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J Biol Chem, Vol. 275, Issue 19, 14231-14241, May 12, 2000
From the Departments of § Physiology and
¶ Biochemistry, Michigan State University,
East Lansing, Michigan 48824
Src homology 3 domain (SH3)-containing
proline-rich protein kinase (SPRK)/mixed-lineage kinase (MLK)-3 is a
serine/threonine kinase that upon overexpression in mammalian cells
activates the c-Jun NH2-terminal kinase pathway. The
mechanisms by which SPRK activity is regulated are not well understood.
The small Rho family GTPases, Rac and Cdc42, have been shown to bind
and modulate the activities of signaling proteins, including SPRK,
which contain Cdc42/Rac interactive binding motifs. Coexpression of
SPRK and activated Cdc42 increases SPRKs activity. SPRKs Cdc42/Rac
interactive binding-like motif contains six of the eight consensus
residues. Using a site-directed mutagenesis approach, we show that SPRK contains a functional Cdc42/Rac interactive binding motif that is
required for SPRKs association with and activation by Cdc42. However,
experiments using a SPRK variant that lacks the COOH-terminal zipper
region/basic stretch suggest that this region may also contribute to
Cdc42 binding. Unlike the PAK family of protein kinases, we find that
the activation of SPRK by Cdc42 cannot be recapitulated in an in
vitro system using purified, recombinant proteins. Comparative
phosphopeptide mapping demonstrates that coexpression of activated
Cdc42 with SPRK alters the in vivo serine/threonine phosphorylation pattern of SPRK suggesting that the mechanism by which
Cdc42 increases SPRKs catalytic activity involves a change in the
in vivo phosphorylation of SPRK. This is, to the best of our knowledge, the first demonstrated example of a Cdc42-mediated change in the in vivo phosphorylation of a protein kinase.
These studies suggest an additional component or cellular environment is required for SPRK activation by Cdc42.
Cdc42-induced Activation of the Mixed-Lineage Kinase SPRK
in Vivo
REQUIREMENT OF THE Cdc42/Rac INTERACTIVE BINDING MOTIF AND
CHANGES IN PHOSPHORYLATION*
§,¶,
, and
*
This work was supported in part by National Institutes of
Health Grant CA76306.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.
Contributed equally to the results of this work.
Supported by the National Science Foundation-REU program at
Michigan State University.
**
To whom correspondence should be addressed: Depts. of Physiology
and Biochemistry, 108 Giltner Hall, Michigan State University, East
Lansing, MI 48824. Tel.: 517-355-6475; Fax: 517-355-5125, E-mail:
gallo@psl.msu.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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