893; Fax: 607-253-3659; E-mail: hab8@cornell.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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