The Tetraspanin CD151 Functions as a Negative Regulator in the Adhesion-dependent Activation of Ras*
Shigeaki Sawada
,
Mitsunori Yoshimoto
,
Elena Odintsova
,
Neil A. Hotchin
and
Fedor Berditchevski
¶
From the
Cancer Research UK Institute for Cancer
Studies and
School of Biosciences, The
University of Birmingham, Edgbaston, Birmingham B15 2TA, United Kingdom
Received for publication, May 16, 2003
, and in revised form, May 29, 2003.
 |
ABSTRACT
|
---|
Transmembrane proteins of the tetraspanin superfamily are associated with
integrins and are thought to regulate adhesion-dependent signaling. The
molecular mechanisms of this regulation remain unknown. We used rat
fibroblasts to analyze the contribution of the tetraspanin CD151 in the
adhesion-dependent signaling. Expression of CD151 specifically attenuated
adhesion-dependent activation of Ras. Furthermore, activation of PKB/c-Akt and
ERK1/2, downstream targets in the Ras signaling pathway, was also diminished
in cells expressing CD151. In contrast, adhesion-dependent activation of FAK
and c-Src were not affected by CD151. The attenuation of Ras signaling did not
correlate with phosphorylation of Tyr925-FAK, tyrosine
phosphorylation of Shc, or with assembly of the p120RasGAP-p62Dok complex.
Using mutants of CD151 we established that the cytoplasmic C-terminal portion
is critical for activity of CD151 toward Ras. Taken together these results
identify CD151 as a negative regulator of Ras and suggest a novel mechanism of
adhesion-dependent regulation of Ras activity.
 |
INTRODUCTION
|
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The four transmembrane domain proteins of the tetraspanin superfamily are
involved in regulation of various biological phenomena
(13).
Although numerous reports have established that tetraspanins are involved in
cell migration
(15),
their role in this process remains unclear. Despite the fact that tetraspanins
are associated with various integrins, in most cells they are excluded from
the focal adhesions (6) and do
not affect adhesion of cells to the extracellular matrix
(2,
5). Therefore, it has been
proposed that tetraspanins may specifically regulate post-ligand binding
integrin-dependent signaling
(2,
5). Indeed, earlier studies
showed that tetraspanins could influence adhesion-dependent downstream
signaling events, including tyrosine phosphorylation of cellular proteins
(7) and activation of the
serine-threonine kinase PKB/c-Akt
(8). However, it is not known
how tetraspanins target these signaling pathways or whether these events are
connected with cell migration.
A number of integrin-dependent signaling pathways have been linked to cell
motility. These include: association with, and activation of, receptor
tyrosine kinases (9);
activation of Src-family non-receptor tyrosine kinases
(10); and activation of focal
adhesion kinase (FAK)1
(11). All of these signaling
events, in turn, trigger a network of parallel and intersecting downstream
signaling reactions (12,
13). Proteins of the Ras
family of small GTPases take one of the central positions in this signaling
map, by regulating the activities of Erk1/2 and Rac1
(13). It has been demonstrated
that several pathways could be responsible for the adhesion-dependent
activation of Ras proteins. Two of them (i.e. the assembly of the
phospho-FAK-(Tyr925)-Grb2-Sos and phospho-Shc-Grb2-Sos complexes)
require the upstream activation of Src kinases
(14,
15). In addition, it has been
reported that cell-ECM adhesion triggers the assembly of the p120RasGAP-p62Dok
complex, an event that suppresses the activity of RasGAP, which, consequently,
leads to the increase in active, GTP-bound, Ras in cells
(16).
Recently, it has been shown that the tetraspanin CD151 is involved in
regulation of migration of neutrophils
(17), endothelial cells
(18), and various tumor cell
lines (19,
20). Furthermore, it appeared
that CD151 could manifest its activity only on the FAK-positive cellular
background, suggesting a role for FAK in CD151-dependent migration
(19). However, no biochemical
signaling events have been ascribed to the activity of CD151.
In this report we investigated in detail how expression of CD151 affects
integrin-dependent signaling in non-transformed fibroblasts. We show that
CD151 specifically attenuates adhesion-dependent activation of Ras and the
corresponding downstream activation of ERK1/2 and PKB/c-Akt. Furthermore, we
establish that this attenuation arises from the marked effect of CD151 on the
inactivation of Ras proteins upon cell detachment. Finally, detailed analysis
of upstream signaling events indicates that CD151 affects the
adhesion-dependent Ras activation via a novel mechanism.
 |
MATERIALS AND METHODS
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Cells, Antibodies, and ReagentsRat-1 cells and various
transfectants of Rat-1 cells were routinely maintained in Dulbecco's modified
Eagle's medium supplemented with 10% fetal calf serum. The Rat-1/CD151wt cells
were described previously
(21). Rat-1/CD151
C and
Rat-1/CD151
N cell lines were generated by transfecting
pZeoSV/CD151
C and pZeoSV/CD151
N plasmids, respectively, into
Rat-1 cells. Zeocin-resistant colonies in each transfection experiment were
pooled together
(2030
individual colonies) and further selected in two cycles of cell sorting using
a mixture of anti-CD151 mAbs, 5C11
(22) and 11G1B4 (kindly
provided by Dr. L. Ashman). Mouse mAbs against FAK, Ras, Rac1, and p120RasGAP
were purchased from BD Biosciences. Mouse mAb to RhoA and rabbit polyclonal Ab
to Cdc42 were from Santa Cruz Biotechnology. Rabbit anti-phospho specific Abs
to FAK and rabbit anti-Src polyclonal serum were from BioSource International.
Rabbit anti-FAK Ab was purchased from Autogen Bioclear. All antibodies to PKB,
anti-pTyr mAb, and anti-pSrc416 were purchased from Cell Signaling
Technology. Mouse anti-Src mAb, GD11, was purchased from Upstate
Biotechnology. All other reagents were purchased from Sigma.
Construction of CD151 MutantsThe CD151
N and
CD151
C mutants were engineered by a standard PCR protocol on the
pZeoCD151 template. The N-terminal Gly2Leu13 and
the C-terminal Ser248Tyr253 regions of human
CD151 were substituted for the hemagglutinin tag sequence (YPYDVPDYA) to
generate CD151
N and CD151
C fragments, respectively. The PCR
fragments were subcloned (HindIII-EcoRI) into the pZeoSV
plasmid.
Small G-protein Pull-down AssaysCells (24 x
106) were washed twice with PBS and then scraped into RIPA buffer
(50 mM Tris, pH 7.2, 1% Triton X-100, 0.5% sodium deoxycholate,
0.1% SDS, 500 mM NaCl, 10 mM MgCl2, 10
µg/ml leupeptin, 10 µg/ml aprotinin, 1 mM
phenylmethylsulfonyl fluoride). Lysates were subsequently incubated with the
appropriate GST-RBD beads for 45min at 4 °C. After the washes with 50
mM Tris, pH 7.2, 1% Triton X-100, 150 mM NaCl 10
mM MgCl2, 10 µg/ml leupeptin, 10 µg/ml aprotinin,
0.1 mM phenylmethylsulfonyl fluoride, the captured material was
eluted into Laemmli buffer and resolved in 11% SDS-PAGE. The proteins were
transferred to the nitrocellulose membrane and probed with the appropriate Ab.
The pGEX-2TK-Rhotekin(RBD), pGEX-2TK-PAK(crib), and pGEX-2TK-Raf1(RBD)
plasmids were kindly provided by Dr. M. Schwartz, Dr. J. Collard and Dr. R.
Marais, respectively.
ImmunoprecipitationProteins were solubilized into 1% Triton
X-100/PBS supplemented with 2 mM phenylmethylsulfonyl fluoride, 10
µg/ml aprotinin, 10 µg/ml leupeptin for 216 h at 4 °C. The
insoluble material was pelleted at 12,000 rpm for 10 min, and protein lysates
were precleared by incubation for 4 h at 4 °C with agarose-conjugated goat
anti-mouse antibodies. Immune complexes were collected on the agarose beads
prebound with mAbs, followed by four successive washes with the
immunoprecipitation buffer. Immune complexes were eluted from the beads with
Laemmli sample buffer, and proteins were resolved in 810% SDS-PAGE.
Analysis of Activation of FAK, ERK1/2, and
PKB/c-AktAdhesion-dependent activation of FAK, ERK1/2,
and PKB/c-Akt was analyzed as described previously
(21).
Analysis of Activation of c-SrcSerum-starved cells plated
on the laminin-5 matrix were scraped into Triton X-100-based lysis buffer, and
the c-Src complexes were immunoprecipitated using GD11 mAb. Equal aliquots of
the immunoprecipitated proteins were resolved in 8% SDS-PAGE, transferred to
the nitrocellulose membrane, and probed either with the
anti-Tyr416-Src Ab or with the polyclonal Ab recognizing total
proteins.
 |
RESULTS AND DISCUSSION
|
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We examined whether CD151 modifies adhesion-dependent signaling using Rat-1
fibroblasts. This model system provided two main advantages for our study.
First, these cells express low levels of the endogenous
CD151.2 Second,
adhesion-dependent signaling in Rat-1 cells is well characterized
(23). Rat-1 cells were
transfected with human CD151 cDNA and further selected by bulk sorting to
obtain a population of cells expressing the tetraspanin at a level similar to
that found in some cancer cell lines (e.g. HT1080, MDA-MB-231).
Initially, adhesion-dependent signaling was analyzed in cells plated on
laminin-5-containing matrix (LN5M), an ECM ligand for
3
1, which is a principal integrin partner
for CD151 in Rat-1/CD151 cells. The ectopic expression of CD151 in Rat-1 cells
did not affect adhesion to, and spreading on, LN5M
(Fig. 1, upper
panels). Furthermore, the number and distribution of vinculin-containing
adhesion complexes were similar in Rat-1 and Rat-1/CD151 cells
(Fig. 1, lower
panels). As illustrated in Fig.
2, the expression of CD151 had a negative effect on the kinetics
and amplitude of adhesion-dependent activation of ERK1/2 and PKB/c-Akt
(Fig. 2, A and
B, lower panels, compare lanes
24 with 68). Specifically, we found that, in
control Rat-1 cells, the level of ERK phosphorylation reached the plateau at
10 min (the earliest time point analyzed). By contrast it required 40 min for
the pERK1/2 to reach their maximum in Rat-1/CD151 cells
(Fig. 2A, lower
panel, compare lanes 25 with 710). On the
other hand, adhesion of Rat-1 and Rat-1/CD151 cells to LN5M induced comparable
increases in tyrosine phosphorylation of Tyr397-FAK and
Tyr416-c-Src (Fig. 2, A
and B, top panels). The differences in the
adhesion-dependent activation of ERK1/2 were observed when the cells were
plated on other ECM ligands (e.g. fibronectin, laminin-10/11)
(Fig. 2C, compare
lanes 25 with 710). In contrast, the kinetics
and degree of ERK1/2 activation were comparable when serum-starved Rat-1 and
Rat-1/CD151 cells were stimulated with EGF
(Fig. 2D). These
results indicated that CD151 specifically attenuated adhesion-dependent
activation of ERK1/2 and PKB/c-Akt but had no effect on the EGF-induced
signaling.

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FIG. 1. Ectopic expression of CD151 in Rat-1 cells does not affect cell adhesion
and spreading. Upper panels, morphology of serum-starved cells
plated on LN5M. Photographs were taken 1 h after plating. Lower
panels, assembly of focal adhesions in cells plated on LN5M.
Serum-starved cells were plated on the LN5M for 1 h. Cells were fixed with
paraformaldehyde and permeabilized with 0.1% Triton X-100. Indirect
immunofluorescence staining was carried out using mAb to vinculin, hVIN-1.
Staining was visualized using fluorescein isothiocyanate-conjugated goat
anti-mouse IgG.
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FIG. 2. The role of CD151 in adhesion-dependent signaling. A, the
role of CD151 in the adhesion-dependent activation of FAK and ERK1/2. Cells
were prepared as described in the legend to A. Cellular lysates were
resolved in 8% SDS-PAGE. Proteins were transferred to a nitrocellulose
membrane and probed with indicated polyclonal Abs. B, the role of
CD151 in the adhesion-dependent activation of c-Src and PKB/c-Akt.
Serum-starved cells were kept in suspension for 60 min before plating on LN5M.
The PKB and c-Src complexes were immunoprecipitated using specific mAbs
(5G3-PKB; GD11-cSrc). Cellular lysates and the immunoprecipitated complexes
were resolved in 8% SDS-PAGE. Proteins were transferred to a nitrocellulose
membrane and probed with indicated polyclonal Abs. C, activation of
ERK1/2 in cells plated on FN and LN10/11 was carried out as described in the
legend to B. D, serum-starved cells were stimulated with EGF (1
ng/ml) and activation of ERK1/2 was analyzed as above.
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Small GTP-binding proteins of the Ras family are the best characterized
activators of ERK1/2 and PI3K in integrin-dependent signaling
(24,
25). Hence, we analyzed the
role of CD151 in adhesion-dependent activation of Ras. As illustrated in
Fig. 3A cell
attachment increases the levels of GTP-loaded Ras in both Rat-1 and
Rat-1/CD151 cells. However, the level of GTP-Ras in Rat-1 cells was higher
than that in Rat-1/CD151 cells (up to
1.8-fold at 20 min after plating to
LN5M). On the other hand, LN5M-dependent modulation of Rho-proteins was
similar for Rat-1 and Rat-1/CD151 cells (results are not shown). It has been
previously reported that integrin-dependent activation of Ras may involve two
signaling pathways: one requires Fyn-dependent phosphorylation of Shc and
subsequent recruitment of the Grb2-Sos1 complex
(15), and another relies on
Src-dependent phosphorylation of FAK on tyrosine 925 followed by assembly of
the FAK-Grb2-Sos1 signaling complex
(14). Although phosphorylation
of Tyr925-FAK was induced upon cell adhesion, no apparent
differences were observed between Rat-1 and Rat-1/CD151 cells
(Fig. 3B, lower
panel). Furthermore, we were unable to detect adhesion-induced
phosphorylation of Shc above the existing baseline in both cell lines
(Fig. 3B, upper
panel). Therefore, it is highly unlikely that CD151-induced differences
in the adhesion-dependent activation of Ras linked to signaling through Fak or
Shc. Rather, we propose that CD151 affects Ras activation through a novel
pathway.

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FIG. 3. CD151 attenuates adhesion-dependent activation of Ras. A,
cells were prepared for the analysis as described in the legend to
Fig. 2A. GTP-loaded
Ras proteins were precipitated from cellular lysates using immobilized
GST-Raf1-RBD. Precipitated proteins and total lysates were resolved in the 12%
SDS-PAGE and transferred to the nitrocellulose membrane. The blots were
developed with the anti-Ras mAb. The graph bars represent the average
fold of changes in Ras-GTP ± S.E. relative to that in detached
(SUSP) Rat-1 cells = 1.0 (four experiments). B, activation
of Ras in Rat-1 cells is independent of phosphorylation of FAK and Shc. Cells
were prepared as described in the legend to
Fig. 2B. The
immunoprecipitation was carried out using rabbit anti-Shc polyclonal Ab and
mouse anti-FAK mAb. Proteins were resolved in 10% SDS-PAGE and transferred to
a nitrocellulose membrane. The membrane was probed with either anti-pTyr mAb
or anti-pTyr925-FAK polyclonal Ab.
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We propose that the attenuation of the adhesion-dependent activation of Ras
is reflective of the lower level of the GTP-Ras complexes in the detached
Rat-1/CD151 cells (Fig.
3A, lanes 1 and 4). Indeed, in separate
experiments we found that detachment of serum-starved Rat-1/CD151 cells
induced a greater decrease in the amount of the precipitated GTP-Ras complexes
than detachment of Rat-1 cells (Fig.
4A, lanes 2 and 4). The dissociation of
the p120RasGAP/p62-Dok complex is thought to be a critical event in the
detachment-induced inactivation of Ras proteins
(16). However, while the
p120RasGAP/p62-Dok complex dissociated upon detachment of both Rat-1 and
Rat-1/CD151 cells, no quantitative differences were observed between the cell
lines (Fig. 4B,
lanes 2 and 4). These results suggest that the effect of
CD151 on inactivation of Ras involves an alternative mechanism(s).

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FIG. 4. CD151 potentiates detachment-induced inactivation of Ras. The
involvement of the p120-RasGAP-p62Dok complex. Serum-starved cells were either
left attached to the tissue culture plastic (ATTACH) or detached and
kept in suspension for 60 min (DETACH). The Ras
"pull-down" assay (A) and immunoprecipitation
(B) were carried out as described in the legend to
Fig. 3. The graph bars
in A were calculated as described in the legend to
Fig. 3A (five
experiments).
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To determine which region(s) of CD151 is responsible for the
adhesion-dependent regulation of Ras activity, we carried out cell detachment
experiments using the Rat-1 cells expressing various CD151 mutants at the
levels similar to that of the wild-type protein. As illustrated in
Fig. 5A the deletion
of the N-terminal cytoplasmic portion of CD151 did not affect significantly
the "Ras-inactivating function" of the tetraspanin. On the other
hand, deletion of the C-terminal cytoplasmic portion completely abolished the
detachment-dependent activity of CD151 toward Ras
(Fig. 5B, lanes 2,
4, and 6). These data indicate that the C-terminal end is
essential for the Ras-inactivating function of CD151.

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FIG. 5. The role of cytoplasmic domains and the large extracellular loop in the
Ras-inactivating function of CD151. Serum-starved cells were either left
attached to the tissue culture plastic (ATTACH) or detached and kept
in suspension for 60 min (DETACH). The assays and calculations (three
to five experiments) were carried out as described in the legend to
Fig. 3A.
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Activation of Ras proteins is one of the central events in the
attachment-dependent signaling mediated by integrins
(12,
26). Here we demonstrate that
the tetraspanin CD151 plays an important role in this process. Specifically,
we identified CD151 as a new negative regulator of Ras proteins, which
potentiates the decrease in the amount of the GTP-Ras complex in cells upon
detachment. Consequently, adhesion-dependent accumulation of GTP-Ras and
subsequent activation of ERK1/2 and PKB is attenuated in cells expressing
CD151. Importantly, the effect of CD151 on the adhesion-dependent signaling is
specific. Indeed, activation of FAK and c-Src and modulation of the activity
of Rho GTPases were comparable in the Rat-1 and Rat-1/CD151 cells.
Importantly, CD151 exhibits its activity toward Ras only when integrins are
disengaged from their ligands. This function of CD151 may be particularly
relevant for cell migration. In migrating cells the dynamic
adhesion-deadhesion cycles are taking place at the front edge of extending
lamellae. Thus, it is conceivable that CD151 facilitates the GTP·Ras
GDP·Ras cycle and specifically affects this step of the
migratory process.
The molecular mechanisms that link integrin disengagement with the
"Ras-inactivating" function of CD151 remain to be established.
CD151 is directly associated with
3
1 and
6
1 integrins through its large
extracellular loop (27,
28). Furthermore, the
conformation of LECL CD151 can be influenced by these interactions
(29). In addition, CD151 is
indirectly associated with other integrins within the tetraspanin-enriched
microdomains (30). Thus, it is
possible that the initial events in signal transduction involve lateral
transmission of conformational changes from the disengaged integrins to CD151.
Subsequently, the signal may be transmitted allosterically to the cell
interior and further involve the C-terminal cytoplasmic part of CD151.
Our results indicate that detachment-induced disassembly of the RasGAP-Dok
complex, the only known pathway that regulates decrease in the amount of the
GTP-Ras complex in suspended cells, is not affected by CD151. This suggests
that the tetraspanin operates through a novel mechanism. This may involve
CD151-dependent membrane recruitment and/or compartmentalization of direct
regulators of Ras proteins (e.g. RasGAP proteins of the GAP1 family,
Ras guanine nucleotide exchange factors
(31,
32)). In this regard,
palmitoylation of CD151 and its association with phosphatidylinositol 4-kinase
may play an important role in this process.
Future study should establish whether function of other "pro-"
or "anti-migratory" tetraspanins (e.g. CD82 and CO-029)
also linked to the Ras pathway. CD151 is associated with various other
tetraspanins, each of which may recruit a unique subset of regulatory proteins
into integrin complexes (2,
5). Hence, by changing a
tetraspanin balance in the integrin/CD151 microdomains it may be possible to
amplify, negate, or even reverse the effect of CD151 in the adhesion-dependent
activation of Ras.
 |
FOOTNOTES
|
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* This work was supported by Cancer Research UK (SP2369/0201 (to F. B.)) and
by the Biotechnology and Biological Sciences Research Council (6/C17261 (to N.
A. H. and F. B.)). The costs of publication of this article were defrayed in
part by the payment of page charges. This 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: Cancer Research UK Inst. for
Cancer Studies, The University of Birmingham, Egdbaston, Birmingham B15 2TA,
UK. Tel.: 44-121-414-2801; Fax: 44-121-414-4486; E-mail:
f.berditchevski{at}bham.ac.uk.
1 The abbreviations used are: FAK, focal adhesion kinase; ECM, extracellular
matrix; Ab, antibody; mAb, monoclonal antibody. 
2 S. Sawada, M. Yoshimoto, E. Odintsova, N. A. Hotchin, and F. Berditchevski,
unpublished results. 
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ACKNOWLEDGMENTS
|
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We thank all of our colleagues who provided us with the reagents used in
this study.
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REFERENCES
|
---|
- Boucheix, C., and Rubinstein, E. (2001)
Cell. Mol. Life Sci. 58,
11891205[Medline]
[Order article via Infotrieve]
- Hemler, M. E. (2001) J. Cell
Biol. 155,
11031107[Abstract/Free Full Text]
- Yanez-Mo, M., Mittelbrunn, M., and Sanchez-Madrid, F.
(2001) Microcirculation
8,
153168[CrossRef][Medline]
[Order article via Infotrieve]
- Baudoux, B., Castanares-Zapatero, D., Leclercq-Smekens, M., Berna,
N., and Poumay, Y. (2000) Eur. J. Cell
Biol. 79,
4151[Medline]
[Order article via Infotrieve]
- Berditchevski, F. (2001) J. Cell
Sci. 115,
41434151[Medline]
[Order article via Infotrieve]
- Berditchevski, F., and Odintsova, E. (1999)
J. Cell Biol. 146,
477492[Abstract/Free Full Text]
- Shaw, A. R. E., Domanska, A., Mak, A., Gilchrist, A., Dobler, K.,
Visser, L., Poppema, S., Fliegel, L., Letarte, M., and Willett, B. J.
(1995) J. Biol. Chem.
270,
2409224099[Abstract/Free Full Text]
- Sugiura, T., and Berditchevski, F. (1999)
J. Cell Biol. 146,
13751389[Abstract/Free Full Text]
- Yamada, K. M., and Even-Ram, S. (2002) Nat.
Cell Biol. 4,
E75E76[CrossRef][Medline]
[Order article via Infotrieve]
- Frame, M. C., Fincham, V. J., Carragher, N. O., and Wyke, J. A.
(2002) Nat. Rev. Mol. Cell. Biol.
3,
233245[CrossRef][Medline]
[Order article via Infotrieve]
- Hauck, C. R., Hsia, D. A., and Schlaepfer, D. D.
(2002) IUBMB Life
53,
115119[Medline]
[Order article via Infotrieve]
- Giancotti, F. G., and Ruoslahti, E. (1999)
Science 285,
10281032[Abstract/Free Full Text]
- Martin, K. H., Slack, J. K., Boerner, S. A., Martin, C. C., and
Parsons, J. T. (2002) Science
296,
16521653[Abstract/Free Full Text]
- Schlaepfer, D. D., Jones, K. C., and Hunter, T. (1998)
Mol. Cell. Biol. 18,
25712585[Abstract/Free Full Text]
- Wary, K. K., Mariotti, A., Zurzolo, C., and Giancotti, F. G.
(1998) Cell
94,
625634[Medline]
[Order article via Infotrieve]
- Noguchi, T., Matozaki, T., Inagaki, K., Tsuda, M., Fukunaga, K.,
Kitamura, Y., Kitamura, T., Shii, K., Yamanashi, Y., and Kasuga, M.
(1999) EMBO J.
18,
17481760[Abstract/Free Full Text]
- Yauch, R. L., Berditchevski, F., Harler, M. B., Reichner, J., and
Hemler, M. E. (1998) Mol. Biol. Cell
9,
27512765[Abstract/Free Full Text]
- Yanez-Mo, M., Alfranca, A., Cabañas, C., Marazuela, M.,
Tejedor, R., Ursa, M. A., Ashman, L. K., De Landazuri, M. O., and
Sanchez-Madrid, F. (1998) J. Cell Biol.
141,
791804[Abstract/Free Full Text]
- Kohno, M., Hasegawa, H., Miyake, M., Yamamoto, T., and Fujita, S.
(2002) Int. J. Cancer
97,
336343[CrossRef][Medline]
[Order article via Infotrieve]
- Testa, J. E., Brooks, P. C., Lin, J. M., and Quigley, J. P.
(1999) Cancer Res.
59,
38123820[Abstract/Free Full Text]
- Berditchevski, F., Odintsova, E., Sawada, S., and Gilbert, E.
(2002) J. Biol. Chem.
277,
3699137000[Abstract/Free Full Text]
- Berditchevski, F., Chang, S., Bodorova, J., and Hemler, M. E.
(1997) J. Biol. Chem.
272,
2917429180[Abstract/Free Full Text]
- Clark, E. A., King, W. G., Brugge, J. S., Symons, M., and Hynes, R.
O. (1998) J. Cell Biol.
142,
573586[Abstract/Free Full Text]
- Downward, J. (1998) Curr. Opin. Genet.
Dev. 8,
4954[CrossRef][Medline]
[Order article via Infotrieve]
- Pouyssegur, J., Volmat, V., and Lenormand, P. (2002)
Biochem. Pharmacol. 64,
755763[CrossRef][Medline]
[Order article via Infotrieve]
- Schwartz, M. A., and Ginsberg, M. H. (2002)
Nat. Cell Biol. 4,
E65E68[CrossRef][Medline]
[Order article via Infotrieve]
- Berditchevski, F., Gilbert, E., Griffiths, M. R., Fitter, S.,
Ashman, L. K., and Jenner, S. J. (2001) J. Biol.
Chem. 276,
4116541174[Abstract/Free Full Text]
- Yauch, R. L., Kazarov, A. R., Desai, B., Lee, R. T., and Hemler, M.
E. (2000) J. Biol. Chem.
275,
92309238[Abstract/Free Full Text]
- Geary, S. M., Cambareri, A. C., Sincock, P. M., Fitter, S., and
Ashman, L. K. (2001) Tissue Antigens
58,
141153[CrossRef][Medline]
[Order article via Infotrieve]
- Ashman, L. K. (2002) J. Biol. Regul.
Homeost. Agents 16,
223226[Medline]
[Order article via Infotrieve]
- Cullen, P. J., and Lockyer, P. J. (2002)
Nat. Rev. Mol. Cell. Biol.
3,
339348[CrossRef][Medline]
[Order article via Infotrieve]
- Hall, B. E., Yang, S. S., and Bar-Sagi, D. (2002)
Front. Biosci. 7,
288294