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(Received for publication, August 13, 1996, and in revised form, November 14, 1996)
From the Department of Biochemistry, University of Tennessee,
Memphis, Tennessee 38163
The Dbl-like guanine nucleotide exchange factor
(GEF) Lbc oncoprotein specifically activates the small GTP-binding
protein Rho in mammalian fibroblasts to induce transformation and actin stress fiber formation, whereas another Dbl-related molecule, Cdc24,
stimulates guanine nucleotide exchange of the Rho family GTPase Cdc42
to elicit effects on both gene induction and actin-based cytoskeleton
change in Saccharomyces cerevisiae. To understand the
mechanism of these functional interactions, we have taken a biochemical
approach to probe the sites on Rho and Cdc42 that are involved in
coupling to their respective GEFs, the Lbc and Cdc24 proteins. Point
mutations in the switch II region of the small G-proteins, many of
which would affect the interaction with GEF in the case of Ras, or a
mutation in the switch I region that was identified as a contact site
between Rab3A and Rab GEF had little effect on RhoA or Cdc42Hs with
regard to the ability to interact with Lbc or Cdc24, suggesting that
there exists a unique mechanism of regulation of the Rho family
proteins by their GEFs. Analysis of a panel of chimeras made between
RhoA and Cdc42Hs, which all maintained the ability to respond to Dbl,
their mutual GEF, and to GTPase-activating protein, revealed that at
least two distinct sites in each of the GTPases are required for
activation by the respective GEFs. Further site-directed mutagenesis
studies showed that the conserved residue Tyr32 in the
putative effector region of both GTPases (numbered by Cdc42Hs) is
critical for binding of the GEFs and that specific recognition for Lbc
or Cdc24 is achieved at least in part through residues
Lys27 of Rho and Gln116 of Cdc42. Moreover, the
loss of GEF responsiveness of a RhoA mutation (D76Q) was found to be
caused by the impaired GEF catalysis, not by a change in the GEF
binding affinity. Together, these results indicate that multiple sites
of the Rho GTPases are involved in the regulation by GEFs, contributing
to GEF binding or GEF catalysis, and raise the possibility that
activation of each Rho family G-protein by a specific GEF may engage in
a distinct mechanism.
Volume 272, Number 8,
Issue of February 21, 1997
pp. 4671-4679
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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