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(Received for publication, October 11, 1995; and in revised form, December 12, 1995) From the
Growth regulation of fibroblasts is important for lung
development and repair of lung injury. In this study, we investigated
the role of transforming growth factor-
Transforming growth factor- TGF- T
Growth responses to TGF-
Figure 1:
Effects of TGF-
In order to elucidate a possible mechanism
whereby TGF-
Figure 2:
Expression of endogenous TGF-
The expression of TGF- To examine the significance of
type II receptor in mediating the growth-promoting and growth
inhibition effects of TGF-
Figure 3:
Expression of the truncated T
[
Figure 4:
Dominant-negative effects of T
Figure 5:
Dominant-negative effects of T
Proliferation of fibroblasts is an important aspect of lung
development and is also a key feature of repair of lung injury.
Expression of TGF- Our data show that TGF- We examined the possible
relationship between the bifunctional action of TGF- We show that
the kinase-deleted truncation of T In conclusion, we found that TGF-
Volume 271,
Number 5,
Issue of February 2, 1996 pp. 2369-2372
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
(TGF-
) Type II Receptor for
TGF-
-induced Proliferation and Growth Inhibition (*)
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
(TGF-) type II
receptor in the TGF--dependent proliferative response of lung
fibroblasts. TGF- stimulated the proliferation of adult lung
fibroblasts at a low concentration (1 ng/ml), but inhibited the growth
of fetal lung fibroblasts in a dose-dependent fashion (0.1-10
ng/ml). Cross-linking and Northern analysis demonstrated that the two
lung fibroblast cell lines expressed the TGF- type I receptor
(TRI) and type II receptor (TRII). We overexpressed in lung
fibroblasts a truncated derivative of TRII that lacked the
cytoplasmic serine/threonine kinase domain (TRII
K).
TRIIK was a dominant-negative inhibitor of TGF- signal
transduction blocking not only TGF--induced mitogenic action upon
adult lung fibroblasts but also TGF--induced growth inhibition of
fetal lung fibroblasts. The results indicate that the type II receptor
is indispensable for mediating both the mitogenic and antiproliferative
effects of TGF- upon lung fibroblasts.
(TGF-) (
)is a
family of multifunctional cytokines that regulates cell growth,
differentiation, and extracellular matrix deposition(1) . Three
isoforms TGF-1, -2, and -3 have been identified in lung and found
to act on many different lung-derived cell types and to regulate a wide
variety of cellular activities(2, 3) . TGF-s
elicit their biological effects on cells through binding to cell
surface transmembrane receptors. A number of different types of
putative receptors for TGF-, including three distinct size classes
termed type I (TRI, 50-60 kDa), type II (TRII,
75-85 kDa), and type III (TRIII, a 280-kDa proteoglycan with
a 120-kDa core protein), have been identified by affinity cross-linking
experiments(4, 5) . Molecular cloning of cDNAs coding
type I and type II receptors for the TGF- superfamily have shown
that both types belong to a novel family of transmembrane
serine/threonine kinases with a small extracellular domain, a single
transmembrane segment, and an intracellular region with a
serine/threonine kinase domain(6, 7, 8) .
Sequence analysis of TRIII revealed that it is a transmembrane
proteoglycan with a short and highly conserved cytoplasmic domain that
has no apparent signal motif (9, 10) . Current
evidence indicates that a complex of TRI and TRII, but not
the individual components, mediates TGF- signal transduction. A
ligand-induced heterodimer model was proposed for TGF- signal
transduction(11, 12) . may act as either
a positive or a negative regulator of cell division. TGF-
stimulates the proliferation of mesenchyme-derived cells such as
fibroblasts and osteoblasts, but acts as a powerful growth inhibitor of
cells of epithelial and endothelial origin(13, 14) .
TGF- inhibits epithelial cell proliferation by delaying or
arresting progression through the late portion of G1(15) .
TRII was found to be essential for TGF- growth inhibition
signal. Mv1Lu mink lung epithelial cells are highly responsive to the
growth inhibition of TGF-. A chemically mutated Mv1Lu cell line
defective in TRII lacks TGF--induced growth inhibition.
Transfection of the human TRII to this mutant cell line restored
the inhibition of growth by TGF-(16, 17) . A
similar conclusion has been drawn by expression of a kinase-defective
truncation of the human TRII in Mv1Lu mink lung epithelial
cells(18) .RII is required to mediate
antiproliferative responses to TGF-, but its involvement in
TGF- signaling that lead to growth stimulation has not been
established. In the present studies, we demonstrate a bifunctional
action of TGF- in lung fibroblast cells. An adult rat lung
fibroblast cell line expressed TRII and was responsive to the
growth stimulation of TGF-, whereas a fetal rat lung fibroblast
cell line expressed TRII and displayed an unexpected response,
growth inhibition, to TGF-. To further determine the role of
TRII in modulating the growth stimulation effects of TGF-, we
transfected into rat lung fibroblast cells an expression plasmid
containing rat TRII cDNA that was lacking the kinase domain.
Overexpression of the dominant-negative TRII mutant blocked both
the stimulating and the inhibitory effects of TGF- on rat lung
fibroblasts. These experiments provide evidence for a functional role
of TRII in TGF--induced proliferation and growth inhibition
of lung fibroblasts.
Cell Cultures
Fetal rat lung fibroblasts were
isolated from day 16 gestational age fetal rat lung tissues as
described(19) . Adult rat lung fibroblasts isolated from
9-week-old rats were kindly provided by Dr. J. Clarke McIntosh from
Duke University Medical Center. These cells exhibited typical
fibroblastoid morphology, and they were vimentin-positive and
cytokeratin-negative. These lung fibroblasts were also characterized by
expression of extracellular matrix protein tenascin and
fibronectin(19) . Cells were maintained in Dulbecco's
modified Eagle's medium (DMEM) with 10% fetal calf serum.
Cultures were grown in humidified 5% CO
and 95% air at 37
°C.Mitogenesis
Assay
[
H]Thymidine incorporation was used
to determine TGF- sensitivity of fibroblasts to exogenous
TGF- treatment. Fetal rat lung fibroblasts or adult rat lung
fibroblasts were plated in 24-well plates at a density of 2 
10
cells/well in DMEM supplemented with 10% fetal bovine
serum. After 48 h of incubation, the cells were serum-starved for 24 h
in serum-free medium. Quiescent cultures were then incubated with
serum-free DMEM in the presence of various concentration of TGF-
(0.1 ng/ml-10 ng/ml), as indicated. After receiving a 6-h pulse with 2
µCi/ml of [H]thymidine (Amersham Corp.),
cells were rinsed with phosphate-buffered saline three times, and twice
with 10% trichloroacetic acid, then lysed in 0.1 M NaOH. The
amount of [H]thymidine incorporated was analyzed
by liquid scintillation counting.Receptor Constructs
A 1762-base pair cDNA
containing the full-length coding sequence for TRII was isolated
from rat lung as described(20) . A 1542-base pair cDNA
containing the full-length coding sequence for TRI was isolated
from rat lung by using reverse transcriptase PCR cloning technique with
primers (sense: 5`-dACAGTGGCAGCGGGACCAT-3`; antisense:
5`-GAGCAGAGTTCCCACGGTG-3`). TRI cDNA was cloned into plasmid pNoTA
(5 Prime 3 Prime, Inc., Boulder, CO) and was characterized by
sequencing analysis. Sequencing was carried out in both directions by
the dideoxy chain termination method (21) using Sequenase
version 2.0 (U. S. Biochemical Corp.) kit and
S-dATP
(Amersham).
Northern Analysis
Total RNA was from cells
prepared by the guanidine thiocyanate/cesium chloride method.
Poly(A) RNAs were selected with the PolyATtract®
mRNA isolation kit (Promega, Madison, WI). Two µg of mRNA was
fractionated on an agarose gel, transferred to Nytran nylon membrane
(Schleicher and Schuell) and fixed by a Stratalinker UV cross-linker
(Stratagene, La Jolla, CA). Filters were hybridized at 42 °C in 50%
formamide solution containing 5
SSPE (1 SSPE is 0.18 M NaCl, 10 mM NaHPO, and 1
mM EDTA), 1 Denhart's solution (1
Denhart's is 0.02% (w/v) each of polyvinylpyrrolidone, bovine
serum albumin, and Ficoll), 0.5% SDS, and 0.2 mg/ml of denatured and
sonicated fish sperm DNA with 10
cpm of P-labeled T
RI or TRII cDNA probes. Equivalent
RNA loading and transfer were confirmed by subsequent reprobing with a
rat glyceraldehyde phosphate dehydrogenase cDNA probe. Filters were
washed twice with 2 SSC (1 SSC is 0.15 M NaCl,
15 mM trisodium citrate), 0.1% SDS for 15 min at room
temperature and finally washed with 0.1 SSC, 0.1% SDS for 20
min at 60 °C. The filters were autoradiographed. Scanning
densitometry (Molecular Dynamics, Sunnyvale, CA) was performed to
quantify the relative amounts of mRNA species.Construction of T
A kinase-defective rat TRII Dominant-negative Mutant and
TransfectionRIIK was
generated by PCR using primers (sense: 5`-dGCCGGTCTATGACGAGC-3`;
antisense: 5`-CCGCTACACCAGCGTGTCCAGCTC-3`). PCR conditions were 1 min
at 92 °C, 1 min at 60 °C, and 1 min at 72 °C for 25 cycles.
The resulting PCR product was cloned into plasmid pNoTA (5 Prime
3 Prime, Inc.) and was characterized by sequencing analysis. For
expression in eukaryotic cells, the truncated T
RII cDNA
(TRIIK) or the full-length wild type TRII cDNA was
released from pNoTA with restriction enzyme EcoRI and EcoRV, and the fragment of TRII or TRIIK was
subcloned into pcDNA3 (Invitrogen, San Diego, CA). This plasmid
contains the cytomegalovirus major intermediate early transcriptional
promoter and enhancer. The subcloned TRII or TRIIK cDNA
was verified by restriction enzyme digestion and confirmed by sequence
analysis.Transfection
Cells were plated in DMEM and 5%
fetal bovine serum 24 h before transfection. Cells were cultured
overnight, and the medium was replaced on the following day by
serum-free medium. Transfection of cells with the dominant-negative
mutant and wild type construction was performed by using the
lipofectamine transfection system (Life Technologies, Inc.). The medium
were replaced at 16 h following the start of transfection, and
TGF-1 was added at the final concentration of 5 ng/ml for fetal
lung fibroblasts and 1 ng/ml for adult lung fibroblasts. The control
cells were transfected with the cloning plasmid without TRII cDNA.
The mammalian reporter vector pCMV (Clontech Laboratories, Inc.,
Palo Alto, CA), which has the lacZ gene under the
transcriptional control of the cytomegalovirus immediate early gene
promoter, was used to optimize the transfection conditions.Receptor Affinity Cross-linking
The affinity
labeling of the TGF- receptor was carried out according to a
procedure described previously(22) . The monolayer cells were
washed with binding buffer (DMEM, 2 mg/ml bovine serum albumin, 25
mM HEPES, pH 7.4) and then incubated for 3 h at 4 °C with
100 pM of I-TGF-
1 (6440 kBq/µg, DuPont
NEN) or 100 pM of I-TGF-
1 plus 80 nM unlabeled TGF-1 in binding buffer. Cells were washed three
times with binding buffer without bovine serum albumin at 4 °C.
Bound I-TGF-
1 was cross-linked to cell membranes by
adding 0.25 mM bis-sulfosuccinimidyl suberate (Pierce) and
incubating on ice for 20 min. Cells were harvested and were solubilized
in 125 mM NaCl, 10 mM Tris-HCl, pH 7.0, 1 mM EDTA, 1% Triton X-100, 1 mM phenylmethylsulfonyl
fluoride, 0.3 µM aprotinin, and 1 µM pepstatin. Cross-linked proteins were resolved by
SDS-polyacrylamide gel electrophoresis on 12% gels under reducing
conditions and autoradiographed.
1 by rat lung fibroblasts were
examined. Confluent fetal rat lung fibroblasts and adult rat lung
fibroblasts were made quiescent and exposed to different concentration
of TGF-1. The adult rat lung fibroblast cell line was responsive
to the growth stimulation of TGF- as expected of most fibroblast
cells, whereas fetal rat lung fibroblasts displayed an unexpected
response, growth inhibition (Fig. 1). The effects of TGF-1
on the proliferation of adult lung fibroblasts were dependent on
concentration (Fig. 1A). TGF-1 stimulated the
proliferation of adult lung fibroblasts at concentration less than 5
ng/ml. Maximal effects were observed at a concentration of 1 ng/ml, and
TGF-1 had no effect at concentrations of over 5 ng/ml. In
contrast, TGF-1 inhibited the proliferation of fetal lung
fibroblasts in a dose-dependent manner up to 10 ng/ml after a 20-h
treatment with TGF-1 (Fig. 1B).
[H]Thymidine incorporation peaked at 24-36
h in adult lung fibroblasts treated with TGF-1, but inhibition of
DNA synthesis of fetal lung fibroblasts by TGF-1 persisted for up
to 72 h (data not shown).
1 on growth of
adult lung fibroblast cells (A) and fetal lung fibroblasts (B). Lung fibroblasts were plated at a density of 2
10 cells/well in a 24-well plate and were made quiescent in
serum-free DMEM for 24 h. Cells were treated with the indicated
concentration of TGF-1 for 20 h and then labeled with
[H]thymidine for 6 h. DNA was precipitated with
10% trichloroacetic acid, and the amount of
[H]thymidine incorporated was analyzed by liquid
scintillation counting. Each value represents the average of three
separate cultures measured for each TGF-1 concentration used. Error bars are S.E.
1 exerts its actions on fibroblast proliferation, the
expression of TGF- receptors by adult and fetal lung fibroblasts
were evaluated. Cross-linking of I-TGF-
1 to fetal
lung fibroblasts or adult lung fibroblasts revealed three species of
receptors with apparent molecular masses of 60, 85 and 280 kDa (Fig. 2A). These proteins were equivalent to the
TGF- type I, II, and III receptors, respectively. A 40-kDa
component was seen in fetal lung fibroblasts, but not in adult lung
fibroblasts. It is not clear whether it was an isoform of the TGF-
type I receptor or an uncharacterized TGF- binding protein. A
lower molecular mass species (35 kDa) was also detected in both adult
and fetal lung fibroblasts.
receptors in lung fibroblasts. A, receptor cross-linking
assays were used to measure cell surface TGF- receptor expression.
Monolayer cultures of adult lung fibroblast cells (lane 1) or
fetal rat lung fibroblasts (lane 2) in six-well plates were
incubated with 100 pM of I-TGF-
1. The
receptors were cross-linked with disuccinimidyl suberate. Cell extracts
were resolved on a SDS-polyacrylamide gel under reducing conditions.
The TGF- receptor type III (TRIII), type II (TRII), and type I (TRI) were visualized
after autoradiography; B, Northern blotting was used to
analyze expression of TRI and TRII mRNAs. Each lane contained
2 µg of mRNA prepared from adult lung fibroblasts (lane 1)
or fetal lung fibroblasts (lane 2). mRNA was subjected to
electrophoresis through a formaldehyde denaturing agarose gel and,
after Northern blotting, hybridized with radiolabeled TRI or
TRII cDNA probe and quantified by scanning densitometry. Scan
values for TRI and TRII mRNA signals were normalized with the
scan data of glyceraldehyde phosphate dehydrogenase. Ratios were
expressed in arbitrary units.
type I and
II receptor were further examined by Northern blot analysis (Fig. 2B). TRII mRNA was detected as a
5.1-kilobase species expressed in adult lung fibroblasts and in fetal
lung fibroblasts. Two TRI mRNA species of approximately 6.1 and
4.0 kilobases were observed in adult lung fibroblasts and in fetal lung
fibroblasts. TRII and TRI were differentially expressed in
fetal and adult lung fibroblasts., we used a dominant-negative inhibitory
approach to create a loss-of-function mutation of TRII. We
constructed a kinase-deficient cytoplasmic deletion mutant of rat
TRII (TRIIK). The truncated TRII and wild type
TRII were cloned into pcDNA3, under the transcriptional control of
the cytomegalovirus immediate early gene promoter and enhancer. We
transfected rat lung fibroblasts with rat TRIIK or TRII.
The expression level of the truncated receptor was tested by affinity
labeling of transfected cells with I-TGF-
1 (Fig. 3). Fibroblasts transfected with TRIIK yielded a
TGF- affinity-labeled product of 45 kDa, the predicted size of the
truncated receptor TRII. A high level of TRIIK were
expressed on the cell surface of fetal and adult lung fibroblasts. The
truncated receptor was able to bind ligand. I-TGF-
1
binding to TRIIK was efficiently competed by unlabeled
ligand, the same as the wild type TRII binding.
RII
lacking the cytoplasmic kinase domain in lung fibroblasts. Monolayer
cultures of fetal rat lung fibroblasts or adult rat lung fibroblasts
transiently transfected with rat TRIIK or empty pCDNA3 vector
were incubated with I-TGF-
1 in the absence(-)
or in the presence (+) of 80 nM unlabeled TGF-1.
Bound I-TGF-
1 was cross-linked with disuccinimidyl
suberate. Cell lysates were subjected to SDS-polyacrylamide gel
electrophoresis under reducing conditions and then were
autoradiographed. Lanes 1, 2, 5, and 6, fetal lung
fibroblasts; lanes 3, 4, 7, and 8, adult lung
fibroblasts.
H]-thymidine incorporation was measured to
assess the proliferation rate of lung fibroblasts expressing the
truncated TRII. Adult lung fibroblasts were transfected with
TRIIK or empty vector. Transfected fibroblasts were cultured
in the absence or presence of TGF-1 (1 ng/ml) for 20 h.
TRIIK completely blocked the TGF-1-dependent DNA
synthesis (Fig. 4A). When adult lung fibroblasts were
transfected with 1 µg of TRIIK and 1 µg of wild type
rat TRII, the growth responsiveness of adult lung fibroblasts to
TGF-1 was restored by adding the wild type TRII cDNA (Fig. 4B). Fetal lung fibroblasts transfected with
TRIIK were unable to convey TGF-1-dependent growth
inhibition (Fig. 5A). Similarly, the diminished
response to TGF-1 by fetal fibroblasts was rescued by
cotransfection of TRIIK with the wild type TRII (Fig. 5B). The results show that the kinase-defective
deletion of TRII is a dominant-acting inhibitor of signal
transduction by TGF- receptor complex and that TRII was
required for TGF--dependent positive and negative growth response.
RII on
TGF--induced growth. A, adult lung fibroblasts were
transfected with TRIIK or empty vector. Transfected
fibroblasts were cultured in the absence or presence of TGF-1 (1
ng/ml) for 20 h. DNA synthesis was assayed by measuring
[H]thymidine incorporation; B,
restoration of TGF-1-dependent growth response. Adult lung
fibroblasts were transfected with 1 µg of TRIIK and 1
µg of wild type rat TRII. The cells were treated with
TGF-1 for 20 h and then assayed for DNA synthesis. The bars represent the means ± S.E. (n =
3).
RII on
TGF--induced antiproliferative response. A, fetal lung
fibroblasts were transfected with TRIIK or empty vector.
Transfected fibroblasts were cultured in the absence or presence of
TGF-1 (5 ng/ml) for 20 h. DNA synthesis was assayed by measuring
[H]thymidine incorporation; B,
restoration of TGF-1-dependent growth inhibition. Fetal lung
fibroblasts were cotransfected with 1 µg of TRIIK and 1
µg of wild type rat TRII. The cells were treated with
TGF-1 for 20 h and then assayed for DNA synthesis. The bars represent the means ± S.E. (n =
3).
isoforms has been detected in the lung at
critical times during development(2, 23) . The
expression pattern and known biological activities of TGF- suggest
an important role for this factor in lung development. In this study,
the effects of TGF- on growth of fetal and adult lung fibroblasts
were characterized, and the role of TRII in TGF--induced
signaling was examined. stimulates
proliferation of adult fibroblasts at low concentration but remains
inactive at higher concentration, while inhibiting growth of fetal
fibroblasts regardless of concentration. An example of the bifunctional
nature of TGF- has been reported in human smooth muscle
cells(24) . TGF- is mitogenic only when used at lower
concentration, whereas at higher concentration it inhibits DNA
synthesis. More recent studies have demonstrated that TGF- can act
as a negative or positive growth regulator in two sublines of the same
epithelial cells, depending on their commitment to
differentiation(25) . TGF- activates two different signal
transduction pathways through activating different Ras proteins and
myelin basic protein kinases(26) . and the
expression of its cellular receptors. The two fibroblast cell lines
possess all three TGF- receptors; however, fetal fibroblasts
expressed a much higher level of cell surface type II receptor at the
mRNA and the protein level than adult lung fibroblasts. The finding is
in agreement with our previous study (20) that the expression
of TRII is developmentally regulated in the lung. This raises the
possibility that the bifunctional action of TGF- on lung
fibroblasts may depend on their developmental stage.RII acts as a dominant inhibitor
of TGF- signal transduction. The proliferative action and the
growth inhibition of TGF- were abolished by overexpression of
TRIIK. TGF--induced signaling events leading to growth
stimulation are likely to be different at some level from that of
growth inhibition. TGF- increases c-fos expression in
growth-inhibited cells but not in growth-stimulated cells (27) . An increase in retinoblastoma protein phosphorylation is
seen in TGF--induced proliferation(28) . However, our
results indicated TRII is essential for both pathways. This
finding suggests that binding of TGF- to TRII may be a common
step required for the TGF- signaling cascade. The TGF- signal
transduction pathways for the growth stimulation and the growth
inhibition may diverge after binding of TGF- to TRII and then
different intracellular signals might be activated. An intriguing
question raised by this study is how TGF- exerts its multiplicity
of effects through interaction with its transmembrane receptors. The
signaling specificity could occur through interaction of TRII with
different types of type I receptor. The characterization of other
members of TGF- receptor family, particularly type I receptors,
might allow us to determine the mechanism of multiple effects of
TGF-. stimulates
proliferation of adult lung fibroblasts, while inhibiting growth of
fetal lung fibroblasts. We have shown that the truncated form of
TRII blocked both growth-stimulating and inhibition effects of
TGF-. The results suggest that TGF- type II receptor is
indispensable for the signal transduction pathway and the diverse
regulatory effects of TGF-.
),
transforming growth factor-; TRI, transforming growth
factor- type I receptor; TRII, transforming growth
factor- type II receptor; TRIII, transforming growth
factor- type III receptor; DMEM, Dulbecco's modified
Eagle's medium; PCR, polymerase chain reaction.
We thank Rob Silbajoris and Erick Larson for technical
support. We also thank Dr. Jo Rae Wright for her critical reading of
the manuscript.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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R. A. Anders, J. J. E. Dore Jr., S. L. Arline, N. Garamszegi, and E. B. Leof Differential Requirement for Type I and Type II Transforming Growth Factor beta Receptor Kinase Activity in Ligand-mediated Receptor Endocytosis J. Biol. Chem., September 4, 1998; 273(36): 23118 - 23125. [Abstract] [Full Text] [PDF]
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