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(Received for publication, January 16, 1997, and in revised form, February 28, 1997)
From the ABSTRACT Cortactin, a prominent substrate for
pp60c-src, is a filamentous actin
(F-actin) binding protein. We show here that cortactin can promote
sedimentation of F-actin at centrifugation forces under which F-actin
is otherwise not able to be precipitated. Electron microscopic analysis
after negative staining further revealed that actin filaments in the
presence of cortactin are cross-linked into bundles of various degrees
of thickness. Hence, cortactin is also an F-actin cross-linking
protein. We also demonstrate that the optimal F-actin cross-linking
activity of cortactin requires a physiological pH in a range of
7.3-7.5. Furthermore, pp60c-src phosphorylates
cortactin in vitro, resulting in a dramatic reduction of
its F-actin cross-linking activity in a manner depending on levels of
tyrosine phosphorylation. In addition,
pp60c-src moderately inhibits the F-actin
binding activity of cortactin. This study presents the first evidence
that pp60c-src can directly regulate the
activity of its substrate toward the cytoskeleton and implies a role of
cortactin as an F-actin modulator in tyrosine kinase-regulated
cytoskeleton reorganization.
INTRODUCTION Cortactin (p80/p85) was initially discovered as a major
phosphotyrosine-containing protein in v-Src-transformed chicken embryo fibroblasts (1). The murine homologue was independently isolated as a
signaling molecule involved in the transition from G0 to G1 phase in response to fibroblast growth factor (2, 3), and the human cortactin was found as an oncogene that is frequently amplified in subsets of tumors and tumor cell lines (4, 5). A strong
association of cortactin with F-actin1 has
been described (14). Consistent with its F-actin binding activity,
cortactin primarily localizes within peripheral cell structures such as
lamellipodia, pseudopodia, and membrane ruffles (9, 14), which are
enriched for cytoskeletal proteins. However, unlike many other
F-actin-binding proteins, the protein sequence of cortactin features a
unique structure characterized by six and a half 37-amino acid tandem
repeats and a Src homology 3 (SH3) domain at the carboxyl terminus.
Between the SH3 and the repeat domains are an Recent evidence has indicated that cortactin is a prominent substrate
for Src-related protein-tyrosine kinases (1, 6-8). Furthermore,
cortactin is implicated in signaling mediated by multiple extracellular
stimuli including fibroblast growth factor (3), epidermal growth factor
(9), thrombin (10), integrin (11), bacteria-mediated cell invasion
(12), and mechanical strain (13). While tyrosine phosphorylation of
cortactin is a profound phenomenon in response to many extracellular
stimuli, the biological function of cortactin and the physiological
role of tyrosine phosphorylation are not clear.
In an attempt to elucidate the function of cortactin, we have examined
biochemical properties of cortactin. The study presented here
demonstrated that cortactin is a potent F-actin cross-linking protein.
Most importantly, the F-actin cross-linking activity is down-regulated
upon phosphorylation mediated by pp60c-src.
Thus, cortactin may act as an important mediator for intracellular tyrosine kinases in regulating the cytoskeleton reorganization in
vivo.
EXPERIMENTAL PROCEDURES Murine cortactin was
expressed in Escherichia coli as a glutathione
S-transferase fusion protein in pGEX-2T plasmid and purified by affinity chromatography using glutathione-Sepharose (Pharmacia Biotech Inc.) as described previously (15). The glutathione S-transferase part of the fusion protein was removed by
cleavage with bovine thrombin (ICN) in a digestion buffer (50 mM Tris-HCl, pH 8.2, containing 100 mM NaCl and
1 mM CaCl2) for 3~4 h at room temperature.
The digested materials were loaded onto a DEAE-Sepharose FF (Pharmacia)
column and eluted with 200 ml of elution buffer (20 mM
Tris-HCl, pH 7.6, containing 1 mM MgCl2, 1 mM dithiothreitol, and 1 mM EGTA, and KCl with
a gradient concentration from 20 to 600 mM). The fractions
containing cortactin were pooled, and undigested fusion proteins were
removed by additional chromatography using glutathione-Sepharose. The
concentration of purified cortactin was determined by the
Dc protein assay (Bio-Rad) according to the manufacturer's
instructions.
Actin was purified from an acetone
powder of rabbit skeletal muscle according to Pardee and Spudich (16).
Pyrene-labeled actin was prepared as described by Kouyama and Mihashi
(17). The labeled actin was further purified by chromatography using Sephadex G-150 (Pharmacia). Globular actin was polymerized into filaments by adding KCl, MgCl2, and ATP to the final
concentrations of 134, 1, and 1 mM, respectively, and
incubated for at least 4 h at room temperature.
Recombinant human
pp60c-src (18) was preactivated and maintained
in a buffer containing 40 µM ATP, 0.8 mM
MgCl2, and 1 mg/ml bovine serum albumin at 0 °C. To
prepare tyrosine-phosphorylated cortactin, purified proteins were
incubated with various amounts of preactivated
pp60c-src in 20 µl of kinase buffer (50 mM Tris-HCl, pH 7.4, containing 5 mM
MgCl2, 5 mM ATP, and 2 µCi of
[ Purified cortactin at the
indicated concentrations in 50 µl of TKM buffer (50 mM
Tris-HCl, pH 7.4, containing 134 mM KCl and 1 mM MgCl2) was mixed with an equal volume of 8 µM pyrene-labeled F-actin and incubated for 30 min at
room temperature. The mixture was then immediately centrifuged at
26,300 × g for 10 min at room temperature in a Beckman
TL-100 centrifuge. The supernatant was carefully transferred to a new
tube and mixed with 300 µl of TKM buffer containing 2 µM phalloidin (Sigma). The fluorescence in the
supernatant was recorded on an LS50B luminescence spectrometer (Perkin-Elmer) at an excitation wavelength of 370 nm with a slit of 2.5 nm and an emission wavelength of 410 nm with a slit 6 nm, respectively.
The decrease in the supernatant fluorescence reflects the precipitation
of F-actin due to cross-linking. In some experiments, the precipitated
pellets were directly analyzed by SDS-PAGE.
F-actin or the mixture of
F-actin and cortactin was mixed with an equal volume of 1%
phosphotungstic acid in 0.1 M phosphate buffer, pH 7.4. The
stained samples (10 µl) were absorbed to a 0.25% Formvar 15/95E
resin- (Sigma) coated film on a gold grid. The grid was then air-dried
overnight. Transmission electron micrographs were taken with a Philips
M12 microscope.
RESULTS AND DISCUSSION In an effort to investigate the function of cortactin, the murine
cortactin was expressed in E. coli as a glutathione
S-transferase fusion protein. The glutathione
S-transferase-free cortactin was used for the evaluation of
its F-actin cross-linking activity by virtue of a co-sedimentation
assay (20). To determine optimal conditions for the assay, cortactin
was incubated with F-actin for 30 min and subjected to centrifugation
at different forces from 13,000 to 30,000 × g for 10 min. Under these conditions, neither filaments in the absence of
cortactin (Fig. 1A) nor cortactin alone could
be precipitated (data not shown). However, the presence of both
cortactin and F-actin resulted in a dramatic increase in the amount of
F-actin associated with pellets in a dose-dependent manner
(Fig. 1B). The half-maximum effect requires an approximately 1:100 molecular ratio of cortactin to actin, and the maximum
sedimentation (80% of total F-actin) can be reached in the presence of
a 1:36 ratio of cortactin to actin. The sedimentation of F-actin
induced by cortactin is also correlated with the association of
cortactin with F-actin, as shown by their co-sedimentation at a ratio
of 1 cortactin molecule to approximately 15 actin subunits (Fig. 1C), which is in agreement with the stoichiometry for the
binding of cortactin to actin (14). The two bands of 85 and 90 kDa
shown on the gel most likely reflect different conformations of
cortactin, since only one band of 85 kDa was visualized when SDS-PAGE
was performed in the presence of 5 M urea (data not shown).
A kinetic study further demonstrated that cortactin-mediated F-actin
precipitation is a rapid process (Fig. 1D). Incubation with
cortactin for 2 min resulted in a sedimentation of more than 60% of
F-actin, although the maximum sedimentation (80% of total F-actin)
only occurred at 30 min after interaction. The cross-linked F-actin in
the presence of cortactin was further examined by electron microscopy
after negative staining. Filaments prepared in the absence of cortactin displayed individual single strands (Fig. 2,
A and C). In the presence of cortactin, however,
most F-actin strands became thicker and formed a bundle-like structure
(Fig. 2, B and D).
Since activities of many F-actin cross-linking proteins are dependent
on Ca2+ and pH, we examined the effects of Ca2+
and pH on the activity of cortactin. In the presence of either EGTA or
various concentrations of Ca2+, the F-actin cross-linking
activity of cortactin was not affected (data not shown). However, when
the cross-linking assay was performed at different pH values, the
optimal sedimentation of F-actin was observed in a range from pH 7.3 to
7.5. The F-actin sedimentation induced by cortactin at pH 6.9 and 8.2 is only approximately 30% of that at pH 7.4 (Fig. 3).
The apparent effect of pH on the F-actin cross-linking is not due to
its potential effect on actin polymerization, since pH has little
influence on the stable polymerization of actin (Fig. 3).
The purified cortactin can be efficiently phosphorylated by
pp60c-src exclusively at tyrosine residues in a
manner depending on time and the amount of Src. By incubating cortactin
with 500 nM pp60c-src at room
temperature for 1 h, a maximum phosphorylation of cortactin was
reached (Fig. 4A). When the phosphorylated
cortactin was used in the co-sedimentation assay, a dramatic inhibition
for the F-actin cross-linking was observed (Fig. 4B). The
treatment of cortactin with 62.5 nM
pp60c-src reduced the efficiency of F-actin
sedimentation from near 60% to approximately 38%, and that with 500 nM pp60c-src reduced further the
sedimentation of F-actin to 10%. In a control experiment where
cortactin was treated with the buffer only but in the absence of
pp60c-src, no reduction of the F-actin
cross-linking was detected (Fig. 4B).
The apparent decrease in the F-actin cross-linking was not due to a
possible inhibitory activity of pp60c-src, since
a solution in the presence of pp60c-src itself
did not have any detectable effect on F-actin cross-linking (data not
shown). Furthermore, we examined whether tyrosine phosphorylation is
essential for the inhibition of cortactin's F-actin cross-linking activity. We carried out the phosphorylation of cortactin in a kinase
buffer in the absence of Mg2+, on which the kinase activity
of pp60c-src is dependent (21). As shown in Fig.
5A, the Src-mediated tyrosine phosphorylation
of cortactin was abolished in the absence of Mg2+. When the
Src-treated cortactin in the absence of Mg2+ was mixed with
F-actin and subsequently subjected to the co-sedimentation analysis, a
significant amount of F-actin was detected in the pellet (Fig.
5B, column 4). Although the level of
sedimentation of F-actin induced by cortactin and
pp60c-src in the absence of Mg2+ was
about 33% lower than that by non-Src-treated cortactin (Fig. 5B, compare columns 2 and 4), the
lower efficiency could be the result of a trace amount of
Mg2+ present in the F-actin buffer, which may have
partially restored the kinase activity of
pp60c-src. Indeed, when Src-treated cortactin in
the absence of Mg2+ was further incubated with F-actin,
cortactin was able to be phosphorylated to the extent of approximately
25% of that in the regular kinase buffer (Fig. 5A,
column 4). Taken together, these data demonstrate that the
inhibition of the F-actin cross-linking activity of cortactin by
pp60c-src is dependent on tyrosine
phosphorylation.
Cortactin has been previously described as a potent F-actin-binding
protein (14). Therefore, we also examined the effect of
pp60c-src on its F-actin binding activity by
co-sedimentation at a high centrifugation force of 366,000 × g, at which actin filaments are able to be precipitated. As
shown in Fig. 6, the Src treatment resulted in an
inhibition of the F-actin binding activity of cortactin. However, the
efficiency of the inhibition is apparently less than that for the
F-actin cross-linking. At the concentration of 62.5 nM
pp60c-src, the co-precipitated cortactin with
F-actin was reduced only from 95 to 85%; at 500 nM
pp60c-src, 42% of cortactin was still bound to
F-actin. The moderate inhibition by pp60c-src
may be due to the existence of multiple F-actin binding sites in
cortactin, which are involved in the F-actin cross-linking activity
(30). The lower sensitivity to pp60c-src could
also be the reason for a failure to observe the inhibition of the
F-actin binding activity of cortactin in a system using lysates from
v-Src-transformed cells (14). However, we cannot rule out the
possibility that different phosphorylation sites or additional
kinase(s) may be involved in that system.
The dependence on neutral pH for the optimal cross-linking activity of
cortactin is uncommon. For example, FOOTNOTES ACKNOWLEDGEMENT We thank Nick Greco for critical
reading of the manuscript and Diana Norman for expert photographic
assistance.
REFERENCES
Volume 272, Number 21,
Issue of May 23, 1997
pp. 13911-13915
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
,,,¶ and
**
Department of Experimental Pathology, The
Holland Laboratory, American Red Cross, Rockville, Maryland 20855, the § Division of Biology, Glaxo and Welcome Research
Institute, Research Triangle Park, North Carolina 27709, and the
Departments of ¶ Pathology and 
Anatomy and Cell
Biology, The George Washington University,
Washington, D. C. 20037
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENT
REFERENCES
-helix domain and a
sequence region rich in proline residues.
-32P]ATP, 6000 ci/mmol) at room temperature for
1 h. For F-actin cross-linking analysis, phosphorylated cortactin
proteins were diluted to a final volume of 50 µl of which the final
concentrations of KCl and MgCl2 were readjusted to 134 and
2 mM, respectively. To confirm and quantitate
phosphorylated cortactin, aliquots of the reactions were combined with
an equal volume of 2 × SDS sample buffer (19) and fractionated by
SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The gel was stained
with Coomassie Blue, and the phosphorylated proteins were visualized by
autoradiography.
Fig. 1.
Sedimentation of cortactin-cross-linked
F-actin. A, pyrene-labeled filaments at a concentration of 4 µM in the presence (shaded bar) or absence
(open bar) of cortactin (400 nM) were incubated
for 30 min at room temperature and subsequently subjected to
centrifugation at different forces as indicated. Fluorescence in the
supernatant was measured, and its decrease was used as an indication of
the precipitation of F-actin. B, cortactin at different
concentrations was incubated with pyrene-labeled F-actin for 30 min
followed by centrifugation at 26,300 × g for 10 min. The F-actin cross-linking activity was determined by fluorescence measurement as described above. The value of each point represents the
mean of four independent experiments. C, the pellets from experiment B were resolved in SDS sample buffer, and aliquots of each
sample were applied to a SDS-PAGE gel. Lane 1, without cortactin; lanes 2-5, with cortactin at concentrations of
26, 53, 106, and 212 nM, respectively. The bands
corresponding to cortactin and actin are indicated. D,
pyrene-labeled F-actin at a concentration of 4 µM was
incubated with cortactin (200 nM) for the times indicated
and subsequently centrifuged at 84,000 × g for 2 min.
F-actin cross-linking was determined as described above.
[View Larger Version of this Image (36K GIF file)]
Fig. 2.
Electron microscopy of cross-linked F-actin
in the presence of cortactin. F-actin or a mixture of F-actin and
cortactin were stained with phosphotungstic acid as described under
"Experimental Procedures." A and C, filaments
only (4 µM); B and D, filaments plus cortactin (4 µM and 107 nM,
respectively). A and B have a magnification
of × 1,800; C and D have a magnification of × 20,000.
[View Larger Version of this Image (130K GIF file)]
Fig. 3.
Effects of pH on the F-actin cross-linking
activity of cortactin. Pyrene-labeled actin was polymerized at 8 µM at different pH values and incubated either with or
without cortactin (50 nM) for 30 min. Fluorescence in the
supernatant of each reaction was recorded. A lower fluorescence value
indicates a higher F-actin cross-linking.
[View Larger Version of this Image (22K GIF file)]
Fig. 4.
Effects of the amount of
pp60c-src on the F-actin cross-linking activity
of cortactin. A, cortactin was incubated with different
amounts of pp60c-src for 1 h in the
presence of [-32P]ATP. The phosphorylated cortactin
was analyzed by SDS-PAGE and visualized by autoradiography
(top). The intensity of each band was quantitated by
densitometry analysis (bottom). B, phosphorylated cortactin proteins using different concentrations of
pp60c-src (
) were analyzed for F-actin
cross-linking. As a negative control (
), cortactin was treated with
the same amounts of the buffer used for
pp60c-src (see "Experimental
Procedures").
[View Larger Version of this Image (17K GIF file)]
Fig. 5.
Src-mediated inhibition of the F-actin
cross-linking activity of cortactin is dependent on tyrosine
phosphorylation. A, cortactin (400 nM) was
incubated with pp60c-src in the presence of
[-32P]ATP in either a regular kinase buffer (with
Mg2+, open bar) or an inhibitory buffer (without
Mg2+, striated bar). Half volume of the
reactions were terminated by adding an equal amount of 2 × SDS
sample buffer (columns 1 and 2), and the other
half were further incubated with F-actin for an additional 30 min
(columns 3 and 4). All reactions were analyzed by
SDS-PAGE followed by autoradiography. The relative levels of tyrosine
phosphorylation of cortactin were determined by densitometry analysis.
B, cortactin treated with pp60c-src
in either the presence (column 3) or absence (column
4) of Mg2+ was subjected to F-actin cross-linking
analysis. Column 1, no cortactin; column 2,
cortactin without pp60c-src treatment.
[View Larger Version of this Image (13K GIF file)]
Fig. 6.
Inhibition of the F-actin binding activity of
cortactin by Src-mediated phosphorylation. Recombinant cortactin
(200 nM) was incubated with
pp60c-src at different concentrations in 20 µl
of 50 mM Tris-HCl, pH 7.4, containing 5 mM
MgCl2 and 5 mM ATP for 1 h at room
temperature. The reactions were diluted to a final volume of 50 µl,
mixed with 50 µl of 4 µM F-actin, and incubated for 30 min on ice. The mixtures were then centrifuged at 336,000 × g for 15 min. The generated supernatants and pellets were
analyzed by immunoblotting analysis with 4F11. The relative amounts of
cortactin bound to F-actin were determined by densitometry analysis
(upper panel). The value for each point represents the mean
of three independent experiments. One representative photography of
immunoblot analysis was also shown (lower panel).
[View Larger Version of this Image (18K GIF file)]
-actinin has the highest
cross-linking activity at pH 6.8 (22). Talin shows a reduced actin
cross-linking activity when pH is increased from 6.5 to 7.3, whereas
its optimal activity is at pH 6.5 (23). EF1 has high
F-actin-cross-linking activity at low pH (6.2-6.5) (24). It has been
well recognized that pH is involved in the regulation of the actin
cytoskeleton (24) and cell motility (25, 26). A recent study also
indicates that the induction of Rho on stress actin filaments is
dependent on Na+/H+ exchange (27). Since both
intracellular pH and tyrosine kinase activities are regulated by a
variety of extracellular signals (28, 29), cortactin could act as an
important mediator for ligands to regulate the cytoskeleton
reorganization.
**
To whom correspondence should be addressed: Dept. of Experimental
Pathology, The Holland Laboratory, American Red Cross, 15601 Crabbs
Branch Way, Rockville, MD 20855. Tel.: 301-738-0568; Fax: 301-738-0879.
1
The abbreviations used are: F-actin, filamentous
actin; SH3, Src homology 3; PAGE, polyacrylamide gel
electrophoresis.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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J. A. Head, D. Jiang, M. Li, L. J. Zorn, E. M. Schaefer, J. T. Parsons, and S. A. Weed Cortactin Tyrosine Phosphorylation Requires Rac1 Activity and Association with the Cortical Actin Cytoskeleton Mol. Biol. Cell, August 1, 2003; 14(8): 3216 - 3229. [Abstract] [Full Text] [PDF]
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 M. C. Martinez, T. Ochiishi, M. Majewski, and K. S. Kosik Dual regulation of neuronal morphogenesis by a {delta}-catenin-cortactin complex and Rho J. Cell Biol., July 7, 2003; 162(1): 99 - 111. [Abstract] [Full Text] [PDF]
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T. Uruno, J. Liu, Y. Li, N. Smith, and X. Zhan Sequential Interaction of Actin-related Proteins 2 and 3 (Arp2/3) Complex with Neural Wiscott-Aldrich Syndrome Protein (N-WASP) and Cortactin during Branched Actin Filament Network Formation J. Biol. Chem., July 3, 2003; 278(28): 26086 - 26093. [Abstract] [Full Text] [PDF]
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D. K. Lynch, S. C. Winata, R. J. Lyons, W. E. Hughes, G. M. Lehrbach, V. Wasinger, G. Corthals, S. Cordwell, and R. J. Daly A Cortactin-CD2-associated Protein (CD2AP) Complex Provides a Novel Link between Epidermal Growth Factor Receptor Endocytosis and the Actin Cytoskeleton J. Biol. Chem., June 6, 2003; 278(24): 21805 - 21813. [Abstract] [Full Text] [PDF]
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H. Cao, J. D. Orth, J. Chen, S. G. Weller, J. E. Heuser, and M. A. McNiven Cortactin Is a Component of Clathrin-Coated Pits and Participates in Receptor-Mediated Endocytosis Mol. Cell. Biol., March 15, 2003; 23(6): 2162 - 2170. [Abstract] [Full Text] [PDF]
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C. S. Chew, X. Chen, J. A. Parente Jr, S. Tarrer, C. Okamoto, and H.-Y. Qin Lasp-1 binds to non-muscle F-actin in vitro and is localized within multiple sites of dynamic actin assembly in vivo J. Cell Sci., March 14, 2003; 115(24): 4787 - 4799. [Abstract] [Full Text] [PDF]
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