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Volume 272, Number 49, Issue of December 5, 1997
pp. 30688-30692
(Received for publication, June 25, 1997, and in revised form, September 25, 1997)
From the ABSTRACT Directed cell migration is essential for a
variety of important biological processes ranging from development and
angiogenesis to metastasis. Ras plays a pivotal role in the signaling
cascade that governs chemotaxis of fibroblasts toward platelet-derived growth factor-BB (PDGF-BB). Ras activates multiple downstream pathways,
which include the extracellular signal-regulated kinase (ERK), Rac, and
Ral signaling cascades. We therefore investigated the role of the Rac
and ERK pathways in cell migration. We showed that migration of
fibroblasts toward PDGF-BB is inhibited by expression of dominant
negative Asn-17 Rac1. Blocking of the ERK pathway by either expression
of dominant negative Ala-218/Ala-222-mitogen-activated protein kinase
kinase (A218/A222-MEK1) or by a MEK-specific inhibitor did not inhibit
migration toward PDGF-BB. In contrast, migration toward soluble
fibronectin was suppressed by inhibition of the ERK pathway but not by
Asn-17 Rac1 expression. These results indicate that directed cell
migration mediated by different receptor classes in response to
different ligands differentially utilizes the Rac and ERK pathways and
suggest that Rac might play a critical role in pathological processes
such as angiogenesis and metastasis.
INTRODUCTION Directed cell migration or chemotaxis is a critical feature of
several physiological and pathological processes, including development, wound healing, atherosclerosis, immunity, angiogenesis, and metastasis (1-4). Chemotaxis involves the sensing of a
concentration gradient of chemoattractant, reorganization of the actin
cytoskeleton, and subsequent movement toward the chemoattractant.
Cytokine-induced reorganization of the actin cytoskeleton is mediated
by members of the Rho family of GTP-binding proteins. Rho regulates
stress fiber assembly, Rac controls lamellipodia formation, and Cdc42 directs the dynamics of filipodia (5-8).
We have shown previously that the GTP-binding protein Ras plays a
central role in the signaling cascade that governs chemotaxis of
fibroblasts toward PDGF-BB1
(9). However, the pathways downstream of Ras that control cell motility
remain unknown. Ras activates several distinct effector pathways,
including the ERK cascade, the pathway controlled by Rac, and the
pathway initiated by RalGDS, the guanine nucleotide dissociation
stimulator for RalA and -B, which are close relatives of Ras (10-17).
Since Rac has been shown to control the formation of lamellipodia
induced by Ras (5, 18), it is a likely candidate for regulating
Ras-mediated directed migration. A possible role for Rac in directed
migration is also suggested by observations showing that Ras- and
growth factor-induced activation of Rac are mediated by
phosphatidylinositol 3-kinase (17, 19), which in turn has been
implicated in chemotaxis (20-22). In this study, therefore, we
investigated the role of Rac in different types of cell migration:
directed migration toward PDGF-BB and soluble fibronectin and random
migration stimulated by lysophosphatidic acid (LPA).
EXPERIMENTAL PROCEDURES Derivatization, properties, and growth
conditions of Asn-17 Rac1 (N17-Rac1)-expressing Rat1 fibroblasts have
been previously described (12). ERK activation by 2.5 ng/ml PDGF-BB or
1 µg/ml LPA in these mutant Rac1-expressing lines is similar to that
of control cells, indicating that the changes in cell migration
stimulated by PDGF-BB and LPA are not a consequence of changes in
expression level of the PDGF- For the establishment of A218/A222-MEK1-expressing lines, Glu-tagged
full-length A218/A222-MEK1 (kindly provided by S. Macdonald and E. Porfiri, ONYX) was subcloned as a BamHI-NotI
fragment into the expression plasmid pAUCT. This is a pBR-based vector
that contains the neomycin resistance gene under the control of the thymidine kinase promoter, the Tet repressor-VP16 fusion cDNA under
the control of the cytomegalovirus promoter, and the Tet operator
driving the expression of the gene of interest (kindly provided by A. Fattaey, ONYX). Rat 1 fibroblast lines expressing A218/A222-MEK1 or the
pAUCT vector control were established after DNA transfection by
selecting G418-resistant clones growing in the presence of tetracycline
to maintain the expression of recombinant MEK1 mutant at low levels.
Clones were maintained in high glucose (4.5 g/liter) Dulbecco's
modified Eagle's medium, supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 units of penicillin, and 2 µg/ml
streptomycin, 400 µg/ml G418, and 2 µg/ml tetracycline and kept at
37 °C and 5% CO2. Prior to experimental analysis, induction of recombinant Rac and MEK mutants was achieved by removing tetracycline for 24 h.
Expression levels of the Myc-tagged Rac mutants were obtained by
immunoblotting using the 9E10 monoclonal antibody as in Ref. 23.
Expression levels of the Glu-Glu-tagged MEK1 mutant were determined
using an anti-Glu-Glu monoclonal antibody (24).
A218/A222-MEK1 expression was induced by
removal of tetracycline for 24 h. Subsequently, cells were starved
from serum for 18 h and induced with 10 nM epidermal
growth factor for various periods of time. Cells were lysed in 20 mM Tris-HCl, pH 8.0, 137 mM NaCl, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 1.5 mM MgCl2, 1 mM sodium vanadate, 1 mM Pefabloc, 20 µM leupeptin, 10 µg/ml aprotinin, and 50 mM NaF. Cleared lysates were incubated
for 2 h at 4 °C with anti-ERK1 E1.2 crude serum and protein
A-Sepharose. The beads were washed twice with lysis buffer and once
with kinase buffer (30 mM Tris-HCl, pH 8.0, 20 mM MgCl2, and 2 mM
MnCl2). The kinase reaction was initiated by adding 30 µl
of kinase buffer (10 µM cold ATP, 2.5 µCi of
[ Cell migration through
collagen-coated filters was assayed as described previously (9). Cell
binding to the collagen-coated filters of the various lines and control
cells was determined at various times after incubation in the
chemotaxis chamber. Nonadherent cells were washed off with
phosphate-buffered saline, and adherent cells were counted under the
microscope. Statistical analysis (two sample t test) was
performed on the values for stimulated migration corrected for
background migration (in the absence of stimulus).
Serum-starved cells were transferred to bicarbonate-free
medium and mounted in a homemade observation chamber. Cell behavior was
followed by means of video time lapse microscopy. Video frames were
collected every 10 s with a Hamamatsu C2400 camera mounted on a
Zeiss Axiovert 100TV inverted microscope provided with a × 40 Plan-NeoFluor NA 0.75 objective. Images were stored on a Panasonic TQ
2028F optical memory disk recorder. The number of ruffles per cell
larger than 10 µm was determined at 2-min time intervals.
RESULTS To investigate the function of Rac in
cell migration, we employed Rat1 fibroblast lines expressing N17-Rac1
(12). We first characterized the migratory response of control Rat1
fibroblasts toward PDGF-BB, using a multiwell Boyden chamber assay
(25). This assay measures the movement of cells across a porous
membrane in response to a concentration gradient of a chemoattractant
and has been shown previously to provide quantitative measurement of
lymphocyte, endothelial cell, and tumor cell motility in response to a
variety of physiological effectors. Control vector-transfected cells
showed optimal migration toward a gradient generated by concentrations
of 2.5-5 ng/ml PDGF-BB in the bottom well. Checkerboard analysis in
which the amount of attractant was varied in both the top and bottom
wells of the Boyden chamber indicated that the Rat1 fibroblasts display
predominantly directional motility (chemotaxis) toward a PDGF-BB
gradient, with a minor component attributed to an increase in random
motility (data not shown). Relative to vector control cells, the three
independent clones of Rat1 fibroblasts expressing N17-Rac1 tested were
strongly inhibited in their migration toward PDGF-BB (p < 0.0005), whereas their basal unstimulated motility was not altered
(Fig. 1a). These results indicate that Rac is a key element in the signaling pathway involved in
directional migration induced by PDGF-BB. Basal cell movement, in
contrast, does not depend on Rac.
[View Larger Version of this Image (15K GIF file)]
To further study the role of Rac in the regulation of cell motility, we
investigated the response of the lines expressing mutant Rac proteins
to LPA, a ligand that activates a G protein-coupled receptor (26).
Checkerboard analysis demonstrated that LPA stimulates random,
nondirectional migration (chemokinesis) in contrast to PDGF-BB, which
stimulates directed cell migration. Here again, Rat1 fibroblasts
expressing N17-Rac1 showed a strong reduction in LPA-stimulated
migration (p < 0.0005) (Fig. 1b),
indicating that Rac also plays an essential role in a signaling pathway
utilized by LPA to control cell motility. Together with the previous
data, these results also indicate that both random and directed
stimulated cell motility are Rac-dependent and that
motility signaling pathways triggered by tyrosine kinase and G
protein-coupled receptors both employ Rac as a mediator.
To test whether the Rac pathway controls cell locomotion stimulated by
other factors, we studied directed migration toward soluble fibronectin
(FN), an integrin-mediated response. We previously showed that
FN-stimulated migration is independent of Ras activity (9). At this
moment it is not clear, however, whether migration toward soluble FN is
chemotactic or haptotactic (migration guided by a gradient of
increasing substrate adhesiveness).
Migration toward FN was not significantly inhibited by expression of
N17-Rac (Fig. 1c). This indicates that, in contrast to motility stimulated by the growth factors PDGF-BB and LPA, Rac activity
is not essential for migration toward fibronectin. These observations
also further differentiate the motility pathway stimulated by
fibronectin from those activated by the growth factors PDGF and
LPA.
In addition to activating Rac,
Ras also stimulates the ERK pathway, which is required for cell
proliferation and transformation (11). The potential role of the ERK
cascade in the regulation of cell motility is not yet clear, however.
To study whether activation of the ERK pathway is necessary for cell
migration, we used Rat1 fibroblast lines expressing
dominant-negative A218/A222-MEK1 (11) from a tetracycline-repressible
promotor (27). Although these lines showed greatly diminished ERK
activation in response to growth factors (up to 90% inhibition of ERK
activation for the line shown in Fig. 2),
migration toward PDGF-BB was unaltered (Fig. 2a). In
addition, although LPA stimulates ERK activity in a
Ras-dependent fashion (28), A218/A222-MEK1 expressing lines did not show any inhibition in LPA-stimulated motility (Fig.
2b). Thus, Rac controls PDGF- and LPA-stimulated motility
independently of the ERK pathway.
[View Larger Version of this Image (15K GIF file)]
In contrast to the above results, A218/A222-MEK1-expressing lines were
significantly inhibited in migration toward soluble fibronectin
(p < 0.0005) (Fig. 2c). The inhibition of
fibronectin-stimulated migration was not caused by decreased adhesion
of the A218/A222-MEK1-expressing lines to the filter separating the two
chambers. Indeed, adhesion to the Boyden chamber collagen-coated filter
of all of the cell lines used in this study (including the lines
expressing the various Rac mutants) was indistinguishable from those of
controls, and adhesion was independent of the presence of growth
factors or soluble fibronectin in the bottom chamber (data not
shown).
We further tested the role of the ERK pathway in cell migration using
PD98059, a MEK-specific inhibitor (29), to block MEK activation.
PD98059 at a concentration of 10 µM, which inhibits growth factor activation of ERK by 50-60% in Rat1 fibroblasts (30),
significantly inhibited migration of vector control lines toward FN
(p < 0.0005) but did not affect migration stimulated by either PDGF-BB or LPA (Fig. 3,
a-c). These results confirm that activation of the ERK
pathway is necessary for migration toward soluble fibronectin,
indicating a novel function for the ERK pathway in integrin-mediated
cell migration.
[View Larger Version of this Image (14K GIF file)]
The control of cell
migration by Rac might be expected to involve the regulation of
lamellipodial dynamics, which has been shown to be controlled by Rac
(5). We therefore quantified PDGF-induced ruffling in Rat1 fibroblasts
expressing N17-Rac1 and controls (Fig.
4). PDGF-induced ruffling was strongly
inhibited by expression of N17-Rac1 in Rat1 fibroblasts, in agreement
with results obtained in other cell types (5, 19). However, LPA at
concentrations up to 1 µg/ml did not induce any ruffling response in
Rat1 fibroblasts (data not shown), in line with earlier observations in
Swiss 3T3 fibroblasts (6). These findings suggest that Rac may regulate
cell motility independently of its role in lamellipodia formation.
[View Larger Version of this Image (13K GIF file)]
DISCUSSION Our data indicate that the Rac and ERK pathways mediate different
types of migratory behavior, with the Rac pathway controlling motility
stimulated by PDGF-BB and LPA and the ERK pathway controlling motility
stimulated by FN (Fig. 5). Because Ras is
essential for both PDGF- and LPA-stimulated motility (9), our results
also indicate that the Rac and ERK pathways can differentially mediate signals that emanate from Ras. This is consistent with results obtained
with Ras effector loop mutants, which indicated that membrane ruffling
and ERK activation are mediated by distinct Ras effectors (17, 18). The
recent observation that Ras activation of Rac is mediated by
phosphatidylinositol 3-kinase, is also in line with previous findings
that chemotaxis toward PDGF is phosphatidylinositol 3-kinase-dependent (20-22). Interestingly, Ras,
phosphatidylinositol 3-kinase, and Rac have also been shown to be
necessary for hepatocyte growth factor/scatter factor-induced
dispersion of Madin-Darby canine kidney cells (31-33), indicating that
this signaling cascade may be utilized in a variety of motile responses
and may play an important role in mammalian development (34).
[View Larger Version of this Image (14K GIF file)]
Adhesion to fibronectin has been shown to activate ERK and may be
responsible for shape-dependent cell proliferation
(35-37). Our results indicate an additional role for the ERK pathway
in fibronectin-stimulated migration. These results are consistent with
a recent report, which shows that activation of the ERK pathway is
necessary for haptotaxis stimulated by a collagen gradient (38). We
have previously shown that migration toward soluble fibronectin is
Ras-independent (9). Whether Ras plays a role in integrin-induced
activation of ERK still remains to be resolved, however (39, 40).
The mechanism by which Rac controls migration remains to be elucidated.
The inhibition of LPA-stimulated motility by N17-Rac1 suggests that the
role of Rac in cell migration could be independent of its function in
the control of lamellipodia. Although this may come as a surprise, it
is consistent with recent studies on actin filament dynamics and
ultrastructure in locomoting heart fibroblasts, which showed that the
rate of cell locomotion correlates with the flow of actin filaments in
the cell body and not with that in lamellipodia (41). Therefore, in
addition to regulating the formation of lamellipodia, Rac may control
more subtle cytoskeletal features, which still remain to be defined.
Rac could also regulate cell migration by inducing the expression of
matrix-degrading proteases, since AP1 and PEA3, two elements that are
implicated in the control of matrix metalloprotease expression (42),
are both activated by Rac (43, 44). A similar mechanism might be used
by the ERK pathway to control cell migration toward fibronectin. Alternatively, the ERK pathway could control migration toward FN via
activation of myosin light chain kinase, as was shown to be the case
for collagen-mediated haptotaxis (38).
The function of Rac in the regulation of directed cell migration is in
line with the role of Tiam1, a Rac guanine nucleotide exchange factor,
which facilitates cell invasion (45, 46). Furthermore, directed
migration is a critical component in angiogenesis (4). Thus, the data
presented in this paper suggest that Rac, in addition to its role in
tumorigenicity (12, 13), may be an important signaling element in
metastasis and angiogenesis.
FOOTNOTES ACKNOWLEDGEMENTS We are grateful to S. Macdonald, E. Porfiri,
and A. Fattaey for gifts of plasmids. We also thank J. Folkman and A. Balmain for critical reading of the manuscript.
REFERENCES
Platelet-derived Growth Factor and Fibronectin-stimulated
Migration Are Differentially Regulated by the Rac and Extracellular
Signal-regulated Kinase Pathways*
§,,,
Departments of Surgery and Cell Biology,
Children's Hospital, Harvard Medical School, Boston, Massachusetts
02115 and ¶ ONYX Pharmaceuticals, Richmond, California 94806
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
and LPA receptors.
-32P]ATP, and 7 µg of myelin basic protein) to the
beads. After incubation for 30 min at 30 °C, reactions were stopped
by adding sample buffer. Phosphorylated myelin basic protein was
resolved on 14% SDS-PAGE and revealed by autoradiography.
Fig. 1.
N17-Rac1 inhibits motility stimulated by
PDGF-BB and LPA but not by fibronectin. a, directed
migration of N17-Rac1-expressing Rat1 fibroblasts toward PDGF-BB.
Filled bars, no chemoattractant; empty bars, 2.5 ng/ml PDGF-BB. b, migration of N17-Rac1-expressing Rat1
fibroblasts stimulated by LPA. Filled bars, no stimulus; empty bars, 1 µg/ml LPA. c, directed migration
of N17-Rac1-expressing Rat1 fibroblasts toward soluble fibronectin.
Filled bars, no chemoattractant; empty bars, 1 µg/ml fibronectin. Values shown indicate the number of cells
migrating for a single well. Error bars indicate the S.E. of
four wells. The results shown are representative of three independent
experiments. d, Western blots showing N17-Rac1 expression levels in the Rat1 fibroblast lines used. Cell line 5-8 is a
tetracycline-sensitive transactivator expressing vector control line
(12).
Fig. 2.
A218/A222-MEK1 selectively inhibits directed
migration toward soluble fibronectin. a, migration of
A218/A222-MEK1-expressing Rat1 cells toward PDGF-BB (2.5 ng/ml).
b, migration of A218/A222-MEK1-expressing Rat1 fibroblasts
stimulated by LPA (1 µg/ml). c, directed migration of
A218/A222-MEK1-expressing Rat1 fibroblasts toward soluble fibronectin (1 µg/ml). Other conditions were as in Fig. 1. d,
upper panel, anti-Glu-Glu Western blots showing
A218/A222-MEK1 expression levels; lower panel,
32P incorporation into myelin basic protein phosphorylated
by immunoprecipitated ERK1 from cells treated with 10 nM
epidermal growth factor for 10 min.
Fig. 3.
The MEK inhibitor PD98059 selectively
inhibits directed migration toward soluble fibronectin. a,
effect of 10 µM PD98059 on migration of Rat1 vector
control cells toward PDGF-BB (2.5 ng/ml). b, effect of 10 µM PD98059 on migration of Rat1 vector control cells
stimulated by 1 µg/ml LPA. c, effect of 10 µM PD98059 on migration of Rat1 vector control cells
toward 1 µg/ml fibronectin. Other conditions were as in Fig. 1.
Fig. 4.
PDGF-induced ruffling is inhibited in Rat1
fibroblasts expressing N17-Rac1. The number of ruffles per cell
was determined at the maximum of the ruffling response caused by the
indicated concentrations of PDGF-BB (see "Experimental
Procedures"). Error bars indicate the S.E. of four fields
of cells, comprising 7-10 cells each.
Fig. 5.
The Rac and ERK pathways mediate different
modes of migration. Rac regulates directed migration toward
PDGF-BB and random migration stimulated by LPA. The downstream pathway
utilized by Rac in the control of cell motility is likely to be
distinct from the pathway involved in lamellipodia formation. Migration toward fibronectin depends on activation of the ERK pathway but is
independent of Ras activation. The relationship between migration and
transcription is still not understood.
§
Present address: Dept. of Cell Biology, Cleveland Clinic Research
Institute, Cleveland, OH 44195.
To whom correspondence should be addressed: ONYX
Pharmaceuticals, 3031 Research Dr., Richmond, CA 94806. Tel.:
510-262-8735; Fax: 510-222-9758; E-mail: msymons{at}onyx-pharm.com.
1
The abbreviations used are: PDGF,
platelet-derived growth factor; LPA, lysophosphatidic acid; N17-Rac1,
Asn-17 Rac1; ERK, extracellular signal-regulated kinase;
A218/A222-MEK1, Ala-218/Ala-222-mitogen-activated protein kinase
kinase.
Volume 272, Number 49,
Issue of December 5, 1997
pp. 30688-30692
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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 M. Oertel, A. Graness, L. Thim, F. Buhling, H. Kalbacher, and W. Hoffmann Trefoil Factor Family-Peptides Promote Migration of Human Bronchial Epithelial Cells . Synergistic Effect with Epidermal Growth Factor Am. J. Respir. Cell Mol. Biol., October 1, 2001; 25(4): 418 - 424. [Abstract] [Full Text] [PDF]
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