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(Received for publication, May 25, 1996, and in revised form, August 16, 1996)
From the Lfc and Lsc are two recently identified
oncoproteins that contain a Dbl homology domain in tandem with a
pleckstrin homology domain and thus share sequence similarity with a
number of other growth regulatory proteins including Dbl, Tiam-1, and
Lbc. We show here that Lfc and Lsc, like their closest relative Lbc,
are highly specific guanine nucleotide exchange factors (GEFs) for Rho,
causing a >10-fold stimulation of [3H]GDP dissociation
from Rho and a marked stimulation of GDP-[35S]GTP
Volume 271, Number 44,
Issue of November 1, 1996
pp. 27374-27381
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
,
Department of Pharmacology, Cornell
University, Ithaca, New York 14853, the § Department of
Pharmacology and the Lineberger Comprehensive Cancer Center, University
of North Carolina, Chapel Hill, North Carolina 27599, and the
¶ Terry Fox Laboratory, British Columbia Cancer Agency,
Vancouver, British Columbia V5Z 4E6, Canada
s
(guanosine 5
-O-(3-thiotriphosphate) exchange. All three
proteins (Lbc, Lfc, and Lsc) are able to act catalytically in
stimulating the guanine nucleotide exchange activity, such that a
single molecule of each of these oncoproteins can activate a number of
molecules of Rho. Neither Lfc nor Lsc shows any ability to stimulate
GDP dissociation from other related GTP-binding proteins such as Rac,
Cdc42, or Ras. Thus Lbc, Lfc, and Lsc appear to represent a subgroup of
Dbl-related proteins that function as highly specific GEFs toward Rho
and can be distinguished from Dbl, Ost, and Dbs which are less specific
and show GEF activity toward both Rho and Cdc42. Consistent with these
results, Lbc, Lfc, and Lsc each form tight complexes with the guanine
nucleotide-depleted form of Rho and bind weakly to the GDP- and
GTPS-bound states. None of these oncoproteins are able to form
complexes with Cdc42 or Ras. However, Lfc (but not Lbc nor Lsc) can
bind to Rac, and this binding occurs equally well when Rac is
nucleotide-depleted or is in the GDP- or GTPS-bound state. These
findings raise the possibility that in addition to acting directly as a
GEF for Rho, Lfc may play other roles that influence the signaling
activities of Rac and/or coordinate the activities of the Rac and Rho
proteins.
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