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Molecular and Cellular Biology, September 2001, p. 5857-5868, Vol. 21, No. 17
Laboratory of Immunobiology, National Cancer
Institute, Frederick Cancer Research and Development Center, Fort
Detrick, Frederick, Maryland 21702,1 and
Neuromuscular Division, Department of Neurology, Johns
Hopkins University, School of Medicine, Baltimore, Maryland
212312
Received 2 November 2000/Returned for modification 26 December
2000/Accepted 8 June 2001
Increased cellular The MET receptor tyrosine kinase (RTK) family contains three members:
MET (17, 34, 81), RON (89), and c-Sea
(42) (Sea may be a chicken RON orthologue). MET is the
receptor for hepatocyte growth factor (HGF) (10). MET is
expressed in a number of cell types, including epithelial cells
(23, 105), endothelial cells (13, 35),
myoblasts (2), spinal motor neurons (27), and
hematopoietic cells (30, 74). Interaction of HGF with MET
activates multiple intracellular signaling pathways involved in muscle
and liver formation (32, 62, 97), cell proliferation (64, 73, 91), morphogenesis (66), and
motility (105, 106). In addition to regulation of normal
cell functions, MET is implicated in development and progression of a
number of tumors. Increased MET expression has been found in papillary
carcinomas of the thyroid gland; carcinomas of colon, pancreas, and
ovary; and osteogenic sarcomas (23-25, 28, 33, 50). Point
mutations in the MET kinase domain have been identified in hereditary
and sporadic papillary renal carcinomas (98, 99).
RON, the receptor for macrophage-stimulating protein (MSP, also known
as HGF-like protein) (115), is another member of the MET
RTK family sharing many common features with MET (89). RON is expressed in different cell types, including macrophages
(47), epithelial cells (113, 114),
osteoclasts (59), and hematopoietic cells, such as
erythroid and myeloid progenitor cells (48) and bone
marrow megakaryocytes (3). Ligand-stimulated RON activates the pathways regulating cell adhesion and motility, growth, and survival (20, 21). Recent investigations have shown that
activated RON is expressed in human primary breast carcinomas
(61) and in a number of cancer cell lines that are removed
from the host tissue environment (15, 31). Truncated RON
confers susceptibility to Friend virus-induced erythroleukemia in mice
(83), and the avian oncogene v-sea, which is
highly homologous to RON, causes erythroblastosis in chickens
(104). Although RON has not yet been implicated as a cause
of any human neoplasm, the above data indicate its oncogenic potential.
Activating mutations in growth factor RTKs may result in oncogenic cell
transformation and tumor development. A number of human neoplastic
syndromes are associated with activating point mutations in a highly
conserved region of the tyrosine kinase domains of the KIT, RET, and
MET receptors (98). Mutation of aspartic acid at
position 816 (D816V) in the KIT receptor causes mast cell leukemia and
mastocytosis (71, 110). Substitution of a threonine for
methionine in RET (M918T) and in MET (M1268T) receptors is associated
with multiple endocrine neoplasia (93) and renal papillary
carcinoma (98), respectively. Experimental mutations in
the conserved region of the RON kinase domain (D1232V, KIT type;
M1254T, RET/MET type) result in a tumorigenic phenotype (95,
117).
In the present work we show that expression of tumorigenic RON (M1254T
and D1232V) or MET (M1268T) mutants causes cellular accumulation of
Antibodies.
RON receptor was immunoprecipitated
from cell lysates by using mouse monoclonal anti-RON antibodies (clone
ID2; a gift from F. Montero-Julian) (65). Rabbit anti-RON
antibodies (C-20; Santa Cruz, Santa Cruz, Calif.) were used for Western
blotting. Protein tyrosine phosphorylation was detected by Western
blotting using antiphosphotyrosine (anti-PY) antibodies (clone 4G10;
UBI, Lake Placid, N.Y.). Rabbit anti-C-terminal Site-directed mutagenesis of RON receptor.
M1254T and D1232V
RON mutants were generated using the GeneEditor (Promega) mutagenesis
kit with mutagenesis oligonucleotides described earlier
(95).
Cells and transfections.
MDCK and NIH 3T3 cells (purchased
from the American Type Culture Collection (Manassas, Va.) were grown in
Dulbecco modified Eagle medium (DMEM) with 10% fetal calf serum
(FCS). For stable expression of RON, cells in 10-cm-diameter dishes
were transfected with 10 µg of RON cDNA by Superfect reagent (Qiagen,
Santa Clarita, Calif.) and were placed in medium with 500 µg of
Geneticin (Life Technologies, Inc.). RON expression was measured by
Western blotting with anti-RON antibodies (Santa Cruz) in total cell
lysates as well as in RON immunoprecipitates (IPs). NIH 3T3 cells
expressing MET WT or M1268T mutant used in this work have been
previously described (51, 72).
Cell stimulation.
Cells were incubated overnight in medium
without serum and were then collected from dishes and stimulated with 5 nM MSP for 15 min. Cells incubated in medium alone served as a control.
For some experiments cells were pretreated with 1 mM sodium pervanadate (PV) for 15 min, after which PV was removed by changing culture medium
after cell centrifugation. The PV solution was prepared as previously
described (85). PV-pretreated cells were used for
subsequent stimulation. To inhibit proteasomal protein degradation, cells were incubated with 25 µM
N-acetyl-Leu-Leu-norleucinal (ALLN) for 6 h.
Cell lysis, immunoprecipitation, and Western blotting.
After
stimulation, cells were lysed in lysis buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 10% glycerol, 1 mM EDTA, 1 mM sodium orthovanadate, 10 mM
sodium pyrophosphate, 100 mM NaF, 1% Triton X-100, 10 µg of
leupeptin/ml, 10 U of aprotinin/ml, and 1 mM phenylmethylsulfonyl fluoride). Cell lysates were immunoprecipitated or were used directly for detection of proteins by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE) and Western blotting.
RON kinase assay in vitro.
RON was immunoprecipitated from
cell lysates by RON antibodies. IPs were washed twice in HNTG buffer
(50 mM HEPES, pH 7.4, 150 mM NaCl, 0.1% Triton X-100, and 10%
glycerol) and twice in kinase buffer (20 mM HEPES, pH 7.4, 10%
glycerol, 10 mM MgCl2, 10 mM
MnCl2, and 150 mM NaCl). To initiate kinase
reactions, 15 µCi of [ RON phosphorylation of Pulse-chase analysis of Luciferase assay.
The reporter plasmids 3× WT
Tcf-binding site (TOPFLASH) and 3× mutated Tcf-binding site
(FOPFLASH) were from Promega. Adenoviral constructs containing
Cell infection with adenoviral constructs and detection of cyclin
D1 and c-myc expression.
NIH 3T3 cells expressing
MET WT or M1268T mutant or MDCK cells expressing RON WT or M1254T
mutant were infected with adenovirus encoding Focus-forming assay.
A focus-forming assay was performed as
described (29). Briefly, NIH 3T3 cells stably expressing
RON WT or RON M1254T or MET WT or MET M1268T were transfected by
Superfect reagent (Qiagen) with 2 µg of pMSCVpuro vector (Clontech,
Palo Alto, Calif.) carrying enhanced green fluorescent protein (EGFP)
as a control or the kinase-dead RON (RONkd) gene in a six-well tissue
culture plate. RONkd (K1114 M) was generated using the GeneEditor
(Promega) mutagenesis kit as described previously (22).
Two days later cells were split and placed in DMEM containing 10% FCS,
500 µg of Geneticin (Life Technologies, Inc.), and 1 µg of
puromycin (Clontech)/ml. Transfected cells were used for the
focus-forming assay and for Western blotting 3 weeks after transfection.
RON mutants induce constitutive phosphorylation of
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.17.5857-5868.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Oncogenic Mutants of RON and MET Receptor Tyrosine
Kinases Cause Activation of the
-Catenin Pathway
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
-Catenin is an oncogenic protein involved in regulation of
cell-cell adhesion and gene expression. Accumulation of cellular -catenin occurs in many types of human cancers. Four mechanisms are
known to cause increases in -catenin: mutations of -catenin, adenomatous polyposis coli, or axin genes and activation of Wnt signaling. We report a new cause of -catenin accumulation involving oncogenic mutants of RON and MET receptor tyrosine kinases (RTKs). Cells transfected with oncogenic RON or MET were characterized by
-catenin tyrosine phosphorylation and accumulation; constitutive activation of a Tcf transcriptional factor; and increased levels of
-catenin/Tcf target oncogene proteins c-myc
and cyclin D1. Interference with the -catenin pathway reduced the
transforming potential of mutated RON and MET. Activation of
-catenin by oncogenic RON and MET constitutes a new pathway, which
might lead to cell transformation by these and other mutant growth
factor RTKs.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-Catenin
(Drosophila homologue Armadillo) is a multifunctional
protein discovered as a component of adherens junctions
(77). -Catenin associated with E-cadherin and
-catenin at the plasma membrane regulates cell adhesion, whereas
cytoplasmic -catenin is involved in signal transduction and
activation of gene expression (12). The amount of
uncomplexed cytoplasmic -catenin is tightly regulated by a
multiprotein complex containing axin, adenomatous polyposis coli (APC),
and glycogen synthase kinase 3 (GSK3). Physical interaction
between these proteins promotes -catenin phosphorylation on serine
residues by GSK3, an event leading to -catenin ubiquitination and
proteasomal degradation (8).
-catenin due to mutations in APC tumor suppressor
or -catenin genes occurs in many human cancers, including those of
colon and skin (14, 57, 68, 92). Mutations in axin
leading to -catenin accumulation have been found in hepatocellular carcinomas (16, 96). All these mutations result in reduced degradation of -catenin, which is believed to promote tumor
formation by constitutive activation of -catenin targets (68,
84). Another pathway leading to -catenin stabilization is
activation of the Wnt signaling, the vertebrate homologue of
Drosophila Wingless (75, 82, 102). Wnt genes
are tumorigenic in mice (75) and may also be implicated in
human cancer (84).
-catenin. The increase in cellular -catenin is accompanied by
constitutive activation of the Tcf-4 transcriptional factor and
Tcf-dependent accumulation of c-myc and cyclin D1 oncogenes. Biochemical data suggest that the initiating step may be -catenin tyrosine phosphorylation by mutated RON and MET. Inhibition of the
-catenin pathway resulted in reduction of RON and MET mutant transforming ability. In light of numerous data reporting increased cellular -catenin in cancer (7, 68, 84), this pathway may contribute to cell transformation by mutated growth factor receptors of the MET family.
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
-catenin (H-102,
Santa Cruz) and anti-N-terminal -catenin (UBI) antibodies were used for -catenin immunoprecipitation and Western blotting, respectively. Antiaxin (Zymed, South San Francisco, Calif.) and mouse monoclonal anti-GSK3 (0011-A; Santa Cruz) antibodies were used for axin and GSK3 immunoprecipitation and Western blotting. Anti-c-myc
(monoclonal, C-8), anti-cyclin D1 (monoclonal, HD11), anti-human and
-mouse MET (rabbit, C-28 and SP260), antiubiquitin (monoclonal, P1A6), and anti-JNK1 (rabbit, FL) antibodies were from Santa Cruz. Mouse monoclonal anti-pMAPK antibodies were from New England BioLabs, Beverly, Mass. Mouse monoclonal anti-mitogen-activated protein kinase
(anti-MAPK) antibody was from Transduction Laboratories (Lexington,
Ky.). Rabbit anti-phospho-JNK antibodies were from Promega (Madison,
Wis.). Mouse monoclonal anti--actin antibody (clone AC-15) was
from Sigma (St. Louis, Mo.).
32-P]ATP (3,000 Ci/mmol; 10 µCi/ml) was added, and IPs were incubated 30 min at room
temperature in 15 µl of total volume. The exogeneous substrate,
myelin basic protein, was added to the kinase reaction mixture at a
concentration of 0.5 µg/reaction tube. Reactions were stopped with 5 µl of 4× sample buffer. Phosphorylated RON or its substrate, myelin
basic protein, was visualized after SDS-PAGE by autoradiography.
-catenin in a kinase assay in
vitro.
After stimulation with MSP (5 nM) for 15 min, cells were
lysed and RON was immunoprecipitated. For the kinase assay,
immunoprecipitated RON wild type (WT) or M1254T mutant from stimulated
or unstimulated cells was mixed with immunoprecipitated -catenin
from unstimulated MDCK cells. The kinase assay was performed as
described above. Phosphorylated RON or -catenin was visualized after
SDS-PAGE and transfer onto a nitrocellulose membrane by
autoradiography. The amount of RON or -catenin in each sample was
determined by probing the same membrane with appropriate antibodies.
-catenin.
MDCK or NIH 3T3 cells
expressing RON WT or mutants were labeled with
[35S]methionine and
[35S]cysteine (100 µCi/ml) for 60 min at
37°C in methionine- and cysteine-free DMEM containing 8% dialyzed
FCS. Labeled cells were rinsed twice in normal DMEM containing
methionine and cysteine and were incubated in this medium for the
indicated times, after which -catenin was immunoprecipitated from
the lysed cells. After SDS-8% PAGE of the IPs, proteins were
transferred to a nitrocellulose membrane for radioautography and
quantification of the labeled proteins by scanning and integration with
National Institutes of Health Image software. Bands corresponding to
-catenin were identified by immunoblotting.
-galactosidase (-Gal) or dominant-negative (DN) human Tcf-4 were
prepared as previously described (38). Cells expressing
RON or MET WT or mutants in 10-cm-diameter dishes were infected with
adenovirus encoding -Gal or DN Tcf-4 as described previously
(37). Twenty-four hours later, these cells were
transfected with luciferase reporter plasmids (10 µg/dish; using
Superfect reagent as described above) containing WT (TOPFLASH) or
mutated (FOPFLASH) Tcf promoter. After an additional 24 h, Tcf
activity was determined by luciferase assay according to the standard
Promega protocol. Luciferase activity was measured in cell lysates by using a chemiluminometer and was normalized to total protein.
-Gal or DN Tcf-4.
After 48 h the amount of c-myc and cyclin D1 was
determined in total lysates from cells by Western blotting with
anti-c-myc or anti-cyclin D1 antibody.
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-catenin.
Single amino acid substitutions (D1232V or
M1254T) in the RON tyrosine kinase domain that mimic the oncogenic
mutations found in KIT (D814V) in human mastocytosis (110)
and RET (M918T) in MEN2B (93) convert normal RON into an
oncogenic receptor (95, 117). To investigate signaling
pathways activated by RON M1254T and D1232V mutants that might
contribute to oncogenic cell transformation, we established MDCK and
NIH 3T3 cell lines expressing the WT, M1254T, or D1232V RON receptor.
To avoid artifacts caused by clonal selection, we used in all
experiments a polyclonal population of stable transfectants. We
observed ligand-independent tyrosine phosphorylation of RON M1254 and
D1232V receptor mutants in both MDCK (Fig.
1A) and NIH 3T3 cell lines (data not
shown). Tyrosine phosphorylation of mutant RON receptors correlated
with enhanced kinase activity of the receptors (data not shown). Both
RON mutants displayed transforming potential, as determined by an in
vitro focus-forming assay (data not shown). Our results are in
agreement with published data on the constitutive activity and
tumorigenicity of these mutants (95).
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FIG. 1.
(A) Constitutive ligand-independent tyrosine
phosphorylation of RON M1254T and D1232V receptor mutants. MDCK cells
expressing RON WT or M1254T or D1232V mutants were lysed, and RON
receptor was immunoprecipitated from lysates by anti-RON antibodies.
RON tyrosine phosphorylation was detected by Western blotting (WB) with
anti-PY antibodies (upper panel). The lower panel represents reblotting
with anti-RON antibodies to obtain the amount of RON in precipitates.
Positions of molecular-weight markers are indicated on the right in
kilodaltons. MOCK, empty vector. (B) Mutant RON M1254T induces
constitutive tyrosine phosphorylation of -catenin. MDCK or NIH 3T3
cells expressing RON WT or M1254T mutant were stimulated with 5 nM MSP
for 15 min. After stimulation cells were lysed, and -catenin was
immunoprecipitated with anti--catenin antibodies. Tyrosine
phosphorylation of -catenin (WB:PY) was detected by Western blotting
with anti-PY antibodies (upper panel). The amount of -catenin in
precipitates was determined with anti--catenin antibodies
(WB:-catenin). Positions of molecular-weight markers are indicated
on the right in kilodaltons.
-catenin
(Fig. 1B, upper panel). In the absence of MSP stimulation, -catenin
was tyrosine phosphorylated in cells with RON M1254T (Fig. 1B, upper
panel) and with RON D1232V (data not shown) but not in cells with RON
WT (Fig. 1B, upper panel). Moreover, treatment of cells expressing RON
WT with MSP did not cause -catenin tyrosine phosphorylation (Fig.
1B, upper panel). These data suggest that activating mutations M1254T
and D1232V may lead to a switch of RON kinase substrate specificity:
-catenin is a substrate for mutant RON but not for RON WT.
Association of -catenin with RON receptor.
To investigate
the potential association of RON with -catenin in intact cells,
MDCK-RON-expressing cell lines were lysed and immunoprecipitated with
antibodies either against RON or -catenin. Western blotting showed
that RON and -catenin were reciprocally coprecipitated from cell
lysates (Fig. 2A). The association was constitutive (Fig. 2A) and was not affected by ligand stimulation (data
not shown). -Catenin coprecipitated with either immunoprecipitated RON WT or M1254T mutant (Fig. 2A, upper blot), and both receptors coprecipitated with immunoprecipitated -catenin (Fig. 2A, lower blot). These data indicate that RON and -catenin are spatially associated. We believe that -catenin-RON association is not due to
RON overexpression. RON expression in established MDCK and NIH 3T3 cell
lines is no greater than endogenous RON expression in a HaCat cell line
(data not shown).
|
Mutated RON tyrosine kinase can phosphorylate -catenin in
vitro.
The association of RON with -catenin suggests that the
observed tyrosine phosphorylation of -catenin in cells expressing M1254T mutant RON might be mediated by RON kinase. To investigate whether -catenin is a potential substrate for RON kinase, we assayed
the capacity of RON to phosphorylate -catenin in vitro. RON was
immunoprecipitated from nonstimulated or MSP-stimulated MDCK cells
expressing either RON WT or M1254T mutant. -Catenin was
immunoprecipitated from nonstimulated, starved, parental MDCK cells,
which do not express detectable RON. After that, beads carrying
precipitated RON receptor (WT or M1254T mutant) were mixed with beads
carrying precipitated -catenin and were incubated in kinase buffer
containing radioactive ATP. We were thus able to detect kinase-mediated
incorporation of 32P into -catenin.
-Catenin was phosphorylated when mixed with precipitated RON M1254T
mutant but not with RON WT (Fig. 2B, upper panel). RON WT did not
phosphorylate -catenin (Fig. 2B, upper panel), even after receptor
activation by the ligand (Fig. 2B, upper panel). -Catenin
phosphorylation by mutant RON was independent of ligand stimulation
(Fig. 2B, upper panel). The kinase assay data (Fig. 2B) correlate with
the results obtained in vivo (Fig. 1B, upper panel). Only RON M1254T
mutant caused phosphorylation of -catenin in vivo (Fig. 1B, upper
panel) or in vitro (Fig. 2B, upper panel). The in vitro results show
that mutant RON, or a kinase that coprecipitates with mutant RON, can
phosphorylate -catenin.
-Catenin tyrosine phosphorylation correlates with its metabolic
stability.
Because of the high amounts of -catenin in cells
expressing RON M1254T (Fig. 1B, lower panel), we postulated that
-catenin catabolism might be decreased in these cells. A pulse-chase
assay was performed to determine the effect of RON M1254T on
-catenin catabolism. The -catenin degradation rate in cells
expressing RON M1254T was significantly lower than the rate in cells
with RON WT (Fig. 3). To answer whether
tyrosine phosphorylation of -catenin affects its stability, we
pretreated parental MDCK cells without detectable RON expression that
had been transfected with the empty vector (MOCK) (control cell line)
with PV, an inhibitor of tyrosine-specific phosphatases (53,
107). Exposure of cells to PV for 15 to 20 min resulted in
tyrosine phosphorylation of a number of cellular proteins, including
-catenin. The level of -catenin tyrosine phosphorylation was
stable and comparable at all experimental time points (data not shown).
PV also decreased the degradation rate of -catenin (Fig. 3). From
the data in Fig. 3, the estimated half-life of -catenin was
approximately 2 h in cells expressing RON WT and longer than
4 h in cells expressing RON M1254T or in MDCK-MOCK cells
pretreated with PV. Since the delayed degradation of -catenin in
both of these experimental models is associated with tyrosine
phosphorylation of -catenin, phosphorylation may mediate -catenin
metabolic stability.
|
RON mutants inhibit -catenin-axin/GSK3 complex
formation.
Four mechanisms are known to cause increases in
cellular levels of -catenin: (i) mutations in the -catenin gene,
(ii) mutations in the APC gene, (iii) mutations in the axin gene, and
(iv) activation of Wnt signaling. All four result in the stabilization
of -catenin (84). The amount of -catenin in cells is
regulated by ubiquitin-dependent proteolysis (1).
Pretreatment of cells with ALLN inhibits proteasome-mediated proteolysis of ubiquitinated proteins, which leads to accumulation of
proteins degraded by this pathway (18). This approach
allows detection of ubiquitinated proteins, including -catenin
(1). Pretreatment of cells expressing RON WT with ALLN led
to the appearance of a high-molecular-weight -catenin, which was
consistent with -catenin coupled to ubiquitin (Fig.
4, -catenin, arrow). By probing the
same membrane with antiubiquitin antibodies, we showed that the
high-molecular-weight -catenin band contained ubiquitin (Fig. 4,
UB). In contrast to cells expressing RON WT, -catenin IPs from cells
expressing RON M1254T, with or without ALLN treatment, were tyrosine
phosphorylated (Fig. 4, PY) and were not ubiquitinated (Fig. 4, UB).
Our results suggest that -catenin tyrosine phosphorylation occurring
constitutively in cells with RON M1254T protects this molecule from
ubiquitination and proteasome-induced degradation.
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-catenin degradation is a complex process involving a
number of intracellular proteins. -Catenin ubiquitination is
preceded by phosphorylation of its N-terminal serine residues by
GSK3 (44), which occurs only in a multimolecular
complex formed between -catenin, axin or axil (related scaffold
protein [5, 44, 56]), GSK3, and APC protein (5,
8, 43, 84). Expression of RON M1254T or treatment of cells
expressing RON WT with PV blocked association of -catenin with axin
and GSK3 (Fig. 4, axin and GSK3). The amounts of axin or GSK3
in cell lysates were comparable for the experimental conditions
illustrated in Fig. 4 (data not shown). We conclude from these
experiments that mutant RON stabilizes -catenin by inhibiting
complex formation between -catenin and axin, which prevents
-catenin serine phosphorylation by GSK3 and its subsequent
ubiquitination and degradation. Because expression of RON M1254T or
pretreatment of RON WT cells with PV each causes -catenin tyrosine
phosphorylation and increased stability, we suggest that inhibition of
complex formation between -catenin and axin might be caused by
tyrosine phosphorylation of -catenin.
Tyrosine-phosphorylated -catenin does not interact with
axin.
To evaluate the possibility that -catenin tyrosine
phosphorylation inhibits its association with axin, we estimated the
amount of -catenin in axin IPs by Western blotting. The amount of
-catenin coprecipitated with axin was decreased in cells expressing
RON M1254T mutant (Fig. 5A, -catenin),
despite the increased total amount of -catenin in these cells (Fig.
1B, lower panel). Reprobing of the same membrane with anti-PY
antibodies gave a negative result: there is no tyrosine-phosphorylated
-catenin in the complex with axin. Conversely, we were able to
detect uncomplexed, tyrosine-phosphorylated -catenin in cell lysate
supernatants collected after immunoprecipitation of axin (Fig. 5B). We
also investigated the association between axin and GSK3 kinase.
Expression of RON M1254T mutant did not inhibit axin and GSK3
association (Fig. 5A, GSK3). Thus our results indicate that RON
M1254T mutant-induced -catenin tyrosine phosphorylation prevents
complex formation between -catenin and axin, an essential event for
-catenin proteasomal degradation.
|
RON mutants cause constitutive transcriptional activation of Tcf-4
and increase c-myc and cyclin D1 expression by the
Tcf-dependent mechanism.
Increased -catenin occurs in many
human cancers (68, 84). It is believed that an increase in
-catenin promotes tumor formation through activation of its
downstream targets. -Catenin can form a complex with Tcf/Lef
transcriptional factors (57, 69). Tcf-4 transactivates
transcription only when it is associated with -catenin
(57). c-myc and cyclin D1 genes contain a
Tcf/Lef binding site in their promoter regions (37, 108).
These genes are potential targets for transcriptional activation by
-catenin/Tcf (37, 101, 108) and have been implicated in
oncogenic cell transformation and tumor development (9, 49, 58,
60, 86).
-catenin in cells expressing RON
mutants results in transcriptional activation of Tcf-4, we transfected
luciferase reporter plasmids containing three copies of the Tcf-binding
site (TOPFLASH) or three copies of mutated Tcf-binding site (FOPFLASH,
used as a negative control, data not shown). Twenty-four hours before
the transfection, these cells were infected with adenoviral constructs
containing the -Gal gene (a control construct) or DN Tcf-4. Results
show that expression of RON M1254T mutant leads to constitutive
transcriptional activation of Tcf as determined by the luciferase assay
(Fig. 6A, third bar from top). In RON
M1254T cells carrying the TOPFLASH and -Gal-containing constructs,
we observed an approximately fourfold increase of luciferase activity.
Similar results were obtained when cells were transfected with only the
TOPFLASH plasmid (data not shown). Expression of DN Tcf-4 in RON M1254T
cells inhibited activity of endogenous Tcf, as shown by a decrease of
luciferase activity in these cells (Fig. 6A, fourth bar from top).
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-catenin/Tcf, we studied expression of these molecules in cells with WT or M1254T RON. We detected c-myc and cyclin D1 in lysates
from MDCK cells expressing RON M1254T (Fig. 6B). In all instances, expression levels were higher than those from lysates of cells expressing RON WT. Expression of DN Tcf-4 decreased the level of both
c-myc and cyclin D1 proteins in cells with RON M1254T mutant
(Fig. 6B). Our results indicate that expression of RON M1254T leads to
constitutive transcriptional activation of Tcf and to a consequent
increase in c-myc and cyclin D1 by the Tcf-dependent mechanism.
Tumorigenic MET mutant M1268T also activates -catenin
pathway.
The finding of germ line and somatic mutations in the MET
proto-oncogene in papillary renal carcimonas directly implicated the
MET gene in the pathogenesis of this disease (98, 99). The
oncogenic mutation M1268T in the MET kinase domain is at the position
that is homologous to the M1254T mutation in RON. The fact that the RON
M1254T mutant causes activation of the -catenin pathway suggested
that MET M1268T could also induce activation of the same pathway. To
test this hypothesis, we used a polyclonal population of NIH 3T3 cell
lines stably expressing MET M1268T or MET WT (as a control)
(72). In agreement with previous data (51,
72), we observed constitutive tyrosine phosphorylation of the
M1268T MET mutant (Fig. 7B). Results also
demonstrated that expression of MET M1268T causes constitutive
activation of Tcf transcriptional activity (Fig. 7A) and that increased
c-myc and cyclin D1 are dependent on Tcf activity (Fig. 7B).
Thus, both mutated RON and MET induce -catenin accumulation and its
activation.
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RONkd inhibits activation of -catenin pathway and decreases
transforming ability of MET M1268T mutant.
It was shown previously
that coexpression of RONkd (lysine at position 1114 in the ATP-binding
pocket of the RON kinase domain was replaced by alanine) with oncogenic
MET mutants reduced the number of foci induced by the MET mutants
(29). Thus, MET transforming ability was impaired by
RONkd; however, the molecular mechanism underlying the effect of RONkd
was not elucidated. We hypothesized that RONkd may inhibit activation
of the -catenin pathway mediated by the oncogenic MET mutants. To
test this hypothesis, RONkd (in our case, Lys1114 was replaced by Met)
was expressed in NIH 3T3 cells carrying M1268T or WT MET (as a
control). The effect of RONkd on mutant MET-mediated transformation was
studied in a focus-forming assay. Results show that RONkd significantly
inhibited the number of foci formed by NIH 3T3 cells expressing the MET
mutant (Fig. 8A). We found that RONkd
inhibited association between MET M1268T and -catenin (Fig. 8B).
-catenin is coimmunoprecipitated with both MET WT and M1268T from
cells transfected with a control plasmid (containing an EGFP gene),
whereas -catenin is not coprecipitated with MET from cells
expressing RONkd (Fig. 8B, IP:MET, WB:-catenin). -Catenin
appeared in RON precipitates (Fig. 8B, IP:RON, WB: -catenin). Relocation of -catenin from MET to RON precipitates is accompanied by reduction of both the intracellular level of -catenin and its
tyrosine phosphorylation level (Fig. 8B, IP:-catenin), but it does
not affect M1268T MET tyrosine phosphorylation (Fig. 8B, IP:MET,
WB:PY). Decreased - catenin in cells coexpressing M1268T MET and
RONkd correlates with the decreased level of -catenin downstream
targets c-myc and cyclin D1 (Fig.
9A), but there is no reduction in
activation of JNK and MAPK pathways induced by the M1268T MET mutant
(Fig. 9B). Similar results were obtained when RONkd was expressed in
cells carrying the M1254T RON mutant (data not shown).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Experimental mutations in the conserved region of the RON kinase domain (D1232V, KIT type; M1254T, RET/MET type) cause the RON receptor to become oncogenic (95, 117). To investigate signaling pathways contributing to RON mutant-mediated oncogenic cell transformation, we established MDCK and NIH 3T3 cell lines expressing WT or M1254T or D1232V RON receptors. Because RON is an RTK which became constitutively active as a result of the M1254T or D1232V mutations, we looked for tyrosine-phosphorylated intracellular proteins that might be substrates for RON mutants.
The investigation showed that -catenin is constitutively tyrosine
phosphorylated in cells expressing mutated but not WT RON even after
its activation by the ligand (Fig. 1B, upper panels). These data
suggest that in addition to constitutive ligand-independent kinase
activation, M1254T and D1232V mutations in RON might cause a switch of
RON kinase substrate specificity or inhibition of catalytic activity of
tyrosine-specific phosphatases responsible for -catenin
dephosphorylation. Previously observed effects on cell signaling caused
by the same RON mutants (95) or by oncogenic RET and MET
receptor mutants (4, 51, 78, 93) favor the possibility
that the kinase substrate specificity of the mutant receptor differs
from that of the WT (54).
What kinases are responsible for growth factor RTK-induced -catenin
tyrosine phosphorylation? We obtained evidence that oncogenic RON
mutants can phosphorylate -catenin. RON and -catenin were reciprocally coprecipitated (Fig. 2A), and in an in vitro kinase assay,
nonphosphorylated -catenin was phosphorylated when it was mixed with
RON mutant IPs (Fig. 2B, upper panel). This indicates that -catenin
is a substrate for mutated RON or for a kinase that associates with and
is activated by mutated RON. In other systems, -catenin has been
found associated with the epidermal growth factor (EGF), c-Erb-2, or
MET receptor (38, 41, 54) and -catenin is tyrosine
phosphorylated in cells stimulated by ligands for these receptors
(40, 41, 45, 80). The capacity to directly phosphorylate
-catenin has been shown only for the EGF receptor (41).
Another possibility is that growth factor-induced -catenin tyrosine
phosphorylation is mediated by c-Src or c-Src-related kinases. Cell
stimulation with growth factors causes activation of c-Src in many
cases (67, 112), and active c-Src can phosphorylate -catenin as well other proteins of adherens junctions (11, 36,
87, 111).
RON mutant-induced -catenin tyrosine phosphorylation is associated
with increased cellular -catenin (Fig. 1B, lower panel) and a
decreased degradation rate (Fig. 3). Likewise, treatment of cells with
PV, a tyrosine phosphatase inhibitor, causes both tyrosine
phosphorylation of -catenin and its metabolic stability (Fig. 3).
These data suggest that -catenin tyrosine phosphorylation may play a
role in its stabilization. Consistent with this idea is a positive
correlation between an EGF-induced increase in the cellular pool of
-catenin and the level of -catenin phosphorylation (70).
A search for the mechanism underlying RON mutant-induced -catenin
accumulation revealed that expression of RON mutants inhibited complex
formation between -catenin and axin (Fig. 4), a step required for
ubiquitination and proteasomal degradation of -catenin (26,
44). Analysis of axin-coupled and uncoupled fractions of
-catenin showed no phosphorylated tyrosine residues in the -catenin coupled to axin (Fig. 5A), whereas axin-free -catenin was tyrosine phosphorylated (Fig. 5B). These results suggest that tyrosine phosphorylation of -catenin prevents its association with
axin. A similar protein stabilization mechanism has been described for
I
B. In resting cells, NF-B is sequestered in an inactive state by
association with IB. Release from this sequestration is caused by
phosphorylation of IB at a consensus phosphorylation motif that
includes serines 32 and 36. This leads to ubiquitination and
proteasome-mediated degradation of IB. Serine phosphorylation of
IB and its resulting degradation can be prevented by phosphorylation of tyrosine 42 (46, 103). Thus, tyrosine phosphorylation
might be a general mechanism for protecting proteins from
ubiquitin-dependent proteolysis.
Three possible mechanisms of -catenin dissociation from axin have
been proposed: (i) Wnt-dependent dephosphorylation of axin leading to
its rapid degradation, (ii) Wnt-induced dephosphorylation of axin that
decreases its affinity for -catenin and GSK3, and (iii)
involvement of FRAT1, a protein which binds to GSK3 and inhibits
GSK-dependent phosphorylation (55, 109, 116, 118). Our
data suggest the existence of an additional mechanism involving tyrosine phosphorylation of -catenin. Because RON mutants did not
block axin interaction with GSK3 (Fig. 5A) and because we did not
detect changes in axin and GSK3 expression levels or inhibition of
GSK3 kinase activity (data not shown), the simplest explanation is
that tyrosine phosphorylation of -catenin causes conformational
changes that decrease its affinity for axin. The data showing that
tyrosine-phosphorylated -catenin undergoes conformational changes
during mouse oocyte development (76) support this view. On
the other hand, our data cannot exclude that tyrosine-phosphorylated
-catenin and axin are located in spatially different subcellular
pools, which prevents complex formation between these proteins.
Tyrosine phosphorylation of -catenin has been observed in a number
of apparently unrelated conditions: in the response to growth factors
and cytokines (39-41, 45, 54, 70, 100), in Src-transformed cells (36, 90, 111), and in mouse oocyte development (76). What is the physiological role of
-catenin tyrosine phosphorylation? Two distinct roles for
-catenin have been established, one in the maintenance of cell-cell
adhesion and the other in transcription of genes involved in growth and development. It is believed that tyrosine phosphorylation of
-catenin causes loss of intercellular adhesion mediated by
E-cadherins (6, 19, 63, 70). In addition to effects on
E-cadherin-associated -catenin, tyrosine phosphorylation is involved
in regulation of the free cytoplasmic pool of -catenin, the pool
that transduces signaling and activates gene expression (68, 79,
84).
We have shown that expression of RON RTK oncogenic mutants leads to
increases in -catenin and its potential downstream oncogene target
products, c-myc and cyclin D1. The increased levels of c-myc and cyclin D1 proteins in cells expressing M1254T or
D1232V RON receptor mutants is due to constitutive transcriptional
activation of Tcf-4 (Fig. 6), which is known to be in the -catenin
pathway. It is believed that the increase in -catenin which occurs
in many human cancers (14, 16, 57, 69, 92, 96) promotes tumor formation through activation of these downstream targets. c-myc and cyclin D1 genes have been implicated in oncogenic
cell transformation and tumor development (9, 49, 58, 60, 86).
We also found that activation of the -catenin pathway by
constitutively active mutated RTK is not unique for RON. Expression of
the oncogenic MET M1268T mutant affects -catenin in a similar way.
In cells with the MET mutant we detected accumulation of -catenin,
constitutive activation of Tcf, and a Tcf-dependent increase in
c-myc and cyclin D1 expression (Fig. 7).
To show a role of the -catenin pathway in cellular transformation
induced by mutated RON and MET, RONkd was coexpressed in NIH 3T3 cells
carrying mutated RON or MET. Our results (Fig. 8A) correlate with
previously published data that the expression of RONkd reduces the
number of foci induced by the active MET mutants (29). We
found that RON kd competes with activating MET (Fig. 8B) and RON
mutants for -catenin association. It can make -catenin unavailable as a substrate for constitutively active MET and RON kinases, leading to reduced -catenin tyrosine phosphorylation and
decrease in -catenin, c-myc, and cyclin D1 (Fig. 8B and
9A). At the same time, expression of RONkd does not affect activation of JNK and MAPK pathways (Fig. 9B) caused by mutated MET. It was shown
previously that activation of JNK and MAPK pathways is essential for
cell transformation by MET (4, 52, 88). Inhibition of
either pathway resulted in significant but partial reduction of MET
transforming potential. It has been shown that expression of the
stabilized -catenin mutant which activates Tcf is not sufficient to
cause cell transformation, whereas Wnt-1-induced -catenin
accumulation and Tcf activation correlate with cell transformation
supports (119). These data together with our results suggest that several pathways can contribute to MET-induced
transformation; cooperation between these pathways might be important.
Using RONkd, we selectively interfered with activation of the
-catenin pathway, leading to inhibition of MET and RON mutant transforming potential. Thus, the mechanism of -catenin accumulation described in this paper is involved in oncogenic cell transformation induced by tumor-causing RON and MET mutants.
| |
ACKNOWLEDGMENTS |
|---|
We thank B. Vogelstein (Johns Hopkins University, Oncology
Center, Baltimore, Md.) for -Gal- and DN Tcf-4-containing adenoviral constructs, R. Breathnach (INSERM U211, Nantes, France) for human RON
WT cDNA, F.A. Montero-Julian (Immunotech, Nantes, France) for mouse
monoclonal anti-RON antibodies, and P. Dashner (Carcinogenesis and
Cellular Defense Section, Basic Research Laboratory, SAIC, Frederick,
Md.) for his help in luciferase assays.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research and Development Center, Fort Detrick, Frederick, MD 21702. Phone: (301) 846-1560. Fax: (301) 846-6145. E-mail: danilkovitch{at}mail.ncifcrf.gov.
Present address: Department of Urology, Yokohama City
University Medical School, Kanazawa-ku, Yokohama, Japan.
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REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Molecular and Cellular Biology, September 2001, p. 5857-5868, Vol. 21, No. 17
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.17.5857-5868.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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