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(Received for publication, February 6, 1997)
From the Department of Cell Biology and Physiology, Washington
University School of Medicine, St. Louis, Missouri 63110 and the
¶ Fred Hutchinson Cancer Research Center, Seattle, Washington
98104
ABSTRACT Activation of Ras stimulates cell surface
membrane ruffling and pinocytosis. Although seen as coupled events, our
study demonstrates that membrane ruffling and pinocytosis are regulated
by distinct Ras signal transduction pathways. Ras controls membrane
ruffling via the small GTPase Rac. In BHK-21 cells, expression of the
constitutively active Rac1(G12V) mutant, via a Sindbis virus vector,
resulted in a dramatic stimulation of membrane ruffling without
affecting the uptake of horseradish peroxidase. Expression of
Ha-Ras(G12V), an activated Ras mutant, stimulated both membrane
ruffling and horseradish peroxidase uptake. The Ha-Ras(G12V)-stimulated
pinocytosis but not membrane ruffling was abolished by either
wortmannin or co-expression with a dominant negative mutant of Rab5,
Rab5(S34N). Expression of the activated Rab5(Q79L) mutant mimics the
stimulatory effect of Ha-Ras(G12V) on pinocytosis but not membrane
ruffling. Our data indicate that Ha-Ras(G12V) separately activates
Rab5-dependent pinocytosis and Rac1-dependent
membrane ruffling.
INTRODUCTION Ras protein is the prototype of a large family of 20-35-kDa
monomeric GTPases that serve as molecular switches in regulating diverse cell functions (1, 2) including cell proliferation and
differentiation (3-5). The best characterized Ras-activated pathway
involves a cascade of protein kinases including Raf, MEK (mitogen-activated protein kinase kinase), and mitogen-activated protein kinase (6-8) resulting in the expression of a specific set of
target genes (9). This signaling pathway is triggered by a direct
interaction between Ras-GTP and Raf (10-14). In addition to Raf,
Ras-GTP also directly interacts with other effector molecules and
activates multiple signal transduction pathways. In mammalian cells, the putative Ras effectors include Ras-GAP (GTPase-activating protein) (15), Ral-GDS (GDP dissociation stimulator) (16, 17),
and phosphatidylinositol-3-OH kinase (PI
3-kinase)1 (18). It has been suggested that
multiple Ras functions contribute to mammalian cell proliferation
(19).
Parallel to the activation of nuclear gene expression, Ras-GTP also
triggers profound changes in the cytoplasm. The Ras signaling cascade
involving the small GTPase Rac1 plays an important role in regulating
the actin cytoskeleton and cell surface membrane ruffles (20). Ras
activation also stimulates pinocytosis (21) and transport to endosomes
and lysosomes. This process involves the small GTPase, Rab5 (22, 23).
Because cell surface ruffling and pinocytosis both involve organized
movements of the plasma membrane, and because Ras stimulates both
processes, the two processes have long been thought to be linked (21).
We have found that membrane ruffling and pinocytosis are regulated by
distinct Ras signal transduction pathways. Whereas Ras-stimulated
ruffling depends on Rac1 and is independent of PI 3-kinase and Rab5,
Ras-stimulated pinocytosis depends on Rab5 and probably PI 3-kinase and
is independent of Rac1.
MATERIALS AND METHODS BHK-21 cells were grown as
described previously (23). Wortmannin (Sigma) in dimethyl sulfoxide at
1 mg/ml (stock solution) was freshly diluted with cDNAs of
Ha-Ras, Rac1, and Rab5 were subcloned into the unique XbaI
restriction site of the Sindbis vector Toto1000:3 Cell lysates (5 µl) were analyzed by SDS-polyacrylamide gel electrophoresis (12%
acrylamide), and the proteins were transferred to an Immobilon-P
membrane (Millipore) using a Bio-Rad semi-dry transfer apparatus. The
membrane was probed with an Ha-Ras specific monoclonal antibody (AB1,
from Oncogene Science), and the immunoblot was developed using the ECL
reagents from Amersham Corp.
Confluent BHK-21 monolayers were
mock-infected or infected with the vector or recombinant viruses as
described (23). At 4 h post-infection or otherwise indicated, cells
were washed twice with serum-free At 4 h post-infection, early endosomes were marked by a 10-min HRP uptake.
Cells were rinsed four times with ice-cold PBS, fixed in 2%
glutaraldehyde (in PBS) for 30 min, and washed four more times with
PBS. HRP reaction was developed for 10 min by incubating with 50 mM Tris-HCl, pH 7.4, containing 2 mg/ml diaminobenzidine (Sigma) and 0.01% H2O2 (Sigma). Cells were
then processed for Poly/Bed (Polysciences, Inc.) embedding, semi-thick
section (~200 nm) preparation, and electron microscopy.
At 4 h post-infection, cells were fixed with 2%
paraformaldehyde (in PBS) for 30 min, peameabilized, and quenched with
PBS containing 0.05% Triton X-100, 0.1 N
NH4Cl, and 0.2% gelatin, followed by staining with
rhodamine-phalloidin (25). The coverslips were mounted in 70% glycerol
(in PBS), and the actin localization and cell edge membrane ruffles
were visualized by a Zeiss axiovert microscope and a Bio-Rad confocal
scanning imaging system.
RESULTS AND DISCUSSION Pinocytosis is regulated by serum growth factors but the
molecular mechanisms and biological significance are not well
understood. Many growth factors also stimulate cell surface membrane
ruffling via rearrangement of actin filaments (20). It has long been thought that membrane ruffling contributes to increased pinocytosis (reviewed in Ref. 26). One example is oncogenic Ras-stimulated pinocytosis and membrane ruffling (21). To understand the molecular basis of the two processes, we used a combination of reagents that
specifically alter pinocytosis and membrane ruffling and found, to our
surprise, that pinocytosis and membrane ruffling are independent
cellular processes regulated by distinct Ras signal transduction
pathways. To determine the effect of Ras activation on pinocytosis, we
transiently expressed a constitutively active Ras mutant, Ha-Ras(G12V),
in cultured BHK-21 cells (23, 24) and monitored pinocytosis of HRP
(23). Fig. 1A shows immunoblot analysis of
Ha-Ras(G12V) expression at different times after virus infection. At
4 h after infection, abundant Ha-Ras(G12V) expression was
detected. Thereafter, the protein accumulated throughout virus infection (Fig. 1A). Endogenous Ras protein was not
detected. HRP accumulation increased dramatically in cells expressing
Ha-Ras(G12V) (Fig. 1B). At 4 h after infection, cells
expressing Ha-Ras(G12V) showed a 3-fold stimulation of HRP uptake
compared with the control cells (Fig. 1B). Ha-Ras(G12V) also
increased the rate of HRP uptake (Fig. 1C). By electron
microscopy, HRP was identified in intracellular endosomes (Fig.
2), which were significantly enlarged in cells expressing Ha-Ras(G12V) (Fig. 2), suggesting increased endosome activity.
Ha-Ras(G12V) interacts with multiple effector molecules via its
effector domain (residues 32-40) (10-19, 27, 28). To identify the Ras
pathway(s) leading to the stimulation of pinocytosis, we expressed an
effector domain mutant of Ha-Ras(G12V), Ha-Ras(G12V,D38A), and tested
the effect on HRP uptake. Ras(G12V,D38A) completely abolished the
ability of Ha-Ras(G12V) to stimulate HRP uptake (Fig.
3A). Since the D38A mutation can abolish the
interaction between Ha-Ras(G12V) and its effector molecules including
PI 3-kinase (18), this result demonstrated the existence of a
responsible Ras signal transduction pathway. Expression of the
constitutively active Raf and RalB mutants (the C-terminal 344 residues
of human c-Raf (29) and RalB(G23V), respectively), putative Ras
effectors, failed to mimic the stimulatory effect of Ha-Ras(G12V) on
HRP uptake (data not shown). Wortmannin, a potent PI 3-kinase inhibitor (30, 31), completely blocked the stimulation of HRP uptake by
Ha-Ras(G12V) (Fig. 3B). Wortmannin (100 nM) also
inhibited HRP uptake in control cells (Fig. 3B) (32,
33).
Early endosome fusion immediately follows the internalization step at
the plasma membrane and appears to be rate-limiting (22, 23).
Wortmannin inhibits a function required for the activation of Rab5
(33), a GTPase essential for early endosome fusion. Expression of the
constitutively active Rab5 mutant, Rab5(Q79L), leads to increased early
endosome fusion and increased pinocytosis while expression of the
dominant negative Rab5(S34N) mutant results in decreased early endosome
fusion and decreased pinocytosis (23, 34). The positive correlation
between early endosome fusion activity and cellular pinocytic activity
led us to suggest that Ha-Ras(G12V) sequentially activates a
wortmannin-sensitive function (possibly PI 3-kinase) and Rab5, leading
to an increase in early endosome fusion and pinocytosis. We found that
Rab5(Q79L) mimicked the stimulatory effect of Ha-Ras(G12V) on HRP
uptake, and this stimulation could be blocked neither by wortmannin
(33) nor by the dominant negative Ha-Ras(S17N) mutant (Fig.
3C). Co-expression of the activated Rab5(Q79L) and
Ha-Ras(G12V) mutants did not lead to a synergistic stimulation of HRP
uptake (Fig. 3C). Furthermore, like cells expressing
Rab5(Q79L) (Fig. 2C), cells expressing Ha-Ras(G12V) exhibited enlarged endosomal structures (Fig. 2B),
indicative of enhanced endosome fusion. Finally, co-expression of the
dominant negative Rab5(S34N) mutant completely blocked the stimulatory effect of Ha-Ras(G12V) on HRP uptake (Fig. 3D).
The pioneering work of Hall and colleagues (20) has partially defined
the Ras signal transduction pathway regulating membrane ruffling. Our
study begins to shed light on this important aspect of Ras signal
transduction. We show that oncogenic Ras-stimulated pinocytosis is
sensitive to wortmannin and is dependent on Rab5 function. Because Ras
can directly activate a PI 3-kinase (18) and PI 3-kinase activity can
stimulate Rab5-dependent early endosome fusion in
vitro (33), we suggest that Ras sequentially activates PI 3-kinase
and Rab5, leading to a quantitative increase in endosome fusion and
pinocytosis. Ridley et al. (20) previously characterized a
Ras signal transduction pathway that promotes membrane ruffling via
activation of the small GTPase Rac1. To further examine the relationship of Ras-stimulated membrane ruffling and pinocytosis, we
expressed the constitutively active and dominant negative Rac1 mutants.
As shown in Fig. 3E, expression of Rac1(G12V) did not stimulate HRP uptake while under the same conditions Ha-Ras(G12V) stimulated HRP uptake 3-fold. Fig. 3F shows the
co-expression of constructs used in this study. These data immediately
suggested that membrane ruffling and pinocytosis are controlled by
distinct Ras signal transduction pathways. We then examined membrane
ruffling (Fig. 4). Consistent with previous reports (20,
25), expression of Rac1(G12V) resulted in a dramatic production of cell
surface membrane ruffles (Fig. 4C). Under the same
conditions, expression of Ha-Ras(G12V) also stimulated membrane
ruffling (Fig. 4D). Cells expressing the activated
Rab5(Q79L) mutant, a strong stimulator of pinocytosis, did not show
membrane ruffling (Fig. 4E), nor did the vector
virus-infected (Fig. 4B) or mock-infected control cells
(Fig. 4A). In agreement with Nobes et al. (25),
we found that wortmannin (100 nM) failed to block
Rac(G12V)-induced or Ha-Ras(G12V)-induced membrane ruffling (data not
shown), under conditions where Ha-Ras(G12V)-stimulated pinocytosis was
completely inhibited (Fig. 3B). From these data, we conclude
that the Ras signal transduction pathway leading to the activation of
Rac1 and membrane ruffling does not contribute to the stimulation of pinocytosis.
CONCLUSIONS Taken together, as summarized in Fig. 5, it is
clear that pinocytosis and membrane ruffling are regulated by distinct
sets of molecules during Ras signal transduction.
FOOTNOTES ACKNOWLEDGEMENTS We thank Rita Boshans for excellent technical
assistance. We are grateful to Anne Votjek and Alan Hall for kindly
providing the cDNAs of RalB and Rac mutants, respectively.
REFERENCES
Volume 272, Number 16,
Issue of April 18, 1997
pp. 10337-10340
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
,
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
CONCLUSIONS
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
-MEM and added to
previously rinsed cell monolayers. The wortmannin treatment (15 min,
37 °C) was followed by horseradish peroxidase (HRP) uptake. Dimethyl
sulfoxide (<0.1% after dilution) had no effect on pinocytosis or
membrane ruffling (data not shown).
2J (23, 24). The
plasmid was then linearized by XhoI digestion and used as a
template for in vitro transcription with SP6 RNA polymerase. The resulting RNA transcripts were used for transfection of confluent BHK-21 cell monolayers using a Lipofectin-mediated procedure (Life Technologies, Inc.). Cells were maintained at 37 °C, and the media containing released viruses were harvested 40 h after
transfection. Virus titers were generally between 108 and
109 plaque-forming units per ml. Virus stocks were
aliquoted and kept frozen at 
80 °C before use.
-MEM, and HRP uptake was initiated
by adding HRP (5mg/ml) in -MEM (1ml) containing 0.2% bovine serum
albumin. Cell lysates were assayed for HRP activity as described (23).
Fig. 1.
Stimulation of HRP uptake by
Ha-Ras(G12V). Confluent BHK-21 cell monolayers were infected with
recombinant virus as described under "Materials and Methods."
A, immunoblot analysis to determine Ha-Ras(G12V) expression.
B, HRP uptake assay. The HRP uptake results are the means of
triplicate samples. C, HRP uptake kinetics. Cells infected
with either the vector virus or the recombinant virus were incubated at
37 °C for 4 h, followed by HRP uptake at 37 °C for the times
indicated. The data are presented as the means of triplicate
samples.
[View Larger Version of this Image (26K GIF file)]
Fig. 2.
Electron microscopy of early endosomal
structures. Expression of Ha-Ras(G12V) or Rab5(Q79L) leads to the
formation of enlarged endosomal structures (B and
C, respectively) that are not seen in control cells
(A). Arrows indicate HRP-marked endosomes.
N denotes nucleus. Magnification 1:12,800.
Bar = 1 cm = 730 nm.
[View Larger Version of this Image (96K GIF file)]
Fig. 3.
Involvement of a wortmannin-sensitive
function and Rab5 but not Rac1 in Ha-Ras(G12V)-stimulated HRP uptake.
Panel A, the stimulation of HRP uptake by Ha-Ras(G12V) is
abolished by the D38A mutation in its effector domain. Panel
B, Ha-Ras(G12V)-stimulated HRP uptake is sensitive to wortmannin.
Panel C, Ras functions upstream of Rab5 in the regulation of
pinocytosis. Panel D, Ha-Ras(G12V)-stimulated HRP uptake is
dependent on Rab5 function. Panel E, Ha-Ras(G12V)-stimulated HRP uptake is independent of Rac1 function. In co-infection experiments (C, D, and E), both viruses were used
at a high multiplicity of infection (50 plaque-forming units/cell) and
under these conditions >60% of the cells expressed both proteins.
Shown are bar graphs indicating the amounts of pinocytosed
HRP activity during a 1-h period and the calculated standard deviations
(A-E). Panel F shows the expression and
co-expression of the mutants of Rac1, Rab5, and Ha-Ras by the Sindbis
vector. BHK-21 cells infected with the vector virus and the respective
recombinant viruses were labeled with [35S]methionine (20 µCi/ml, ICN) for 3 h from 3 to 6 h post-infection. Cells
were lysed in 200 µl of 1% SDS, and 5 µl of the lysates were
analyzed directly by SDS-polyacrylamide gel electrophoresis (12% gel).
Shown is the autoradiography result of the dried gel. Molecular mass
standards (in kilodaltons) are indicated. The overexpressed Rac, Rab5,
and Ras proteins were identified by their size and confirmed by either
immunoprecipitation (23) (Rac and Rab5) or immunoblot analysis (Ras).
The Rac1 antibody (C-14) was purchased from Santa Cruz Biotechnology
Inc., and Ha-Ras antibody (AB1) was from Oncogene Science.
[View Larger Version of this Image (31K GIF file)]
Fig. 4.
Membrane ruffling induced by Ha-Ras(G12V) and
Rac1(G12V) but not Rab5(Q79L). BHK-21 cells grown on coverslips
were either mock-infected (A) or infected with the vector
virus (B) or the recombinant viruses expressing Rac1(G12V)
(C), Ha-Ras(G12V) (D), and Rab5(Q79L)
(E), respectively. Following rhodamine-phalloidin staining
(25), the actin localization and cell edge membrane ruffles were
visualized by a Zeiss axiovert microscope and a Bio-Rad confocal
scanning imaging system. Bar, 10 µm.
[View Larger Version of this Image (138K GIF file)]
Fig. 5.
Ras separately regulates membrane ruffling
and pinocytosis. Ridley et al. (20) previously
identified a Ras signaling pathway that stimulates membrane ruffling
via activation of Rac1. Here we suggest a distinct Ras signal
transduction pathway that stimulates pinocytosis via activation of Rab5
and endosome fusion.
[View Larger Version of this Image (18K GIF file)]
Supported by a fellowship from the Parker B. Francis Foundation.
To whom correspondence should be addressed: Dept. of Biochemistry and
Molecular Biology, The University of Oklahoma Health Sciences Center,
940 S. L. Young Blvd., P. O. Box 26901, Oklahoma City, OK 73190. Tel.:
405-271-2227; Fax: 405-271-3092; E-mail: guangpu-li{at}vokhsc.edu.
§
Lucille P. Markey Special Emphasis Pathway Fellow.
Present address: Dept. of Cell Biology and Physiology,
Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110. Tel.: 314-362-6950; Fax: 314-362-7463.
1
The abbreviations used are: PI 3-kinase,
phosphatidylinositol 3-kinase; -MEM, -minimum essential medium;
HRP, horseradish peroxidase; PBS, phosphate-buffered saline.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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