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University of Torino, School of Medicine, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo, Italy
1Correspondence: Institute for Cancer Research, Department of Molecular Oncology, University of Torino Medical School, Strada Provinciale 142, Km 3.95, 10060 Candiolo (Torino), Italy. E-mail: sgiordano{at}ircc.unito.it
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: tyrosine kinase receptor • mutations • invasive growth • branching morphogenesis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2)
. Receptor activation triggers a unique process of
differentiation called ‘branching morphogenesis’ that involves the
promotion of cell growth, protection from apoptosis, control of cell
dissociation, and migration into extracellular matrices (3
, 4)
. In transformed epithelia, deregulated activation of the
MET proto-oncogene can mediate invasive growth, a feature of
neoplastic progression in which cancer cells invade surrounding tissues
and penetrate vascular walls, eventually leading to systemic metastases
(5
6
7
8
9
10)
.
The role of MET in human tumors has been well documented.
Previous studies from this and other laboratories have shown that the
MET oncogene is overexpressed in tumors of specific
histotypes, including thyroid (11)
and pancreatic
carcinomas (12)
, or is activated through autocrine
mechanisms (13
, 14)
. Moreover, the MET gene is
amplified in liver metastases of colorectal carcinomas
(15)
. Recently, a genetic connection between
MET and hereditary papillary renal carcinoma (HPRC)
established a direct role for this receptor in human cancer
(16)
. Sequencing the MET gene from affected
members of HPRC families and from tumor samples of patients with
sporadic papillary carcinoma identified nine different mutations
(referred to as MetPRC mutations)
that result in amino acid substitutions in the kinase domain of the
receptor. Three of these mutations (D1228N, D1228H, and M1250T) are
located in codons homologous to those mutated in the tyrosine kinase
receptors Kit and Ret. Mutated Kit
alleles are found in patients with mastocytosis and acute myeloid
leukemia of M2 subtype (17
, 18)
and missense mutations in
Ret are associated with multiple endocrine neoplasia type 2B
(MEN2B) (19)
. This suggests that alteration of these
residues is a critical event in deregulating tyrosine kinase receptors.
HGF binding to Met up-regulates the tyrosine kinase
(2
, 20)
and results in phosphorylation of a unique docking
site located in the Met carboxyl-terminal tail, which
contains the sequence
Y1349VHV-Y1356VNV
(21)
. The two phosphorylated tyrosines within this
sequence couple the receptor to multiple intracellular effectors, among
which are the Grb2/SOS complex, the p85 regulatory subunit of
PI-3-kinase, Stat-3, src, and the multiadaptor protein Gab1
(21
22
23
24
25
26
27
28)
. The mechanism by which mutated Met
drives neoplastic transformation has been shown to involve constitutive
receptor coupling to downstream signal transducers as the substitution
of these ‘docking tyrosines’ with phenylalanines abrogates
transformation (21)
. Recent studies have shown that some
of the PRC mutations increase the kinase activity and confer
transforming ability (29)
. However, in all cases,
MET-mediated transformation requires an intact docking site
(30)
.
All of the METPRC mutations segregate with the disease; however, only some of them display transforming potential in vitro and nothing is known about the biological properties of the nontransforming METPRC mutations. The present study investigates the different mechanisms linking METPRC mutations to the development of human tumors.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and detected by Western blotting with
polyclonal antibodies (C-28, Santa Cruz Biotechnology, Santa Cruz,
Calif.). COS-7 cells were purchased from ATCC (American Type Culture
Collection, Rockville, Md.). Cultures of mammalian cells were
maintained in DMEM supplemented with 10% fetal calf serum (FCS) in a
humidified atmosphere of 5% CO2-air. MLP29 is an
epithelial cell line derived from liver oval cells (32)
.
Plasmid constructs
Reproduction of PRC mutations in the human Met cDNA
was mediated by polymerase chain reaction as described
(30)
. Human Met residues are numbered according to Gene
Bank # X54559 (33)
Wild-type or mutant Met cDNA
was subcloned into the pCEV29.1 expression vector, which carries the
resistance to G418 (34)
, and into the pMT2 expression
vector.
Transfections and transformation assays
To establish stable transfectants, MLP 29 were transfected by
the calcium phosphate method using 40 mg of carrier DNA (calf thymus
high molecular weight DNA; Boehringer Mannheim, Mannheim, Germany) per
100 mm plate. Each plate was transfected with 2 mg of the pCEV29.1
vector containing either no insert or a cDNA encoding Met
(wild-type or mutant). Selection of stable transfectants was performed
in DMEM containing 10% FBS and 750 µg/ml G418. Clones resistant to
G418 were pooled and used for Western blot analysis and biological
assays.
Two days after transfection, cells were split into four plates for transformation assays: three plates were cultured in DMEM containing 5% FCS and used for measuring focus formation; the fourth was cultured in DMEM containing 10% FCS and the selective drug G418 (750 µg/ml) to establish stable transfectants. Foci were scored 2 wk after transfection following fixation with p-formaldehyde and Giemsa staining.
For transient transfections, cDNAs cloned in the pMT2 vector were transfected in COS-7 cells by the calcium phosphate method.
Precipitation experiments
GST fusion proteins were kindly donated by Dr. P. P.
DiFiore. GST fused to the amino-terminal SH2 domain of the p85 subunit
of Pi3Kinase (~500 ng/point) was coupled to glutathione-Sepharose
beads. Lysates from COS-7 cells (one confluent 10 cm dish, lysis
conditions as described in ref 21
) transfected with
wild-type or mutant METPRC cDNAs
were incubated with the immobilized SH2-GSTs for 90 min at 4°C in the
presence of 1 mM sodium o-vanadate. The beads were washed
and proteins were eluted with boiling Laemmli buffer before Western
blot analysis. Specific detection of proteins by antibodies was
visualized by chemiluminescence (ECL+Plus detection system, Amersham.
Little Chalfont, U.K.).
Soft agar and branching morphogenesis assays
For analysis of colony formation in soft agar, MLP 29 cells were
diluted to a concentration of 25,000 cells/ml in DMEM containing 10%
FCS, 0.5% Seaplaque agar with or without added HGF (200 scatter
units/ml). Cells were seeded in 6-well plates (2 ml/well) or 24-well
plates (0.5 ml/well) containing a 1% agar underlay and supplemented
with DMEM containing 10% FCS three times a week (HGF, 200 scatter
units/ml). Colonies were scored 2 wk after seeding.
For evaluation of branching morphogenesis, cells were cultured in
collagen as described previously (32)
.
In vitro motility assay
105 cells were seeded on the upper side of
a Transwell chamber on a porous polycarbonate membrane (8.0 µM pore
size); the lower chamber of the Transwell was filled with DMEM
containing 2% FCS in presence of 100 units/ml of recombinant
Baculovirus-produced human HGF. After 24 h of incubation, cells
attached to the upper side of the filter were mechanically removed;
cells that migrated to the lower side of the filter were fixed, stained
with Toluidine blue, and counted (10 microscopic fields/sample).
In vitro invasion assay
105 cells were seeded on the upper side of
a porous polycarbonate membrane (8.0 µM pore size) coated with the
artificial basement membrane Matrigel (12.5 µg per filter;
Collaborative Biomedical Products; Becton Dickinson Labware, Waltham,
Mass.). The lower chamber of the Transwell was filled with DMEM
containing 2% FCS in the presence of 100 units/ml of recombinant
Baculovirus-produced human HGF. After 24 h of incubation, the
filters were removed and cells that invaded the Matrigel and attached
to the lower chamber of the transwell were fixed with glutheraldeyde,
stained with crystal violet, and photographed.
Apoptosis assays
10,000 cells were plated in each well of a 96-well Costar
microtiter plate in either the presence or absence of 100 U/ml HGF.
Apoptosis was induced with 100 nM Staurosporin for 12 h. Anoikis
assay was performed as described previously (35)
.
Apoptosis detection was monitored by TUNEL reaction (Boehringer). The
fluorescence labeling was converted into a colorimetric signal for
analysis by light microscopy using TUNEL AP (Boehringer). Cells
positive for the reaction were scored under the microscope.
Luciferase assay
NIH 3T3 cells were transfected with 1 mg of fos luciferase
reporter plasmid and 300 ng of the different Met constructs
either in the presence or absence of pRSV-Ras N17 (36)
.
After 24 h, the cells were harvested in 200 ml luciferase-lysis
buffer containing 25 mM glycylglycine·NaOH, pH 7.8, 1 mM DTT, 15%
glycerol, 8 mM MgSO4, 1 mM EDTA, and 1% Triton
X-100. Total protein (10 mg) was transferred to microtiter plates and
luciferase activity was measured in a luminometer after injecting 100
ml of luciferin solution containing 25 mM glycylglycine·NaOH, pH 7.8,
10 mM MgSO4, 1.5 mM ATP, and 330 mM luciferin.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) display different abilities to induce transformation in
NIH 3T3 cells (29
, 30)
. Only mutations that alter residues
located in the kinase activation loop efficiently transform mouse
fibroblasts. Furthermore, the METPRC
mutant with the highest transforming ability
(METM1250T) also displays the highest catalytic
activity.
|
Activation of the Ras pathway is critical for MET-induced
transformation (21
, 37
, 38)
. To evaluate the ability of
METPRC mutants to activate this pathway,
we performed a transient transfection assay in NIH 3T3 fibroblasts
using a luciferase expression system. A luciferase construct containing
a fos-responsive promoter was induced 8- and 7-fold by coexpression of
the transforming mutants METM1250T and
METD1228H, respectively (Fig. 1B
). This
increase was strongly suppressed by a cotransfected dominant negative
mutant of Ras (Ras N17), indicating that the increase in luciferase
activity is strictly dependent on activation of the Ras pathway. In the
same assay, METPRC mutants
METL1195V and
METY1230C, which are almost devoid of
transforming ability, induce the luciferase construct to a lower
degree, displaying a 60% reduced ability to activate the Ras pathway.
METPRC mutants mediate motility in epithelial
cells
The Met receptor is expressed in cells of ectodermal origin, where
it elicits different biological responses such as cell proliferation,
protection from apoptosis, and invasion of surrounding extracellular
matrices. To determine whether cells expressing
METPRC mutants show an increase in some
of these properties, we transfected the human MET cDNAs
harboring the different PRC mutations into MLP 29 murine epithelial
liver oval cells. These cells display a full spectrum of biological
responses on HGF treatment (39)
. The selected stable cell
lines express comparable amounts of exogenous receptor, which is
constitutively tyrosine phosphorylated (Fig. 2A
). As expected, tyrosine phosphorylation can be further
increased by stimulation with HGF (data not shown).
|
Cells expressing METPRC mutants display a
‘scattered’ phenotype, disassembling the tightly packed islands and
inducing cell detachment and migration (Fig. 2B
). The
scattering response can be further stimulated by the addition of HGF
and this response is enhanced compared to that observed in MOCK
transfected cells or in cells expressing normal human MET
(data not shown).
The increased motility displayed by MLP 29 cells expressing
METPRC mutants was quantified by a Boyden
chamber assay. After HGF stimulation, cells expressing
METPRC mutants exhibited increased
migration, compared to MOCK or cells expressing WT MET (Fig. 2C
).
METPRC mutants induce ‘invasive growth’
The morphogenetic response induced by Met in epithelial
cells is unique for this receptor and cannot be elicited by other
tyrosine kinases (40)
. Under physiological conditions, the
coordinated activation of multiple signaling pathways underlying this
invasive growth leads to the formation of tubular structures by
epithelial organs, a response termed branched morphogenesis
(41)
, which plays an essential role during embryogenesis.
Deregulated activation of the invasive-growth phenotype by the
MET oncogene confers transformed and metastatic properties
to cells (37)
.
MLP 29 cells are a sensitive target for signals controlling polarized
growth. When stimulated by HGF, they migrate in tridimensional collagen
gels and form long and branched tubules. MLP 29 cells expressing
METL1195V and METY1230C mutants
(which are only weakly transforming in a focus forming assay) showed
the best morphogenetic response, developing many long tubular
structures (Fig. 3A
). Moreover, in the absence of HGF, these cells developed
typical cystic structures with outwardly projecting spikes, not
observed in MOCK transfected cells. Conversely,
METM1250T and METD1228H mutants,
which display the highest transforming potential in vitro,
develop shorter, mainly unbranched tubules.
|
To evaluate whether cells expressing
METPRC mutants display an invasive
phenotype, we tested their ability to invade in vitro
reconstituted basement membranes (Matrigel). As shown in Fig. 3B
, cells expressing METL1195V and
METY1230C mutants, which also induced branched
morphogenesis, were effective in invading the reconstituted basal
membrane. Since it has been shown that Pi3Kinase plays a critical role
in invasion and tubulogenesis (42)
, we evaluated the
ability of METPRC mutants to interact
with the p85 subunit of Pi3Kinase. Pull-down experiments of the
METPRC mutants with the GST protein fused
to the amino-terminal SH2 domain of p85 showed that
METL1195V and METY1230C mutants,
displaying the best invasive and tubulogenic ability, interact very
efficiently with Pi3Kinase (Fig. 3C
). This was specifically
observed with the SH2 domain of Pi3Kinase, because additional pull-down
experiments with GST-fusion proteins comprising the SH2 domains of
Src, PLC
, and Shc did not reveal any differential binding to the
mutants (data not shown). The decreased invasive and morphogenetic
ability of METM1250T and METD1228H
mutants, which also interact with Pi3Kinase, albeit at a lower level
than METL1195V and METY1230C, could
be due to an unbalanced activation of the Ras and Pi3Kinase pathways as
sustained activation of the Ras pathway causes disorganized growth
resulting in reduced invasion and tubulogenesis (42)
.
METPRC mutants induce protection from apoptosis
and anchorage-independent growth
Protection from apoptosis is a critical step during tumor
progression. Cells that are resistant to apoptotic stimuli can undergo
multiple lesions that would otherwise lead to cell death. Some of these
lesions, affecting genes involved in promoting tumor progression, could
thus be stabilized.
To evaluate how cells expressing
METPRC mutants respond to apoptotic
stimuli, we treated the cells with the apoptosis-inducing drug
staurosporin. As shown in Fig. 4A
, cells expressing METL1195V and
METY1230C mutants display an increased resistance to
apoptosis, which is further enhanced by HGF stimulation. Similar
results were also obtained when cells were tested for they ability to
overcome anoikis (data not shown). Notably, the increased resistance to
apoptosis is shown by mutants, which display a low transforming
potential in vitro.
|
MLP 29 cells expressing METPRC
mutants were also assayed for their ability to form colonies in soft
agar either in the absence or presence of HGF. As shown in Fig. 4B
, control cells formed very few small colonies in the
absence or presence of HGF. Cells expressing
METPRC mutants displayed dramatically
increased anchorage-independent growth potential and formed numerous
large colonies in the presence of HGF. The most effective mutants
were METL1195V and METY1230C, which
were also more resistant to apoptosis.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, we show that the METPRC mutations can be broadly divided into two groups based on their biological properties. Mutants belonging to one group, including METM1250T and METD1228H, display increased tyrosine kinase activity, stimulate efficiently the Ras pathway, and transform recipient cells in focus forming assays. Conversely, the other group of mutations, including METL1195V and METY1230C, are almost devoid of in vitro transforming potential but are effective in inducing protection from apoptosis, sustaining anchorage-independent growth, and promoting invasion. The transforming mutations of the first group are characterized biochemically by preferential activation of the Ras pathway, whereas the second group is characterized by a more efficient interaction with the intracellular transducer Pi3Kinase, whose role in invasive growth and protection from apoptosis is well known. We also show that the mutated forms of METPRC remain responsive to HGF and the biological properties induced by these mutants are better revealed in the presence of the ligand.
The pleiotropic activity of Met results from the concomitant
activation of several signal pathways (37)
. It is known
that Ras activation is strictly required and is sufficient for growth
and transformation, but not for anchorage-independent growth and
invasion. In contrast, Pi3Kinase activation alone does not suffice for
these same responses (43)
. A balance between the
activation of Ras and Pi3Kinase is mandatory for anchorage-independent
and invasive growth (42)
. This has been shown in the case
of an activated form of Met that preferentially couples to
Grb2 and activates the Ras pathway (37)
. This mutant is
highly efficient in transformation but is devoid of invasive
properties; however, when one of the two Grb2 binding sites is replaced
by a Pi3Kinase binding site, the resulting mutant displays both
transforming and invasive potential (43)
. Similarly, a
natural example is provided by the activated form of c-sea,
a receptor belonging to the same subfamily of receptors as
Met. Activated c-sea, which contains a double
Grb2 binding site, transforms but does not invade, whereas its viral
counterpart v-sea, which contains a point mutation
introducing a Pi3Kinase binding site, is effective in both
transformation and invasion (37)
.
Several hypotheses could account for the differential ability of the
MET mutants to activate the Pi3Kinase pathway. First, some
mutations could result in the preferential phosphorylation of Y1349 of
the docking site compared to that of Y1356. This could increase the
binding of Pi3Kinase, since Y1349 lacks the consensus sequence for Grb2
and would prevent competition with Grb2, whose SH2 domain displays an
affinity for Y1356 one log higher than the p85 SH2 domain of Pi3Kinase.
Alternatively, a conformational change induced by mutations could
result in an alternative phosphorylation of Gab1: preferential
phosphorylation of Gab1 tyrosines responsible for Pi3Kinase binding
could therefore increase Met-mediated activation of this
pathway. Moreover, the increase of Pi3Kinase activation via
Met could enhance the localization of Gab1 to the membrane
and its further recruitment by Met (44)
. It has
been shown, in fact, that lipid products of Pi3Kinase enhance the
membrane localization of Gab1 by interacting with Gab1 PH domain
(44)
.
In summary, this is the first report highlighting distinct biological properties elicited by different point mutations in a tyrosine kinase oncogene. In some instances, oncogenic mutations can directly confer a growth advantage by mainly activating the Ras pathway; other mutations activate different intracellular signaling pathways, such as Pi3Kinase, resulting in protection from apoptosis and invasive growth. It could be speculated that in the latter case the affected oncogene may not be directly responsible for transformation, but may allow accumulation of mutations in other genes, which in turn are responsible for transformation. Since the Ret and Kit oncogenes are also activated in human cancers through similar molecular mechanisms, the reported findings are possibly not unique to Met and could provide a general mechanism by which tyrosine kinase receptors are involved in human malignancies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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