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Tumor Biology |
Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, Rockville, Maryland 20850 [P. B., W. G. A., P. N., J. T., L. M. N.]; Oncology and Hematology Branch, Clinic of Pediatrics, University of Padova, Padova 35128, Italy [P. B., A. R.]; Institut Municipal d’Investigacio Medica, Universitat Pompeu Fabra, Barcelona 08003, Spain [G. H.]; and Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Bellaterra 08193, Spain [M. D.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-catenin
(7, 8, 9, 10, 11)
. ß-catenin-E-cadherin association is critically
important for the maintenance of tight cell-cell contacts (12
, 13)
. When released from E-cadherin, uncomplexed ß-catenin is
rapidly degraded by cytosolic proteasomes (14
, 15)
.
Failure to properly degrade ß -catenin, primarily attributable to an
impairment in its ubiquitination, results in ß-catenin accumulation
and migration to the nucleus where, via interaction with the Tcf/Lef
family of transcription factors, it can up-regulate transcription of a
number of growth-promoting genes, including c-myc and
cyclin D (16, 17, 18, 19)
. In a large number of
cancers, including colon carcinoma and melanoma, proteasomal
degradation of cytoplasmic ß-catenin is subverted, either by mutation
of a
GSK-3ß2
phosphorylation site in the amino terminus of ß-catenin or by
deletion of the APC ß-catenin-binding protein (20, 21, 22)
.
The resultant nuclear accumulation of ß-catenin is thought to play a
pivotal role in tumor progression (23, 24, 25, 26, 27)
. Although many studies have focused on mechanisms that abrogate the proteasome sensitivity of uncomplexed cytoplasmic ß-catenin in tumor cells, less attention has been paid to the status and regulation of ß-catenin-E-cadherin association in cells that either express GSK-3ß-resistant ß-catenin or lack the APC protein. In normal epithelial cells, association of the cadherin-catenin complex with the cytoskeleton is essential for maintenance of functional epithelial tissues (28) , but dynamic regulation of this complex is necessary for the epithelial migration characteristic of embryogenesis and wound healing (29) . ß-catenin-E-cadherin association/dissociation seems to be regulated, at least in part, by tyrosine phosphorylation/dephosphorylation of ß-catenin (28) , inasmuch as tyrosine phosphorylated ß-catenin associates poorly, if at all, with E-cadherin (30) . During normal epithelial migration, ß-catenin has been shown to accumulate in the cytoplasm in a free, tyrosine-phosphorylated form concomitant with increased nuclear localization of ß-catenin (28 , 31 , 32) . In contrast, in confluent cells, ß-catenin is found primarily in a tyrosine-dephosphorylated form and in complex with E-cadherin. Because the loss of ß-catenin-E-cadherin association correlates directly with tumor invasion and metastasis, a second level of ß-catenin deregulation in tumor cells, particularly in situations where ß-catenin degradation is already compromised, might result from an imbalance in the tyrosine phosphorylation state of ß-catenin (33) .
In a recent report, ErbB2 (Her2/Neu) tyrosine kinase overexpression was
observed in 40% of cutaneous malignant melanomas and in 80% of
metastasized malignant melanomas (34)
, whereas a second
study found ErbB2 protein to be overexpressed in four of five melanoma
cell lines (35)
. Interestingly, ErbB2 as well as several
transmembrane tyrosine phosphatases, including PTPµ, PTP
, PTP
,
and LAR, have been found to be associated with ß-catenin-E-cadherin
complexes in epithelial cells, suggesting opposing roles for these
proteins in modulating ß-catenin-E-cadherin association (28
, 36, 37, 38, 39, 40, 41, 42)
. ErbB2 interacts with the carboxyl terminus of
ß-catenin, at a site containing Tyr-654 (43)
. Recently,
Roura et al. (30)
reported that the Tyr-654
residue of ß-catenin is preferentially phosphorylated under
conditions that disrupt ß-catenin-E-cadherin association.
Furthermore, these investigators observed that a Tyr-654Phe (Y654F)
point mutant, which mimics an unphosphorylated tyrosine residue, bound
E-cadherin in vitro with an affinity similar to that of
wild-type ß-catenin, whereas a Tyr-654Glu (Y654E) point mutant, whose
negative charge mimics a phosphorylated tyrosine residue, bound
E-cadherin with less than one-tenth the affinity of wild-type
ß-catenin. Thus, it is reasonable to conclude that the
phosphorylation status of the Tyr-654 residue of ß-catenin, contained
within an ErbB2-binding domain, regulates ß-catenin association with
E-cadherin.
Preliminary characterization of the three melanoma cell lines used in this study demonstrated constitutive expression of both ErbB2 and LAR. Here, we have examined the tyrosine phosphorylation state of ß-catenin and its association with E-cadherin, ErbB2, and LAR in these cell lines. These cell lines were chosen for study because one, 1011, expresses ß-catenin, which is recognized and degraded normally by cytosolic proteasomes. Another, 928, expresses wild-type ß-catenin but lacks the APC protein. A third cell line, 1241, expresses APC but contains ß-catenin whose GSK-3ß amino terminal phosphorylation site is mutated (Ser-37Phe). In the latter two cell lines, uncomplexed ß-catenin is not degraded efficiently by the proteasome and accumulates to high levels in both cytoplasm and nucleus, whereas in 1011 cells the ß-catenin steady-state level is low because of rapid proteasome-mediated degradation of uncomplexed ß-catenin (22 , 44) . We used GA, a drug which efficiently stimulates the proteasome-mediated degradation of ErbB2 (45 , 46) , to assess its effects on the tyrosine phosphorylation state of ß-catenin, on the association of both LAR and E-cadherin with ß-catenin, and on ß-catenin-sensitive transcriptional activity. Finally, we transiently transfected 1241 melanoma cells with the ß-catenin point mutants Y654F and Y654E to confirm that our findings with GA are attributable to the altered tyrosine phosphorylation status of ß-catenin. Our data demonstrate the importance of tyrosine phosphorylation in regulating ß-catenin activity in melanoma cells regardless of whether these cells express proteasome-sensitive or -insensitive ß-catenin.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture.
The melanoma cell lines 1011, 928, and 1241 (obtained from Mona
El-Gamil and Paul Robbins, NIH, Bethesda, MD) were maintained in
RPMI 1640 containing 5% bovine calf serum, 2 mM
L-glutamine, and 10 mM HEPES (pH 7.5) under
standard tissue-culture conditions.
Immunoprecipitation and Immunoblotting.
Cells were washed twice in ice-cold PBS and incubated with
ice-cold Triton X-100 lysis buffer [Tris-HCl (pH 8), 20
mM; Triton X-100, 1%; NaCl, 140 mM; Glycerol,
10%; EGTA, 1 mM; MgCl2, 1.5
mM; DTT, 1 mM; sodium vanadate, 1
mM; and NaF, 50 mM] containing 1
mM phenylmethylsulfonyl fluoride, 20 µg/ml
leupeptin, and 20 µg/ml aprotinin. Cells were scraped after 15 min,
and cell lysates were clarified by centrifugation (at 4°C) at
14,000 x g for 30 min. Immunoprecipitations
from cell lysates, SDS-PAGE, electrotransfer, and immunoblotting were
carried out as described previously. Proteins were visualized by
chemiluminescence using a commercial kit (Pierce). X-OMAT AR films
(Kodak) were scanned into a computer, and the images were quantified
using image analysis software (NIH Image).
To analyze ß-catenin in cytosolic and nuclear fractions, intact nuclei were prepared from exponentially growing 928, 1011, and 1241 cells by scraping cells into nuclei isolation buffer (100 mM NaCl, 10 mM Tris-HCl, 5 mM sodium butyrate, 10 mM iodoacetamide, 0.1% NP-40, and phosphatase inhibitors, as described above). Cell suspensions were gently homogenized in an ice-cold glass homogenizer. A cytosolic fraction (supernatant) was separated from intact nuclei by low-speed centrifugation at 4°C. To obtain final cytosolic fractions, these low-speed supernatants were subjected to high-speed centrifugation, and supernatants were isolated again. Intact nuclei, observed by staining with trypan blue, were then lysed in nuclei-isolation buffer supplemented with 1% Triton X-100. Aliquots of these samples were fractionated by 10% SDS-PAGE, electrotransferred to nitrocellulose membranes, and analyzed by Western blotting.
Immunofluorescence of ErbB2 and LAR.
Melanoma cells (928) were grown on coverslips and exposed to GA
(1 µM) for 14 h or left untreated. After being
rinsed in PBS, cells were fixed in 3.7% formaldehyde in PBS and
permeabilized with 0.2% Triton X-100. LAR and ErbB2 were visualized by
immunofluorescence as described previously (47)
. The
DNA-intercalating dye DAPI was used to identify cell nuclei.
Transient Transfections.
To determine specific effects of nuclear accumulation of ß-catenin on
Tcf/Lef-dependent transcription, melanoma cells were transiently
transfected with the reporter constructs pTOPFLASH and
pFOPFLASH, which contain, respectively, three copies of the
optimal (CCTTTGATC) or mutant (CCTTTGGCC) Tcf-binding motif upstream of
a minimal c-Fos promoter-driving luciferase expression. A second
Tcf/Lef-responsive reporter plasmid, 7Lef-fosLuc, was also used. For
the transient transfection experiment shown in Fig. 4D
, 1
µg of the reporter was transfected into 928 or 1241 cells
(1 x 106 cells for each cell
line) using lipofectamine, according to manufacturer’s instructions
(Life Technologies, Inc.). To avoid nonspecific, drug-dependent effects
on luciferase expression, we performed a DUAL-Luciferase reporter assay
(Promega). A control reporter, pRL-TK (0.5 µg), which contains a
herpes simplex virus thymidine kinase promoter driving a Renilla
luciferase gene, was cotransfected with the ß-catenin-specific
luciferase constructs, and Renilla luciferase activity was used
to normalize the results. After 24 h, cells were lysed in Triton
X-100 lysis buffer and luciferase activity was monitored in 30 µg of
cell lysate using luciferase assay reagents as described by
the manufacturer (Promega). ß-catenin(Y654F) and
ßcatenin(Y654E) have been described previously
(30)
. Cells (293 and 1241) were transfected as
above and as described in the legend to Fig. 6
.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Unlike normal epithelial cells, which must be treated with
phosphatase inhibitors to detect tyrosine phosphorylated ß-catenin
(28)
, the three melanoma cell lines contained readily
detectable tyrosine phosphorylated ß-catenin in the absence of
phosphatase inhibition (Fig. 1A
, Lane 1). After
exposure to GA, the level of tyrosine phosphorylated ß-catenin
declined markedly without any overall change in the ß-catenin
steady-state level (Fig. 1, A and C)
. The amount
of ß-catenin coimmunoprecipitated with E-cadherin dramatically
increased as the proportion of tyrosine phosphorylated ß-catenin
declined (Fig. 1B)
, although total E-cadherin levels
remained unchanged (Fig. 1D)
. Mutated (S37F) and wild-type
ß-catenin responded similarly; APC status also did not affect the
results. Thus, abrogation of ß-catenin tyrosine
phosphorylation markedly enhances ß-catenin-E-cadherin association
even when ß-catenin is resistant to proteasome degradation.
The Tyrosine Kinase ErbB2 and the Tyrosine Phosphatase LAR
Associate with ß-Catenin in Melanoma Cells.
Cells (928, 1241, and 1011) were treated with 0.5
µM GA for 12 h, lysed in Triton X-100 lysis buffer,
and immunoprecipitated with antibodies specific for ErbB2, LAR, or HA
(negative control). After SDS-PAGE of immunoprecipitates, immunoblots
were probed for ß-catenin (Fig. 2, A–C)
. Duplicate lysates were immunoblotted for ErbB2 (Fig. 2D)
, or immunoprecipitated/immunoblotted for LAR (Fig. 2E)
. In untreated cells, ß-catenin was readily
coimmunoprecipitated with both ErbB2 and LAR, and this was independent
of ß-catenin mutation or APC status. However, after GA treatment,
ß-catenin could no longer be coimmunoprecipitated with ErbB2, whereas
its association with LAR was unaffected (Fig. 2, A and B)
. Because GA is known to rapidly deplete ErbB2 via
stimulation of its proteasome-dependent degradation (46)
,
we examined whether the apparent loss of association of ß-catenin
with ErbB2 after GA treatment was attributable to depletion of ErbB2
from the cells. As can be seen in Fig. 2D
, GA caused
essentially complete loss of ErbB2 from all three melanoma cell lines
without affecting LAR protein levels (Fig. 2E)
. These
results were confirmed by immunofluorescence analysis of ErbB2 and LAR
proteins in 928 cells treated with GA (Fig. 3)
. The loss of ErbB2 after exposure of the melanoma cells to GA, without
perturbation of either the LAR protein level or its association with
ß-catenin, is consistent with GA-induced tyrosine dephosphorylation
of ß-catenin, as seen in Fig. 1
.
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. GA specifically and significantly inhibited both Topflash
and 7LEF-fosLuc reporters in both 928 and 1241 cells. At the same time,
ß-catenin immunoblots of intact nuclei revealed a decrease in nuclear
ß-catenin content after GA treatment (Fig. 4A)
. To examine
the effects of GA on an endogenous protein whose transcription is
stimulated by ß-catenin, we monitored the effects of GA on cyclin D
protein levels in 928 and 1241 cells (Fig. 4B)
. Cyclin D
protein disappeared from these cells, but was unaffected in 1011 cells,
after GA. Thus the sensitivity of cyclin D to GA is observed only in
those melanoma cells that contain transcriptionally active ß-catenin.
Next, we wished to determine whether the loss of cyclin D protein after
GA was mediated at a pretranslational level. We monitored cyclin
D-specific mRNA in 928 and 1241 cells before and after GA treatment,
and we observed that the message for cyclin D completely
disappeared in GA-treated cells (Fig. 4C)
. Thus, in two
melanoma cell lines with constitutive ß-catenin-stimulated
transcription, as measured by two different reporter plasmids and the
endogenous ß-catenin-sensitive cyclin D gene, GA markedly
inhibited ß-catenin-driven transcription.
GA Inhibits Melanoma Cell Motility.
Because the abundance of membrane-associated ß-catenin-E-cadherin
complexes is inversely related to cell motility (28)
, we
wished to determine whether GA reduced the motility of 928 and 1241
melanoma cells in vitro. When added to a 48-h in
vitro motility assay, GA at 0.5 µM
almost completely abolished motility in both cell lines without
affecting cell viability as assessed by trypan blue staining (Fig. 5)
. These results are consistent with the increased association of
ß-catenin and E-cadherin seen after GA treatment.
|
. Endogenous E-cadherin was coimmunoprecipitated with
ß-catenin(Y654F) but not with ß-catenin(Y654E), although the Y654E
ß-catenin mutant was expressed at a somewhat higher level in 1241
cells. Importantly, GA had no effect on E-cadherin association with
either ß-catenin point mutant, nor did GA alter the tyrosine
phosphorylation of either mutant.
Transcriptional Activity of Transiently Transfected ß-Catenin
Point Mutants Y654E and Y654F.
To examine further whether the inhibition by GA of
ß-catenin-stimulated transcription can be directly attributed to its
effect on the tyrosine phosphorylation status of ß-catenin, we
transiently transfected each ß-catenin point mutant into 293 cells
together with either Topflash or Fopflash reporter plasmids, and we
determined ß-catenin-sensitive reporter activity 24 h after
transfection. Both ß-catenin point mutants were transcriptionally
active, and, importantly, GA did not affect their activity (Fig. 6B)
. However, the transcriptional activity of
ß-catenin(Y654F) in 293 cells was twice as sensitive to
cotransfection of E-cadherin as was the transcriptional activity of
ß-catenin(Y654E) (37% versus 76% of control activity,
Fig. 6C
).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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GA rapidly depletes ErbB2 protein from cells by stimulating its proteasome-dependent degradation, and we observed in this study that GA efficiently abrogated the tyrosine phosphorylation of ß-catenin coincident with the loss of ErbB2 from the treated cells without affecting either the ß-catenin steady-state level or its association with LAR. In GA-treated cells, association of tyrosine dephosphorylated ß-catenin with E-cadherin was enhanced, and this occurred concurrently with dramatically reduced cell motility. Similar results have been obtained by transfecting tumor cells with LAR (28) . In cells that overexpressed ectopic LAR, ß-catenin tyrosine phosphorylation was abrogated and the free pool of cytoplasmic ß-catenin was decreased, whereas ß-catenin association with E-cadherin was increased, and cell motility in response to growth factors was markedly reduced. Our data suggest that, like overexpression of LAR, pharmacological depletion of ErbB2 shifts the balance of the tyrosine phosphorylation/dephosphorylation of ß-catenin in favor of the latter. Because the Tyr-654 residue of ß-catenin is contained within its ErbB2-binding domain (43) , we confirmed the data obtained with GA by transiently transfecting 1241 cells with two ß-catenin point mutants mimicking the phosphorylated (Y654E) and dephosphorylated (Y654F) states of Tyr-654, respectively. As predicted, endogenous E-cadherin was efficiently coprecipitated with ß-catenin(Y654F) but not with ß-catenin(Y654E).
Although the Tyr-86 residue of ß-catenin can be phosphorylated by pp60c-src in vitro, this site appears not to be heavily phosphorylated in vivo, nor does its phosphorylation state influence ß-catenin association with E-cadherin (30) . In the current experiments, minimal tyrosine phosphorylation was observed when transiently transfected Tyr-654 point mutants were examined, suggesting that Tyr-654 is the principal ß-catenin tyrosine phosphorylation site in these melanoma cell lines. However, GA did not affect residual tyrosine phosphorylation of either Tyr-654 mutant, further implicating the destabilizing effects of GA on ErbB2 in mediating the drug’s inhibition of ß-catenin tyrosine phosphorylation.
By disrupting contact with E-cadherin, tyrosine phosphorylation of ß-catenin has been shown to lead to an increase in the free, uncomplexed cytoplasmic pool of the protein as well as to its subsequent nuclear accumulation (28) . Reversal of ß-catenin tyrosine phosphorylation by GA was accompanied by a reduction in both nuclear ß-catenin content and ß-catenin-sensitive transcriptional activity, as measured using two independent reporter constructs as well as the endogenous cyclin D gene. Although we cannot exclude the possibility that the effects of GA on ß-catenin-sensitive transcription might be mediated by alternative mechanisms not involving ß-catenin, four observations support a more direct role for ß-catenin in this process. First, the transcriptional activity of cotransfected Renilla luciferase was not significantly affected by GA. Second, GA only affected cyclin D levels in the two cell lines (928 and 1241) harboring stabilized ß-catenin and displaying significant ß-catenin-sensitive transcriptional activity. In the third cell line (1011), GA had no effect on cyclin D (although the activity of the drug in these cells was confirmed by depletion of ErbB2). Third, GA caused the loss of cyclin D mRNA as well as of cyclin D protein in the ß-catenin-overexpressing cell lines. In contrast, in cell lines which neither express aberrantly stabilized ß-catenin nor demonstrate constitutive ß-catenin-sensitive transcriptional activity, the effects of a closely related GA-derivative, herbimycin A, on cyclin D were shown conclusively to be posttranslationally mediated (48) . Lastly, GA did not affect the transcriptional activity of either Tyr-654 point mutant transiently transfected into 293 cells, suggesting that ability of GA to alter ß-catenin-stimulated transcription is mediated by its indirect but specific effect on the state of ß-catenin tyrosine phosphorylation at residue 654.
In cells that are able to degrade efficiently uncomplexed cytoplasmic ß-catenin, deregulation of ß-catenin tyrosine phosphorylation may not cause an elevation in the cytoplasmic free pool of the protein, but the lack of association of ß-catenin with E-cadherin in such cells would still result in enhanced motility and decreased cell-cell contacts. In support of this possibility, tyrosine phosphorylation of ß-catenin has been reported to correlate with carcinoma formation and tumor invasiveness (33) . In cells unable to efficiently degrade free cytoplasmic ß-catenin, increased tyrosine phosphorylation of the protein should augment the level of the free pool and result in the increased nuclear accumulation of ß-catenin. Thus, pharmacological abrogation of ß-catenin tyrosine phosphorylation, even in cells expressing aberrantly stable ß-catenin, may antagonize the tumorpromoting activity of nuclear-localized ß-catenin while simultaneously enhancing the tumor suppressive activity of plasma membrane ß-catenin-E-cadherin complexes. These results may be of particular relevance to the clinical utility of GA, inasmuch as a GA derivative is currently undergoing a multi-institution Phase I clinical trial in cancer patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at: 9610 Medical Center Drive, Suite 300, Rockville, MD
20850. Phone: (301) 402-3128, extension 318; Fax: (301) 402-4422;
E-mail: len{at}helix.nih.gov 
2 The abbreviations used are: GSK-3ß, glycogen
synthase kinase-3ß; APC, adenomatous polyposis coli; GA,
geldanamycin; HA, hemaglutinin.
3 A. G. de Herreros and M. Dunach,
unpublished observations.
Received 6/27/00. Accepted 12/12/00.
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,
-E-cadherin; 
, +E-cadherin.
