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(Received for publication, April 14, 1995; and in revised form, June 30, 1995) From the
Integrin receptors can mediate transmembrane signaling in
response to ligand binding. To further examine the role of the integrin
The ability of integrins to function as transmembrane signaling
receptors has been well-established (reviewed in (1, 2, 3) ). This function is based on the
findings that integrin-mediated adhesion of cells to extracellular
matrix ligands or clustering of integrins with antibodies increases the
tyrosine phosphorylation of cytoplasmic proteins and alters
intracellular pH,
[Ca In this study, we addressed the question of whether the cytoplasmic
domain of the
For
immunoblot analysis of total paxillin, filters were blocked for either
1 h at room temperature or overnight at 4 °C in a 50 mM Tris buffer, pH 7.5, containing 0.15 M NaCl and 0.05%
Tween 20 (TBST) and 5% (w/v) Carnation milk. The filters were then
incubated for 2 h at room temperature in the same buffer containing the
monoclonal antibody 165 (1:20 culture supernatant). After three 10-min
washes in TBST, the filters were incubated for 1 h at room temperature
in this buffer containing 5% Carnation milk and a goat anti-mouse
antibody conjugated to horseradish peroxidase (0.5 µg/ml;
Kirkegaard and Perry). The filters were washed as before and proteins
were detected by enhanced chemiluminescence (Amersham Corp.). The
Figure 1:
Surface expression of the human
The transfected cells were either maintained in
suspension or allowed to adhere for 30 min to an EHS laminin
substratum. Cell extracts containing equivalent amounts of total
protein were analyzed for their phosphotyrosine content by
immunoblotting with the phosphotyrosine-specific mAb 4G10. As shown in Fig. 2A, identical patterns of basal phosphorylation
were observed for the
Figure 2:
Total tyrosine phosphorylation in the
P388D1 transfectants. A,
To investigate further the differences in
the tyrosine kinase signaling pathways that are activated by the
Figure 3:
Tyrosine phosphorylation of paxillin in
the
The tyrosine
phosphorylation of paxillin in neutrophils is dependent upon expression
of
Figure 4:
Tyrosine phosphorylation of paxillin in
the
One
question that arises from the results obtained is whether the
differences in morphology of the
Figure 5:
Mn
Figure 6:
Mn
Figure 7:
Mn
Our data demonstrate that integrin More emphasis should be placed on elucidating
the mechanism by which The identification of paxillin as one of the
substrates of the differential tyrosine phosphorylation induced by the
Although the The identity of the three major proteins that are
phosphorylated in response to The results obtained in this study for the
Volume 270,
Number 40,
Issue of October 06, pp. 23648-23652, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
6A
1
and
6B
1 Integrin Variants Signal Differences in the Tyrosine
Phosphorylation of Paxillin and Other Proteins (*)
subunit in these signaling functions, we assessed the
contribution of the 6 cytoplasmic domain variants to the signaling
properties of the 6
1 integrin using P388D1 cells that had
been transfected with either the 6A or the 6B cDNA. The
6A1 and 6B1 receptors induced marked quantitative
differences in the tyrosine phosphorylation of several proteins after
binding to laminin. Specifically, the 6A cytoplasmic domain was
more effective than the 6B cytoplasmic domain in inducing the
tyrosine phosphorylation of three major proteins (molecular mass, 120,
110, and 76 kDa). In addition to these proteins, we also observed that
the tyrosine phosphorylation of the cytoskeletal protein paxillin was
increased significantly more by 6A1 integrin-mediated
adhesion to laminin than by that of 6B1. This differential
pattern of tyrosine phosphorylation induction does not appear to be a
secondary event initiated by cell shape changes. Also, differences in
tyrosine phosphorylation in the 6 transfectants were not evident
in response to attachment to other substrates. These findings provide
biochemical evidence for functional differences between subunit
cytoplasmic domain variants of the same integrin.
]
, and gene
expression(1, 2, 3) . Although integrin
cytoplasmic domains do not contain intrinsic kinase motifs(4) ,
it is assumed that these domains associate either directly or
indirectly with other proteins to affect signaling functions. In this
connection, a role for
subunit cytoplasmic domains in the
activation of tyrosine kinase signaling has been reported.
Specifically, chimeric proteins containing the 1, 3, and
5 cytoplasmic domains induced the tyrosine phosphorylation of
pp125 when clustered with
antibodies(5, 6) . The ability of some but not all
1 integrin heterodimers to induce pp125 tyrosine
phosphorylation after antibody clustering suggests that the
subunit can influence the signaling capabilities of the subunit
cytoplasmic domain(7) . However, there are no data at present
that focus specifically on the role of the subunit cytoplasmic
domain in the regulation of integrin-mediated tyrosine phosphorylation. 6 subunit contributes to tyrosine kinase-mediated
signaling by the 61 integrin. This possibility was supported
by our previous functional data that demonstrated that the
6A1 and 6B1 integrin receptors, which are identical
except for the sequence of the 6 cytoplasmic
domain(8, 9) , differed in their ability to promote
cell migration on EHS (
)laminin. Cells transfected with the
6A subunit extended numerous pseudopodia and were more motile on
EHS laminin than cells transfected with the 6B
subunit(10) . We hypothesized that these differences could be
attributed to differential activation of signaling pathways by these
receptor variants. We report here that the 6A1 and
6B1 receptors induce marked quantitative differences in the
tyrosine phosphorylation of several proteins after binding to EHS
laminin. Specifically, the 6A cytoplasmic domain was much more
effective in inducing tyrosine phosphorylation of specific proteins
than the 6B cytoplasmic domain. One of these proteins has been
identified as the cytoskeletal protein paxillin(11) . Our
findings are significant because they are the first to attribute
differences in the regulation of integrin-dependent tyrosine
phosphorylation to subunit cytoplasmic domain variants.
Cells
The P388D1 mouse macrophage cell
line was obtained from the American Type Tissue Collection (Rockville,
MD). Cells were transfected with either the human 6A or 6B
cDNAs as described previously(12) . Cells were maintained in
RPMI containing 25 mM Hepes, 15% certified fetal bovine serum
(Life Technologies, Inc.), and 300 µg/ml G418 (Life Technologies,
Inc.). Transfected cells expressing equivalent levels of 6 surface
expression were obtained by fluorescence-activated cell sorting (FACS)
using the 6 specific antibody, 2B7(12) .Adhesion to Substrates
Tissue culture
plates (60 mm; Costar) were coated overnight with 4 ml of PBS
containing murine EHS laminin (30 µg/ml). EHS laminin was purified
from the Englebreth-Holm-Swarm sarcoma as described
elsewhere(13) . Plates were washed three times with PBS before
the addition of cells to remove nonadsorbed laminin. P388D1 cells were
removed from tissue culture plates by scraping and maintained in
suspension for 30 min at room temperature in either RPMI culture medium
containing 25 mM Hepes or Puck's saline A containing 25
mM Hepes and 500 µM MnCl
. After this
incubation, the cells were either maintained in suspension or added to
either EHS laminin-coated or uncoated tissue culture plastic plates and
allowed to adhere for 30 min at 37 °C. The plates were then washed
two times with RPMI to remove nonadherent cells.Cell Extraction and
Immunoprecipitation
After washing, the cells were
solubilized at 4 °C for 15 min in a 50 mM Tris buffer, pH
7.5, containing 0.15 M NaCl, 0.1% NaN
, 2 mM EDTA, 0.1 M sodium orthovanadate, 0.1% Triton X-100, 0.1%
sodium deoxycholate, 2 mM phenylmethylsulfonyl fluoride, 5
µg/ml aprotinin and pepstatin, and 50 µg/ml leupeptin. Nuclei
were removed by centrifugation at 12,000 
g for 10 min.
The protein concentration of the cell extracts was determined using the
Bio-Rad microprotein assay. Cell extracts were normalized for protein
concentration, and aliquots containing 60-200 µg of protein
were incubated overnight at 4 °C with the paxillin-specific
monoclonal antibody 165(14) . Immune complexes were recovered
with a goat anti-mouse IgG antibody conjugated to agarose beads
(Sigma). The agarose beads were added for 1 h at 4 °C with constant
agitation. The beads were washed two times with a 50 mM Tris
buffer, pH 7.5, containing 0.1% Triton X-100, 0.15 M NaCl, and
0.1 M sodium orthovanadate, two times with the same buffer
containing 0.5 M NaCl, and one time with 0.05 M Tris,
pH 6.8 containing 0.1 M sodium orthovanadate. Laemmli sample
buffer containing 5% -mercaptoethanol and 0.1 M sodium
orthovanadate was added to the samples, which were then incubated for 4
min at 100 °C. Immunoprecipitates were resolved by SDS-PAGE (8%)
and transferred to nitrocellulose filters. In addition, aliquots of
total cell extracts (5-10 µg of protein) from each condition
were resolved in a similar manner.Immunoblotting
To analyze the
phosphotyrosine content of the immunoprecipitates, the nitrocellulose
filters were blocked for 1 h at room temperature in PBS containing 3%
(w/v) Carnation dry milk. The filters were then incubated for 90 min at
room temperature in the same buffer containing the
phosphotyrosine-specific monoclonal antibody, 4G10 (1 µg/ml;
Upstate Biotechnology Incorporated, Lake Placid, NY). The filters were
washed three times for 10 min in PBS containing 0.05% Tween 20 (PBST).
The filters were then incubated for 1 h at room temperature in PBST
containing 3% (w/v) Carnation dry milk and an anti-mouse IgG antibody
conjugated to horseradish peroxidase (0.2 µg/ml; Kirkegaard and
Perry Laboratories, Inc.). After four 10-min washes in PBST, protein
was detected by enhanced chemiluminescence (Amersham Corp.).
6 integrin subunit exists as two structural
variants, 6A and 6B, that differ only in the sequence of
their cytoplasmic domains(8, 9) . Expression of these
structural variants can differentially influence the behavior of P388D1
cells upon 61-mediated adhesion to an EHS laminin
substratum(10) . In this report, we investigated the
possibility that the 6A1 and 6B1 receptors induce
either qualitative or quantitative differences in tyrosine
phosphorylation in response to laminin attachment and that such
differences contribute to the distinct functional properties of these
receptors. To compare the ability of the 6A1 and
6B1 integrin receptors to activate tyrosine kinase signaling
pathways subsequent to ligand binding, we used P388D1 cells, an
6-deficient mouse macrophage cell line, that had been transfected
with either the human 6A or 6B cDNAs(12) .
Populations of transfected cells that expressed equivalent levels of
61 on the cell surface were obtained by FACS. Expression
levels were examined frequently by flow cytometry, and only cells that
had comparable levels of surface expression were used for experiments (Fig. 1).
6A
and 6B integrin subunits in P388D1 transfectants. Populations of
transfected P388D1 cells expressing either the 6A or 6B
subunits on the cell surface were isolated by sequential FACS using
2B7, a mAb specific for the 6 integrin subunit, and then analyzed
by flow cytometry. The left-hand scan in each profile
corresponds to the mock transfectants, and the right-hand scan
corresponds to the indicated 6
transfectants.
6A-P388D1 and 6B-P388D1 cells when they
were maintained in suspension. Interestingly, after adhesion of these
cells to an EHS laminin substratum, the phosphotyrosine content of
proteins of approximately 120, 110, and 76 kDa increased markedly more
in the 6A-P388D1 cells than in the 6B-P388D1 cells (Fig. 2A). These quantitative differences in tyrosine
phosphorylation were 61-specific because similar patterns of
tyrosine phosphorylation were obtained in the 6A-P388D1 and
6B-P388D1 cells after adhesion to tissue culture plastic (Fig. 2B).
6A-P388D1 and 6B-P388D1
transfectants were maintained in suspension or allowed to adhere to an
EHS laminin substratum for 30 min. B, 6A-P388D1 and
6B-P388D1 transfectants were allowed to adhere to tissue culture
plastic for 30 min. Aliquots of total cell extracts were normalized for
protein content and resolved by 8% SDS-PAGE under reducing conditions,
transferred to nitrocellulose, and immunoblotted with the
phosphotyrosine-specific mAb, 4G10. Molecular mass markers are as
indicated. Arrows indicate proteins that have increased
phosphotyrosine content. S, suspension; L, EHS
laminin.
6A1 and 6B1 integrins, we sought to identify other
proteins that are phosphorylated on tyrosine in response to EHS laminin
attachment. The cytoskeletal protein paxillin is phosphorylated on
tyrosine in response to extracellular matrix adhesion and by growth
factor stimulation in many cell
types(15, 16, 17, 18, 19, 20, 21) .
Moreover, paxillin phosphorylation has been correlated with cell
spreading(16) . In light of the fact that the 6A-P388D1
and 6B-P388D1 transfectants adhere to EHS laminin to the same
extent but exhibit differences in their morphology(10) , we
hypothesized that this difference in cell ``spreading'' might
be a result of differential tyrosine phosphorylation of paxillin by the
6A1 and 6B1 receptors. This possibility was also
supported by the presence of a diffuse band in the phosphotyrosine blot
of total cellular protein (Fig. 2A) that approximated
the size of paxillin (molecular mass, 68 kDa). To examine this
possibility, aliquots of cell extracts containing equivalent amounts of
total protein were immunoprecipitated with the paxillin-specific
monoclonal antibody 165 (14) and then immunoblotted with 4G10.
Very little tyrosine phosphorylation of paxillin was detected when the
cells were maintained in suspension (Fig. 3A). However,
there was a substantial increase in the phosphorylation of paxillin on
tyrosine residues when the 6A-P388D1 transfectants adhered to an
EHS laminin substratum. In contrast, the increase in paxillin
phosphorylation observed for the 6B1 cells was considerably
less than that seen in the 6A1 cells. Aliquots of total
protein were also immunoblotted with the paxillin-specific antibody to
confirm that equal amounts of paxillin protein were present in all of
the cell extracts (Fig. 3B).
6A-P388D1 and 6B-P388D1 transfectants. A,
6A-P388D1 and 6B-P388D1 transfectants were maintained in
suspension or allowed to adhere to an EHS laminin substratum for 30
min. Aliquots of total cell extracts were normalized for protein
content and immunoprecipitated with the paxillin-specific mAb 165.
Immunoprecipitates were resolved by 8% SDS-PAGE, transferred to
nitrocellulose, and immunoblotted with the phosphotyrosine-specific
mAb, 4G10. B, aliquots of total cell extracts were normalized
for protein content and resolved by 8% SDS-PAGE under reducing
conditions, transferred to nitrocellulose, and immunoblotted with the
paxillin-specific mAb, 165. Molecular mass markers are as indicated. S, suspension; L, EHS
laminin.
2 integrins(16, 20) . Neutrophils that do not
express 2 integrins fail to induce the phosphorylation of paxillin
in response to adhesion or growth factor stimulation. To demonstrate
that the low level of paxillin phosphorylation in the 6B-P388D1
transfectants was not the result of differences in 2 expression,
we compared the 6A-P388D1 and 6B-P388D1 transfectants for
their ability to induce tyrosine phosphorylation of paxillin in
response to adhesion to another substrate. As shown in Fig. 4A, paxillin phosphorylation was induced in both
the 6A-P388D1 and 6B-P388D1 transfectants after adhesion to
tissue culture plastic and, more importantly, the level of paxillin
tyrosine phosphorylation was the same for both populations. In
contrast, markedly increased levels of paxillin tyrosine
phosphorylation after adhesion to EHS laminin were observed only for
the 6A-P388D1 transfectants. Therefore, the 6B-P388D1
transfectants are capable of phosphorylating paxillin to equivalent
levels as the 6A-P388D1 transfectants in response to substrates
other than EHS laminin. Similar amounts of total paxillin protein were
present in all of the cell extracts (Fig. 4B).
6A-P388D1 and 6B-P388D1 transfectants after adhesion to
either EHS laminin or tissue culture plastic. A,
6A-P388D1 and 6B-P388D1 transfectants were allowed to adhere
to either EHS laminin or tissue culture plastic for 30 min. Aliquots of
total cell extracts were normalized for protein content and
immunoprecipitated with the paxillin-specific mAb 165.
Immunoprecipitates were resolved by 8% SDS-PAGE, transferred to
nitrocellulose, and immunoblotted with the phosphotyrosine-specific mAb
4G10. B, aliquots of total cell extracts were resolved by 8%
SDS-PAGE under reducing conditions, transferred to nitrocellulose, and
immunoblotted with the paxillin-specific mAb 165. Molecular mass
markers are indicated. S, suspension; L, EHS laminin; Pl, tissue culture plastic.
6A-P388D1 and 6B-P388D1
transfectants on laminin are responsible for the observed differences
in protein tyrosine phosphorylation. This possibility derives from the
fact that the 6 transfectants exhibit quite different morphologies
on laminin in normal culture medium(10) . To resolve this
issue, the 6A- and 6B-transfectants were plated on laminin in
medium containing the divalent cation Mn. Previously,
we had observed that both populations of transfectants exhibit maximal
attachment to laminin in the presence of this cation(10) . As
shown in Fig. 5, they also exhibit a similar morphological
appearance and degree of pseudopod extension in medium containing
Mn
. However, quantitative differences in the pattern
of tyrosine phosphorylation induced by laminin attachment were similar
to those seen in normal culture medium (Fig. 6). Specifically,
the phosphotyrosine content of proteins of approximately 120, 110, and
76 kDa increased noticeably more in the
6A-P388D1 cells than in
the 6B-P388D1 cells. Importantly, the difference in paxillin
phosphorylation between these two cell populations was also evident in
response to Mn-induced laminin attachment (Fig. 7A), even though these cells expressed equivalent
amounts of paxillin protein (Fig. 7B).
-induced laminin
attachment: Morphology. The
6A-P388D1 (A) and
6B-P388D1 (B) transfectants were plated on EHS laminin in
medium containing MnCl (500 uM) for 30 min. After
washing, adherent cells were photographed using brightfield optics.
Magnification, 1000.
-induced laminin
attachment: Total tyrosine phosphorylation. The
6A-P388D1 and
6B-P388D1 transfectants were maintained in suspension or allowed
to adhere to an EHS laminin substratum in medium containing MnCl for 30 min (the same conditions used to obtain the
photomicrographs in Fig. 5). Aliquots of total cell extracts
were normalized for protein content and resolved by 8% SDS-PAGE under
reducing conditions, transferred to nitrocellulose, and immunoblotted
with the phosphotyrosine-specific mAb 4G10. Molecular mass markers are
as indicated. Arrows indicate proteins that have increased
phosphotyrosine content. S, suspension; L, EHS
laminin.
-induced laminin
attachment: Paxillin phosphorylation. The
6A-P388D1 and
6B-P388D1 transfectants were maintained in suspension or allowed
to adhere to an EHS laminin substratum in medium containing MnCl for 30 min (the same conditions used to obtain the
photomicrographs in Fig. 5). A, aliquots of total cell
extracts were normalized for protein content and immunoprecipitated
with the paxillin-specific mAb 165. Immunoprecipitates were resolved by
8% SDS-PAGE, transferred to nitrocellulose, and immunoblotted with the
phosphotyrosine-specific mAb 4G10. B, aliquots of total cell
extracts were normalized for protein content, resolved by 8% SDS-PAGE
under reducing conditions, transferred to nitrocellulose, and
immunoblotted with the paxillin-specific mAb 165. Molecular mass
markers are as indicated. S, suspension; L, EHS
laminin.
subunit cytoplasmic
domain variants can differentially influence the activation of tyrosine
kinase signaling pathways by an integrin receptor. Previous studies had
demonstrated the importance of the subunit in regulating tyrosine
phosphorylation. For example, chimeric molecules comprised of the
extracellular and transmembrane domains of the interleukin-2 receptor
and subunit cytoplasmic domains were capable of phosphorylating
pp125 after clustering with
antibodies(5, 6) . This finding suggested that these
domains contain the information that is necessary for linking signaling
proteins to integrin receptors. A role for integrin
subunits in
influencing integrin-mediated signaling of tyrosine phosphorylation was
suggested by a report that antibody clustering of the 31
integrin but not the 21, 51, and 61
integrins resulted in tyrosine phosphorylation of
pp125(7) . However, no studies to date have
addressed the specific role of the
subunit cytoplasmic domain in
this regulation. In this regard, several functional studies have
provided data that indicate that the subunit cytoplasmic domain
is important for influencing integrin
signaling.(10, 22) . The data presented here provide
biochemical evidence for such an involvement. Moreover, a recent
finding that the 6A1 and 6B1 integrins exhibit
different properties on size fractionation columns supports the
possibility that these receptors associate with distinct complexes of
proteins(23) . subunits influence tyrosine kinase
activity. The 6 cytoplasmic domains could interact directly with
tyrosine kinases and modulate activity through such associations.
Alternatively, the 6 cytoplasmic domain variants could function
indirectly by modulating the interactions of the subunit
cytoplasmic domain with signaling components. The latter possibility is
supported by the fact that the cytoplasmic domains of integrin
subunits can influence receptor activities that have been shown to be
dependent upon the subunit cytoplasmic domain. For example, the
cytoplasmic domain of the subunit is required for receptor
localization to cell substratum attachment sites, but the subunit
cytoplasmic domain can determine the type of adhesive structure that is
formed (i.e. focal adhesion, point contact, or
podosome)(24) .6 structural variants is intriguing in light of the known
properties of this protein. Paxillin is a cytoskeletal protein that is
localized to sites of cell substratum attachment such as focal
adhesions(14) . In in vitro binding experiments,
paxillin associates with the cytoskeletal protein
vinculin(14, 25) . More recently, it has been shown
that tyrosine-phosphorylated paxillin can also interact with components
of the cellular signaling machinery such as pp125,
p47
, Csk, and pp60
, presumably by
binding to the SH2 and SH3 domains of these
proteins(25, 26, 27, 28) . These
interactions implicate a role for paxillin in organizing the downstream
signaling complexes that are required for integrin signaling. One issue
that arises in this context is whether quantitative differences in
paxillin phosphorylation could contribute to the functional differences
observed between the
6A1 and 6B1 transfectants such
as migration. Cell migration is a complex and dynamic process that most
likely requires cycles of phosphorylation and dephosphorylation of
cellular components(29) . The increased tyrosine
phosphorylation of paxillin in the cells that express the 6A1
integrin could enhance the recruitment of signaling molecules necessary
for regulating such dynamic events.6A- and
6B-transfectants exhibit markedly different morphologies on
laminin(10) , the results obtained in this study indicate that
the observed differences in the induction of tyrosine phosphorylation
between these cells are not dependent upon cell shape. When these cells
were allowed to adhere to laminin in the presence of
Mn, they exhibited similar morphologies, but the
6A cells still yielded significantly more phosphorylation of
paxillin and other proteins than the 6B cells. We conclude from
these data that these two integrin isoforms differ in their intrinsic
ability to activate tyrosine kinase signaling and that this induction
of tyrosine phosphorylation is not a secondary event initiated by cell
shape changes.6A1-mediated adhesion to
laminin is being investigated. Although the size of the 120-kDa protein
is indicative of pp125, we have shown that these cells
express very low levels of this kinase. (
)This finding
agrees with the previous report that monocytes and macrophages express
little if any pp125(30) . For this reason, it is
unlikely that pp125
is the sole kinase responsible for
the increased tyrosine phosphorylation induced by the
6A1
integrin. However, additional pp125 family members have
been identified in hematopoietic cells, and these related kinases could
contribute to integrin signaling in P388D1
cells(30, 31) . The 76-kDa protein may be the same
protein that was recently reported to be the major protein that is
phosphorylated on tyrosine residues in response to monocyte attachment
to tissue culture plastic and several extracellular matrix
substrates(32) .
6 subunit may be relevant for other integrin subunits that
have cytoplasmic domain variants (4) . Although the existence
of alternately spliced forms of integrin subunits has been known for
some time, their functional significance is just beginning to be
understood. Subsequent work should focus on the mechanisms by which the
cytoplasmic domains of these variants exert differences in the
activation of specific integrin-mediated signaling pathways.
))
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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S Tavella, G Bellese, P Castagnola, I Martin, D Piccini, R Doliana, A Colombatti, R Cancedda, and C Tacchetti Regulated expression of fibronectin, laminin and related integrin receptors during the early chondrocyte differentiation J. Cell Sci., January 9, 1997; 110(18): 2261 - 2270. [Abstract] [PDF]
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M Falk, K Salmivirta, M Durbeej, E Larsson, M Ekblom, D Vestweber, and P Ekblom Integrin alpha 6B beta 1 is involved in kidney tubulogenesis in vitro J. Cell Sci., January 12, 1996; 109(12): 2801 - 2810. [Abstract] [PDF]
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