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J Biol Chem, Vol. 275, Issue 18, 13406-13410, May 5, 2000
From the Department of Biochemistry and Molecular Biology and
Walther Oncology Center, Indiana University School of Medicine,
Indianapolis, Indiana 46202
Guanine nucleotide exchange factors (GEFs) are
responsible for coupling cell surface receptors to Ras protein
activation. Here we describe the characterization of a novel family of
differentially expressed GEFs, identified by database sequence homology
searching. These molecules share the core catalytic domain of other Ras
family GEFs but lack the catalytic non-conserved (conserved
non-catalytic/Ras exchange motif/structurally conserved region 0)
domain that is believed to contribute to Sos1 integrity. In
vitro binding and in vivo nucleotide exchange assays
indicate that these GEFs specifically catalyze the GTP loading of the
Ral GTPase when overexpressed in 293T cells. A central proline-rich
motif associated with the Src homology (SH)2/SH3-containing adapter
proteins Grb2 and Nck in vivo, whereas a pleckstrin
homology (PH) domain was located at the GEF C terminus. We refer to
these GEFs as RalGPS 1A, 1B, and 2 (Ral GEFs with PH domain and SH3
binding motif). The PH domain was required for in vivo GEF
activity and could be functionally replaced by the Ki-Ras C terminus,
suggesting a role in membrane targeting. In the absence of the PH
domain RalGPS 1B cooperated with Grb2 to promote Ral activation,
indicating that SH3 domain interaction also contributes to RalGPS
regulation. In contrast to the Ral guanine nucleotide dissociation
stimulator family of Ral GEFs, the RalGPS proteins do not possess a
Ras-GTP-binding domain, suggesting that they are activated in a
Ras-independent manner.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF221098.
Identification and Characterization of a New Family of Guanine
Nucleotide Exchange Factors for the Ras-related GTPase Ral*
*
This work was supported by National Institutes of Health
Grant CA63139 and American Cancer Society Grants RPG 97-007-01-BE and
RPG-00-125-01-TBE to LAQ.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 should be addressed: Dept. of Biochemistry
and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Dr., MS-4053, Indianapolis, IN 46202. Tel.: 317-274-8550; Fax:
317-274-4686; E-mail: lquillia@iupui.edu.
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