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doi: 10.1242/10.1242/jcs.00229
Hypothesis |
Departments of Cell Biology and Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
* Author for correspondence (e-mail: annesj01{at}med.nyu.edu)
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Summary |
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 Top Summary IntroductionThe components and assembly...The latent TGFß...TGFß activation, or...TGFß biology and the...ConclusionReferences |
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Key words: Transforming growth factor-ß, Activation, Sensor
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Introduction |
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TopSummaryIntroductionThe components and assembly...The latent TGFß...TGFß activation, or...TGFß biology and the...ConclusionReferences |
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). Defects in TGFß function are associated with a number
of pathological states, including tumor cell growth, fibrosis and autoimmune
disease (Blobe et al., 2000).
The TGFß signal transduction pathway is a topic of intense investigation,
and much progress has been achieved in characterizing the proteins involved.
The extracellular concentration of TGFß activity is primarily regulated
by the conversion of latent TGFß to active TGFß; tissues contain
significant quantities of latent TGFß and activation of only a small
fraction of this latent TGFß generates maximal cellular responses. Yet,
despite this fact, many researchers overlook or misunderstand latent TGFß
activation. This may be because TGFß biology is unusual: (1) the
TGFß propeptide remains tightly bound to the cytokine after the bonds
between the propeptide and mature TGFß are cleaved; (2) the interaction
between TGFß and its propeptide renders the growth factor latent; (3) the
TGFßs are secreted as a complex in which a second gene product is
covalently bound to the TGFß propeptide; and (4) upon secretion, the
TGFß large latent complex (LLC) may be covalently linked to the
extracellular matrix (ECM) (Fig.
1). Moreover, the multiple activators of the latent TGFß
complex comprise a seemingly unrelated group of molecules, and the three
TGFß isoforms — TGFß1, TGFß2 and TGFß3 — have
similar properties in vitro, but distinct effects in vivo. Here, we present a
model in which latent TGFß is considered to be a molecular sensor that
responds to specific signals by releasing TGFß. These signals are often
perturbations of the ECM that are associated with phenomena such as
angiogenesis, wound repair, inflammation and, perhaps, cell growth. Changes in
the cell's environment are relayed to the sensor by a number of different
molecules, including proteases, integrins and thrombospondin (TSP). We propose
that consideration of latent TGFß in this manner unifies the processes of
TGFß secretion, sequestration and activation and clarifies features of
TGFß biology.
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The components and assembly of the sensor |
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TopSummaryIntroductionThe components and assembly...The latent TGFß...TGFß activation, or...TGFß biology and the...ConclusionReferences |
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, are
cleaved from the mature TGFß 24-kDa dimer in the trans Golgi by
furin-type enzymes. Early in the assembly of the TGFß LLC, disulfide
linkages are formed between cysteine residues of LAP and specific cysteine
residues in the latent-TGFß-binding protein (LTBP)
(Fig. 2, step 1)
(Saharinen et al., 1996;
Gleizes et al., 1996;
Miyazono et al., 1991). LTBP
is a member of the LTBP/fibrillin protein family, which comprises fibrillin-1,
fibrillin-2 and fibrillin-3, and LTBP-1, LTBP-2, LTBP-3, and LTBP-4
(Ramirez and Pereira, 1999).
These proteins contain multiple epidermal-growth-factor-like repeats as well
as unique domains containing eight cysteine residues (8-cys domains)
(Fig. 1)
(Kanzaki et al., 1990;
Tsuji et al., 1990;
Sinha et al., 1998). LTBP-1,
LTBP-3 and LTBP-4 form a subset within the family based on their ability to
bind LAP. Only the third of the four 8-cys domains within each of the
LAP-binding LTBPs can disulfide bond to LAP
(Saharinen and Keski-Oja,
2000); the other 8-cys domains may localize LTBPs to the ECM
(Unsold et al., 2001). As part
of the LLC, TGFß cannot interact with its receptors, because the
TGFß1, 2 and 3 prodomains (LAPs) function as inhibitors owing to their
noncovalent, high-affinity association with TGFß
(Lawrence et al., 1984;
Dubois et al., 1995). We use
the term `TGFß activation' to refer to the liberation of TGFß from
the latent complex. LTBP and its bound latent TGFß are found primarily as
components of the matrix. Indeed, the N-terminal region of LTBP-1 is
covalently cross-linked to ECM proteins by transglutaminase (tTGase)
(Fig. 1;
Fig. 2, step 3)
(Nunes et al., 1997). However,
an LTBP binding partner in the ECM has not been unambiguously identified.
(Although our discussion is based primarily upon LTBP-1, the similar sequences
and domain structures of the LTBPs suggest that most of our statements are
generally applicable.) LTBP-1 exists in a range of sizes (125-210 kDa) owing
to the use of two independent promoters as well as differences in splicing and
glycosylation (Koski et al.,
1999). Most forms of LTBP-1 have two protease-sensitive regions;
proteolysis at the more N-terminal site can release a truncated form of LTBP-1
(or LLC) from the ECM (Fig. 2,
step 4) (Taipale et al.,
1994). The functions of LTBP-1 may vary depending on its size. For
example, LTBP-1 that contains an N-terminal extension (LTBP-1L) generated by
use of the upstream promoter associates more readily with the ECM than does
LTBP-1 (LTBP-1S) formed by use of the downstream promoter
(Olofsson et al., 1995).
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In our model the three components of the LLC —TGFß, LAP and
LTBP- constitute a sensor (Fig.
1). This sensor consists of an effector (TGFß), a localizer
(LTBP) and a detector (LAP). We consider TGFß to be the effector because
it is the output of the sensor, LTBP to be the localizer because it interacts
with the ECM, and LAP to be a detector because any activation mechanism must
act on LAP, since LAP is sufficient to inhibit TGFß bioactivity
(Gentry and Nash, 1990). The
characterization of the mechanisms controlling the liberation of TGFß
from the latent complex is central to the consideration of TGFß action
because the release of TGFß determines the free TGFß levels. Several
mechanisms for the activation of latent TGFß complexes are known
(Munger et al., 1997;
Koli et al., 2001), and a
diverse group of activators, including proteases, TSP-1, the integrin
vß6, reactive oxygen species (ROS) and low
pH, can activate TGFß. However, the biological advantage of releasing
TGFß as a latent complex and the relationships between the various
activators are obscure. By considering the LLC as a sensor, we think that the
role of the latent complex and its activators is clarified.
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The latent TGFß complex as a sensor |
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TopSummaryIntroductionThe components and assembly...The latent TGFß...TGFß activation, or...TGFß biology and the...ConclusionReferences |
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These features of a smoke detector have analogies in the structure/function
of the LLC. The latent TGFß complex is a sensor that responds to
extracellular perturbations and couples these events with the activation of
latent TGFß. As in the case of a smoke detector, the LLC must be
appropriately assembled to function properly. The latent TGFß complex is
formed intracellularly and proTGFß that fails to complex with LTBP is
inefficiently secreted (Miyazono et al.,
1991). Furthermore, failure to localize appropriately the latent
TGFß complex in the extracellular milieu alters the effectiveness of
activation of latent TGFß. Evidence to support this supposition derives
from the ability of both inhibiters of tTGase
(Kojima and Rifkin, 1993) and
antibodies raised against LTBP-1 to block the activation of latent TGFß
(Flaumenhaft et al., 1993;
Dallas et al., 1995;
Nakajima et al., 1997;
Gualandris et al., 2000). In
addition, mice that are null for LTBP-3 or LTBP-4 demonstrate phenotypes
consistent with altered TGFß signaling
(Dabovic et al., 2002;
Sterner-Kock et al., 2002).
Specific LTBP isoforms may differentially localize the latent complex, and
different LTBP isoforms may preferentially associate with specific TGFß
isoforms. In fact, the third 8-cys domain of LTBP-4 is reported to bind only
to TGFß1 (Saharinen and Keski-Oja,
2000).
As with many sensing devices, the TGFß complex must be made competent
to signal (i.e. turned on). Competence requires proteolytic separation of LAP
from TGFß (i.e. processing of proLLC into LLC;
Fig. 2, step 2). ProLLC cannot
be activated by any known mechanism, including heat (85°C for 10 min) or
pH (1.5). Although proteolytic cleavage of proTGFß may occur in the
Golgi, this is not always the case. For example, multiple glioblastoma cell
lines primarily secrete unprocessed proTGFß as part of proLLC
(Leitlein et al., 2001). To be
a substrate for TGFß activation, this proTGFß must be processed at
the furin protease site by a plasma-membrane-bound furin or another
extracellular protease, such as plasmin
[(Lyons et al., 1988) our own
observation]. Indeed, the addition of furin inhibitors to glioma cultures
blocks proTGFß processing. Once pro-TGFß is processed, the complex
is `on' (competent), and it can be activated. In our model, we distinguish
between the processing of proTGFß (turning the sensor on or making it
competent) and activating TGFß. Thus, processing of proTGFß is a
regulated step affecting TGFß bioavailability. Furthermore, it is
interesting to speculate that proTGFß performs a distinct signaling
function from TGFß (perhaps through integrin ligation) similar to the
separate signaling capacities of proNGF and NGF
(Lee et al., 2001).
We propose that the sensing function of the latent TGFß complex
resides mainly within LAP. This conclusion is supported by several facts: (1)
the known TGFß activators (e.g. plasmin, TSP-1 and
vß6 integrin) interact directly with LAP
(Lyons et al., 1988;
Ribeiro et al., 1999;
Munger et al., 1999); (2) the
physical conditions that release active TGFß (e.g. heat and pH extremes)
denature LAP but not TGFß (Lawrence
et al., 1985); and (3) LAP adopts different conformations in
unbound and TGFß1-bound states
(McMahon et al., 1996).
Moreover, the relative lack of amino acid sequence conservation among LAP
isoforms compared with TGFß isoforms may provide a mechanism for
diversification of TGFß activation. For example, latent TGFß1 and
TGFß3 can be activated by vß6, whereas
TGFß2 cannot (Annes et al.,
2002; Munger et al.,
1999). This is due to the presence of the integrin-binding
sequence RGD in TGFß1 and three LAPs but not TGFß2 LAP. Sequence
analysis reveals only 34-38% amino acid sequence identity among LAP isoforms
(LAPß1, ß2, ß3) compared with 75% identity among TGFß
isoforms (TGFß1, 2, 3). However, there is considerable conservation of
LAP isoform sequences across species (Table
1). The amino acid sequence identity shared by human TGFß1
LAP and chicken TGFß1 LAP is 90%
(Table 1). We suggest that the
relative lack of conservation between LAP isoforms allows LAPs to act as
isoform-specific detectors. The divergence between LAP amino acid sequences
may explain, in part, the isoform-specific functions of TGFß in vivo,
despite the overlapping expression patterns of the isoforms in vivo and their
virtually identical functions in vitro. For example, TGFß1 and TGFß2
mRNAs are the predominant isoforms observed in the mouse heart during
endocardial cushion and valvular genesis
(Akhurst et al., 1990;
Millan et al., 1991), and both
recombinant TGFß1 and TGFß2 function in in vitro assays of
endocardial cell transformation (Nakajima
et al., 1997). However, TGFß2-/- but not
TGFß1-/- mice have defects in endocardial and
valvular genesis (Sanford et al.,
1997). Structural differences in LAP may provide a mechanistic
basis for activation of TGFß2 and not TGFß1 in this setting.
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The paradigm of latent TGFß as a sensor also suggests that the response threshold of the latent TGFß complex might be modulated. Although no examples have been reported, the existence of molecules that either bind LAP and prevent an activator from binding or, conversely, alter the conformation of LAP to facilitate recognition by an activating molecule is a likely possibility.
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TGFß activation, or tripping the TGFß sensor |
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TopSummaryIntroductionThe components and assembly...The latent TGFß...TGFß activation, or...TGFß biology and the...ConclusionReferences |
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Proteolytic activation of latent TGFß
A number of proteases including plasmin, MMP-2 and MMP-9 have been
identified in vitro as latent TGFß activators
(Sato and Rifkin, 1989;
Yu and Stamenkovic, 2000).
Plasmin and MMP2/9 belong to the serine protease and metalloprotease families,
respectively. These protease families, along with the adamalysin-related
membrane proteinases, are the primary enzymes involved in ECM degradation
(Werb, 1997). The ability of
these enzymes to activate the latent TGFß complex couples matrix turnover
with the production of a molecule, TGFß, that has a primary role in
maintaining matrix integrity and stability
(Ignotz and Massague, 1986;
Verrecchia et al., 2001).
There are three ways in which proteases might facilitate the activation of
latent TGFß. First, the protease-sensitive hinge region in LTBP is a
potential target for the liberation of a still-latent remnant of the LLC,
which would have to be further processed for activation
(Taipale et al., 1994).
Second, as discussed above, proteases can act in the extracellular environment
to convert proLLC to LLC and thereby render the latent complex activation
competent. Third, proteolytic cleavage of LAP, resulting in destabilization of
LAP-TGFß interactions, might release active TGFß from its latent
complex (Lyons et al., 1988).
Degradation of LAP is an attractive mechanism for sensor activation because
heightened levels of proteases are associated with several processes that
involve increased TGFß activation. However, thus far, mice that have null
mutations in the genes that encode the known activating proteases do not
demonstrate any phenotype consistent with TGFß deficiency. This may
reflect redundancy among the activating enzymes or the fact that these mice
have not been studied in the correct context.
Activation by thrombospondin-1
The matricellular protein TSP-1 activates latent TGFß
(Schultz-Cherry and Murphy-Ullrich,
1993). The mechanism involves a direct interaction between TSP-1
and LAP (reviewed by Murphy-Ullrich and
Poczatek, 2000). A short amino acid sequence (RFK) located between
the first and second type 1 properdin-like repeats is believed to be
responsible for latent TGFß activation. Surprisingly, a tetrapeptide
(KRFK) also functions as a TGFß activator in vitro and in vivo
(Crawford et al., 1998). This
peptide probably acts by disrupting the non-covalent interactions between LAP
and TGFß. Interestingly, TSP-1 null mice demonstrate a partial phenotypic
overlap with TGFß1-null animals, thereby supporting the contention that
TSP-1 is an in vivo activator of latent TGFß
(Crawford et al., 1998). TSP-1
facilitates wound repair in several ways: modulation of cell adhesion,
promotion of angiogenesis, and reconstruction of the matrix
(Frazier, 1991). The
correlation between wounding and enhanced TSP-1 expression suggests that TSP-1
is an appropriate molecule for activation of the latent complex, since
TGFß plays a prominent role in wound healing
(Border and Ruoslahti, 1992).
TSP-1 is also expressed throughout development in a number of tissues, where
it may function as a TGFß activator
(Iruela-Arispe et al., 1993;
Majack et al., 1987).
Activation by integrins
Integrins are dimeric cell surface receptors composed of and ß
subunits (reviewed by van der Flier and
Sonnenberg, 2001). The first integrin to be identified as a
TGFß activator was vß6
(Munger et al., 1999). The
mechanism of activation depends upon a direct interaction between
vß6 and the RGD amino acid sequence present
in LAP ß1 and LAP ß3 (Fig.
1). The expression of vß6 is
restricted to epithelia, and in most epithelia the integrin is normally
expressed at low levels (Breuss et al.,
1993). In response to wounding or inflammation, the expression of
vß6 increases
(Breuss et al., 1995;
Miller et al., 2001).
Therefore, epithelial cell upregulation of
vß6 and subsequent TGFß activation is a
situation in which the cellular response to a process (inflammation) produces
a potent suppressor of that process. Consistent with both the ability of
ß6 integrin to activate latent TGFß and the pro-fibrotic effects of
TGFß (Border and Ruoslahti,
1992) is the observation that wild-type mice develop pulmonary
inflammation followed by fibrosis in response to the inflammatory and
profibrotic drug bleomycin, but integrin ß6-/- mice have only
a minor fibrotic response (Munger et al.,
1999). In addition, global analysis of gene expression in the
lungs of integrin ß6-/- mice treated with bleomycin compared
with similarly treated wild-type mice demonstrates a pronounced failure to
induce expression of TGFß-regulated genes in the mutant mice. These
results indicate that fibrosis is the result of excess TGFß produced by
heightened expression of vß6 in response to
the inflammatory stimulus. Since TGFß dramatically increases the
generation of vß6 by primary airway
epithelial cells in vitro (Wang et al.,
1996), it is likely that bleomycin triggers a feed-forward
mechanism for coordinately up-regulating integrin expression and TGFß
generation. We suggest that fibrosis is the result of a failure to interrupt
this feed-forward loop that is perpetuated by persistent ECM perturbation
after wounding or inflammation.
Recently, Mu et al., reported that the integrin
vß8 can activate latent TGFß1
(Mu et al., 2002). It is
interesting that activation by vß8 requires
protease (MT1-MMP) activity in addition to the integrin. Although the exact
roles of MT1-MMP and vß8 in this activation
mechanism remain to be elucidated, the authors suggest that the integrin
concentrates latent TGFß on the cell surface, where it is subsequently
activated by MT1-MMP. A cooperative interaction between different classes of
latent TGFß activator has been suggested previously
(Yehualaeshet et al., 1999):
the cell-surface-associated proteins (CD36 and TSP-1) concentrate latent
TGFß on the membrane where it is subsequently activated by plasmin.
Activation by reactive oxygen species (ROS)
Barcellos-Hoff and her co-workers showed that when ROS are produced in
vitro (either by ionizing radiation or a metal-catalyzed ascorbate system) or
in vivo after irradiation, latent TGFß1 is activated
(Barcellos-Hoff et al., 1994;
Barcellos-Hoff and Dix, 1996).
This is probably a result of scissions and side group modifications caused by
hydroxyl radicals that disable LAP. The response of the TGFß sensor to
certain types of oxidative stress may reflect a need to produce TGFß
during processes such as inflammation and apoptosis that can cause ECM damage
through the production of ROS.
Activation by pH
Latent TGFß present in conditioned medium is activated by mild acid
treatment (pH 4.5) (Lyons et al.,
1988), which probably denatures LAP, thereby disturbing the
interaction between LAP and TGFß. In vivo, a similar pH is generated by
osteoclasts during bone resorption when an integrin-dependent sealing zone is
generated between the bone and the cell
(Teitelbaum, 2000). Since the
bone matrix deposited by osteoblasts is rich in latent TGFß, the acidic
environment created by osteoclasts in vitro might result in latent TGFß
activation (Oreffo et al.,
1989; Oursler,
1994).
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TGFß biology and the role of the sensor |
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TopSummaryIntroductionThe components and assembly...The latent TGFß...TGFß activation, or...TGFß biology and the...ConclusionReferences |
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The effect of improper LLC assembly is illustrated in the phenotypes of
mice that have null mutations in the LTBP-3 or LTBP-4 genes.
LTBP-3-/- mice display bone phenotypes including
osteoarthritis and osteopetrosis (Dabovic
et al., 2002), which also occur in mice that have defective
TGFß signaling pathways resulting from either mutations in Smad3
(osteoarthritis) (Yang et al.,
2001) or the expression of a dominant negative type II TGFß
receptor in osteoblasts (osteopetrosis)
(Filvaroff et al., 1999).
LTBP-4-/- mice develop pulmonary emphysema, cardiac
myopathy and colorectal cancer
(Sterner-Kock et al., 2002).
It is interesting that the defects in LTBP-4-/- animals
are consistent with both increased and decreased TGFß activity: (1)
emphysema has been associated with both increased and decreased TGFß
activity (Kaartinen et al.,
1995; Zhou et al.,
1996); (2) cardiac myopathy is associated with increased TGFß
activity (Schultz Jel et al.,
2002); and (3) colorectal cancer is associated with a lack of
TGFß activity (reviewed by Gold,
1999). Thus, the phenotypes displayed by the LTBP-mutant mice are
not necessarily described by a simple deficit in TGFß.
Does consideration of TGFß biology in terms of the sensor model
clarify aspects of this situation? In the absence of a specific LTBP,
TGFß may be (a) inefficiently secreted and unable to localize to the ECM
or (b) secreted in a complex with a different LTBP, presuming the cell
expresses more than one LTBP isoform. According to the sensor model, these
scenarios have varying effects on TGFß activity. Whereas decreasing
TGFß secretion results in less TGFß activity, eliminating or
changing the isoform of LTBP is predicted to modulate the localization and/or
activation pattern of the complex in a context-dependent manner. Therefore, it
is not accurate to say that there is more or less TGFß in these LTBP-null
mice; rather, the distribution and timing of TGFß activities may be
modified. For instance, LTBP-3-null mice have increased bone density, which is
similar to transgenic mice expressing a dominant negative type II TGFß
receptor under control of the osteocalcin promoter, but TGFß1-null mice
become osteoporotic rather than osteopetrotic as they age
(Geiser et al., 1998). It is
likely that the LTBP-3-/- phenotype emphasizes the effect
of altered local distribution of a TGFß in a cell or tissue type, whereas
the TGFß1-null phenotype illustrates the result of a global loss of the
cytokine.
A localization defect can occur not only when there is a defect in LLC
assembly but also if there is an alteration in ECM binding. This might occur
if the binding partner for LTBP is missing or defective or if tTGase, which
cross-links LLC to the matrix, is absent. However, mice with a null mutation
in the TGase2 gene do not display a phenotype consistent with a
global deficit in TGFß (Nanda et al.,
2001; De Laurenzi and Melino,
2001). This may indicate the existence of redundant TGases. We
suggest that closer examination will reveal TGFß-related changes in those
tissues or cells that depend exclusively upon TGase2 for fixing of the sensor
into the ECM.
An example of a human pathology related to altered TGFß latency is
Camurati-Engelmann disease (CED). This autosomal dominant disease results from
mutations in the TGFß1 LAP sequence and is characterized by hyperostosis
and sclerosis of the base of the skull and long bones, respectively
(Janssens et al., 2000;
Kinoshita et al., 2000;
Nishimura et al., 2002). Most
of the mutations in CED occur at or close to the cysteine residues involved in
the interchain bonds of the LAP dimer. Earlier work with mutated
TGFß cDNAs indicated that proper disulfide bond formation is
required to produce latent TGFß, because mutation of C223 and C225 yields
constitutively active TGFß (Brunner et
al., 1989). Studies with fibroblasts from three patients with CED
mutations at or close to C225 indicate that the mutant cells produce
substantially more active TGFß1 than do wild-type cells
(Saito et al., 2001). Why the
CED cells generate enhanced levels of active TGFß is not clear, since
disulfide bonds between the appropriate cysteine residues do form; however,
the answer to this question may be clarified by consideration of the available
data on CED in terms of the sensor model of latent TGFß.
There are curious differences between the TGFß produced by wild-type
and CED fibroblasts. First, CED and normal cells produce similar amounts of
total TGFß1 as judged by TGFß1 LAP immunoblotting; however, after
acid activation of the latent TGFß, medium conditioned by CED cells
contains five times the amount of active TGFß1 compared with medium
conditioned by normal cells (Saito et al.,
2001). Thus, there is a discrepancy between the amounts of
immunoreactive and biologically active TGFß1 produced by the two cell
types. Second, there is a difference in the degree of proteolytic processing
of proTGFß1 by CED fibroblasts compared with wild-type cells
(Saito et al., 2001). Whereas
wild-type cells produce substantial amounts of unprocessed proTGFß1, CED
cells process all of the proTGFß1 to LAP and TGFß1. According to the
sensor model, all of the latent complex produced by CED, but not wild-type,
cells is in an activation-competent state (i.e. the CED LLC is `on' because it
has been proteolytically cleaved) (Fig.
2, step 2). This is in contrast to the primarily proTGFß1
produced by wild-type cells. This form of TGFß is considered to be `off'
and cannot be activated by any known mechanism. Our definition of `on' or
competent latent TGFß clarifies why there is significantly more TGFß
activity in CED, compared with wild-type, conditioned medium following acid
activation, despite the fact that the cells secrete equal amounts of the
TGFß propeptide. Apparently, the CED mutation alters the susceptibility
of LAP to proteolysis by furin and or other processing proteases. It is
interesting to speculate that this same conformational change might make LAP
more sensitive to activating proteolytic events. Therefore, we suggest that
the latent TGFß complex of CED individuals is assembled and localized
normally but is hyper-responsive.
Two reports indicate that altered expression of molecules that activate the
latent complex result in pathologies. The first report describes lung fibrosis
after bleomycin treatment (Munger et al.,
1999). In this example, fibrosis is impaired in mice missing
ß6 integrin, an activator important for generating TGFß during
inflammatory states (Munger et al.,
1999). A second example is the developmental pulmonary emphysema
observed in fibrillin-1-hypomorphic mice (E. R. Neptune, P. A. Frischmeyer, D.
A. Arking et al., personal communication). These animals have a defect in the
terminal septation of the alveoli that correlates with excess of both
TGFß and TGFß signaling. It is likely that the defect in terminal
alveolar septation in these mice is due to excess TGFß, because higher
levels of TGFß activity were detected in the lungs of mutant animals, and
the administration of TGFß-neutralizing antibodies reverses the
pathology. The lack of fibrillin might result in defective localization of LLC
and subsequent TGFß activation, because the LLC normally localizes with
fibrillin-1 (Taipale et al.,
1996). Thus, the abnormal distribution of LLC results in
inappropriate activation. An additional explanation as to why
fibrillin-1-/- mice have altered TGFß levels is revealed
through consideration of latent TGFß as a sensor. We propose that the
altered ECM of the mutant mice cues cells to remodel the matrix and that this
remodeling is associated with the inappropriate and persistent expression of a
TGFß activator.
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Conclusion |
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TopSummaryIntroductionThe components and assembly...The latent TGFß...TGFß activation, or...TGFß biology and the...ConclusionReferences |
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The sensor model clearly separates two aspects of TGFß biology that are often misunderstood: the processing of the proTGFß (turning the sensor `on') and the liberation of TGFß from the latent complex. Visualizing the latent TGFß complex as a sensor has offered insight into the somewhat confusing results reported for Camurati-Engelmann syndrome. Moreover, the consideration of active TGFß formation in terms of a matrix-localized sensor makes it easier to imagine the existence of accessory molecules that interact with the sensor and either potentiate or dampen activation as well as the context-specific use of or localization by specific LTBP forms. In addition, a commonality of TGFß activators is made apparent by representing TGFß activation as a process involving sensor detection: all identified TGFß activators are associated with ECM perturbation. Finally, the latent TGFß sensor could allow the activities of the three nearly identical TGFß cytokines to be distinguished, in part, through a diversity in LAP sequences that permits differential response to individual activators. By viewing latent TGFß as a matrix-localized sensor, we can understand TGFß assembly, latency, activation and activity as coordinated events rather than as disparate aspects of TGFß biology.
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Acknowledgments |
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Footnotes |
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We refer to the N-terminal sequence of the TGFß proprotein
(proTGFß) as either the TGFß propeptide or LAP. We also distinguish
between two forms of LLC; LLC consists of LTBP, TGFß and LAP, whereas
complexes that contain LTBP plus proTGFß are called proLLC. 
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References |
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TopSummaryIntroductionThe components and assembly...The latent TGFß...TGFß activation, or...TGFß biology and the...ConclusionReferences |
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Annes, J. P., Rifkin, D. B. and Munger, J. S. (2002). The integrin alpha Vbeta6 binds and activates latent TGFbeta3. FEBS Lett. 511, 65-68.[CrossRef][Medline]
Barcellos-Hoff, M. H. and Dix, T. A. (1996).
Redox-mediated activation of latent transforming growth factor-beta 1.
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Barcellos-Hoff, M. H., Derynck, R., Tsang, M. L. and Weatherbee, J. A. (1994). Transforming growth factor-beta activation in irradiated murine mammary gland. J. Clin. Invest. 93,892 -899.
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(2000). Role of transforming growth factor beta in human disease.
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N. Shweke, N. Boulos, C. Jouanneau, S. Vandermeersch, G. Melino, J.-C. Dussaule, C. Chatziantoniou, P. Ronco, and J.-J. Boffa Tissue Transglutaminase Contributes to Interstitial Renal Fibrosis by Favoring Accumulation of Fibrillar Collagen through TGF-{beta} Activation and Cell Infiltration Am. J. Pathol., September 1, 2008; 173(3): 631 - 642. [Abstract] [Full Text] [PDF]
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E.-S. Akool, A. Doller, A. Babelova, W. Tsalastra, K. Moreth, L. Schaefer, J. Pfeilschifter, and W. Eberhardt Molecular Mechanisms of TGF{beta} Receptor-Triggered Signaling Cascades Rapidly Induced by the Calcineurin Inhibitors Cyclosporin A and FK506 J. Immunol., August 15, 2008; 181(4): 2831 - 2845. [Abstract] [Full Text] [PDF]
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A. Alfranca, J. M. Lopez-Oliva, L. Genis, D. Lopez-Maderuelo, I. Mirones, D. Salvado, A. J. Quesada, A. G. Arroyo, and J. M. Redondo PGE2 induces angiogenesis via MT1-MMP-mediated activation of the TGF{beta}/Alk5 signaling pathway Blood, August 15, 2008; 112(4): 1120 - 1128. [Abstract] [Full Text] [PDF]
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 L. D. Moore, T. Isayeva, G. P. Siegal, and S. Ponnazhagan Silencing of Transforming Growth Factor-{beta}1 In situ by RNA Interference for Breast Cancer: Implications for Proliferation and Migration In vitro and Metastasis In vivo Clin. Cancer Res., August 1, 2008; 14(15): 4961 - 4970. [Abstract] [Full Text] [PDF]
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M. J. Gros, P. Naquet, and R. R. Guinamard Cell Intrinsic TGF-{beta}1 Regulation of B Cells J. Immunol., June 15, 2008; 180(12): 8153 - 8158. [Abstract] [Full Text] [PDF]
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J. H. McCarty, M. Barry, D. Crowley, R. T. Bronson, A. Lacy-Hulbert, and R. O. Hynes Genetic Ablation of {alpha}v Integrins in Epithelial Cells of the Eyelid Skin and Conjunctiva Leads to Squamous Cell Carcinoma Am. J. Pathol., June 1, 2008; 172(6): 1740 - 1747. [Abstract] [Full Text] [PDF]
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T. Tabata, H. Kawakatsu, E. Maidji, T. Sakai, K. Sakai, J. Fang-Hoover, M. Aiba, D. Sheppard, and L. Pereira Induction of an Epithelial Integrin {alpha}v{beta}6 in Human Cytomegalovirus-Infected Endothelial Cells Leads to Activation of Transforming Growth Factor-{beta}1 and Increased Collagen Production Am. J. Pathol., April 1, 2008; 172(4): 1127 - 1140. [Abstract] [Full Text] [PDF]
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S. B. Anderson, A. L. Goldberg, and M. Whitman Identification of a Novel Pool of Extracellular Pro-myostatin in Skeletal Muscle J. Biol. Chem., March 14, 2008; 283(11): 7027 - 7035. [Abstract] [Full Text] [PDF]
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 R. G. Wells and D. E. Discher Matrix Elasticity, Cytoskeletal Tension, and TGF-{beta}: The Insoluble and Soluble Meet Sci. Signal., March 11, 2008; 1(10): pe13 - pe13. [Abstract] [Full Text] [PDF]
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 Yan Wen, Y.-Y. Zhao, M. L. Polan, and B. Chen Effect of Relaxin on TGF-{beta}1 Expression in Cultured Vaginal Fibroblasts From Women With Stress Urinary Incontinence Reproductive Sciences, March 1, 2008; 15(3): 312 - 320. [Abstract] [PDF]
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 R. Mishra and M. S. Simonson Oleate Induces a Myofibroblast-Like Phenotype in Mesangial Cells Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): 541 - 547. [Abstract] [Full Text] [PDF]
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 L. J. Dawes, J. A. Eldred, I. K. Anderson, M. Sleeman, J. R. Reddan, G. Duncan, and I. M. Wormstone TGF{beta}-Induced Contraction Is Not Promoted by Fibronectin-Fibronectin Receptor Interaction, or {alpha}SMA Expression Invest. Ophthalmol. Vis. Sci., February 1, 2008; 49(2): 650 - 661. [Abstract] [Full Text] [PDF]
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 C.-J. Liang, H. E. Ives, C.-M. Yang, and Y.-H. Ma 20-HETE inhibits the proliferation of vascular smooth muscle cells via transforming growth factor- J. Lipid Res., January 1, 2008; 49(1): 66 - 73. [Abstract] [Full Text] [PDF]
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K. Puthawala, N. Hadjiangelis, S. C. Jacoby, E. Bayongan, Z. Zhao, Z. Yang, M. L. Devitt, G. S. Horan, P. H. Weinreb, M. E. Lukashev, et al. Inhibition of Integrin {alpha}v 6, an Activator of Latent Transforming Growth Factor- , Prevents Radiation-induced Lung Fibrosis Am. J. Respir. Crit. Care Med., January 1, 2008; 177(1): 82 - 90. [Abstract] [Full Text] [PDF]
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 P.-J. Wipff, D. B. Rifkin, J.-J. Meister, and B. Hinz Myofibroblast contraction activates latent TGF- 1 from the extracellular matrix J. Cell Biol., December 17, 2007; 179(6): 1311 - 1323. [Abstract] [Full Text] [PDF]
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 T. Kempf, E. Bjorklund, S. Olofsson, B. Lindahl, T. Allhoff, T. Peter, J. Tongers, K. C. Wollert, and L. Wallentin Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction Eur. Heart J., December 1, 2007; 28(23): 2858 - 2865. [Abstract] [Full Text] [PDF]
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P. A. Knight, J. K. Brown, S. H. Wright, E. M. Thornton, J. A. Pate, and H. R.P. Miller Aberrant Mucosal Mast Cell Protease Expression in the Enteric Epithelium of Nematode-Infected Mice Lacking the Integrin {alpha}v{beta}6, a Transforming Growth Factor-{beta}1 Activator Am. J. Pathol., October 1, 2007; 171(4): 1237 - 1248. [Abstract] [Full Text] [PDF]
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S. H. Wrzesinski, Y. Y. Wan, and R. A. Flavell Transforming Growth Factor-{beta} and the Immune Response: Implications for Anticancer Therapy Clin. Cancer Res., September 15, 2007; 13(18): 5262 - 5270. [Abstract] [Full Text] [PDF]
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Q. Chen, P. Sivakumar, C. Barley, D. M. Peters, R. R. Gomes, M. C. Farach-Carson, and S. L. Dallas Potential Role for Heparan Sulfate Proteoglycans in Regulation of Transforming Growth Factor-beta (TGF-beta) by Modulating Assembly of Latent TGF-beta-binding Protein-1 J. Biol. Chem., September 7, 2007; 282(36): 26418 - 26430. [Abstract] [Full Text] [PDF]
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S. Belmadani, J. Bernal, C.-C. Wei, M. A. Pallero, L. Dell'Italia, J. E. Murphy-Ullrich, and K. H. Berecek A Thrombospondin-1 Antagonist of Transforming Growth Factor-{beta} Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II Am. J. Pathol., September 1, 2007; 171(3): 777 - 789. [Abstract] [Full Text] [PDF]
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J. L. Coombes, K. R.R. Siddiqui, C. V. Arancibia-Carcamo, J. Hall, C.-M. Sun, Y. Belkaid, and F. Powrie A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-{beta} and retinoic acid dependent mechanism J. Exp. Med., August 6, 2007; 204(8): 1757 - 1764. [Abstract] [Full Text] [PDF]
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G. Fitsialos, A.-A. Chassot, L. Turchi, M. A. Dayem, K. LeBrigand, C. Moreilhon, G. Meneguzzi, R. Busca, B. Mari, P. Barbry, et al. Transcriptional Signature of Epidermal Keratinocytes Subjected to in Vitro Scratch Wounding Reveals Selective Roles for ERK1/2, p38, and Phosphatidylinositol 3-Kinase Signaling Pathways J. Biol. Chem., May 18, 2007; 282(20): 15090 - 15102. [Abstract] [Full Text] [PDF]
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H.-R. Kang, C. G. Lee, R. J. Homer, and J. A. Elias Semaphorin 7A plays a critical role in TGF-{beta}1-induced pulmonary fibrosis J. Exp. Med., May 14, 2007; 204(5): 1083 - 1093. [Abstract] [Full Text] [PDF]
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 G. Otsuka, A. Stempien-Otero, A. D. Frutkin, and D. A. Dichek Mechanisms of TGF-{beta}1-Induced Intimal Growth: Plasminogen-Independent Activities of Plasminogen Activator Inhibitor-1 and Heterogeneous Origin of Intimal Cells Circ. Res., May 11, 2007; 100(9): 1300 - 1307. [Abstract] [Full Text] [PDF]
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 M. Bujak and N. G. Frangogiannis The role of TGF-{beta} signaling in myocardial infarction and cardiac remodeling Cardiovasc Res, May 1, 2007; 74(2): 184 - 195. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, J. Rodriguez-Vita, E. Sanchez-Lopez, G. Carvajal, and J. Egido TGF-{beta} signaling in vascular fibrosis Cardiovasc Res, May 1, 2007; 74(2): 196 - 206. [Abstract] [Full Text] [PDF]
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P. L. Hermonat, D. Li, B. Yang, and J. L. Mehta Mechanism of action and delivery possibilities for TGF{beta}1 in the treatment of myocardial ischemia Cardiovasc Res, May 1, 2007; 74(2): 235 - 243. [Abstract] [Full Text] [PDF]
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 F. Pisati, M. Belicchi, F. Acerbi, C. Marchesi, C. Giussani, M. Gavina, S. Javerzat, M. Hagedorn, G. Carrabba, V. Lucini, et al. Effect of Human Skin-Derived Stem Cells on Vessel Architecture, Tumor Growth, and Tumor Invasion in Brain Tumor Animal Models Cancer Res., April 1, 2007; 67(7): 3054 - 3063. [Abstract] [Full Text] [PDF]
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Z. Yang, Z. Mu, B. Dabovic, V. Jurukovski, D. Yu, J. Sung, X. Xiong, and J. S. Munger Absence of integrin-mediated TGF{beta}1 activation in vivo recapitulates the phenotype of TGF{beta}1-null mice J. Cell Biol., March 12, 2007; 176(6): 787 - 793. [Abstract] [Full Text] [PDF]
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 J. A. Williams, B. L. Loeys, L. U. Nwakanma, H. C. Dietz, P. J. Spevak, N. D. Patel, K. Francois, J. DeBacker, V. L. Gott, L. A. Vricella, et al. Early Surgical Experience With Loeys-Dietz: A New Syndrome of Aggressive Thoracic Aortic Aneurysm Disease Ann. Thorac. Surg., February 1, 2007; 83(2): S757 - S763. [Abstract] [Full Text] [PDF]
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C. Moore, X.-D. Shen, F. Gao, R. W. Busuttil, and A. J. Coito Fibronectin-{alpha}4{beta}1 Integrin Interactions Regulate Metalloproteinase-9 Expression in Steatotic Liver Ischemia and Reperfusion Injury Am. J. Pathol., February 1, 2007; 170(2): 567 - 577. [Abstract] [Full Text] [PDF]
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S. S. Chaudhry, S. A. Cain, A. Morgan, S. L. Dallas, C. A. Shuttleworth, and C. M. Kielty Fibrillin-1 regulates the bioavailability of TGF{beta}1 J. Cell Biol., January 29, 2007; 176(3): 355 - 367. [Abstract] [Full Text] [PDF]
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 D. G. Morris and D. Sheppard Pulmonary Emphysema: When More is Less. Physiology, December 1, 2006; 21(6): 396 - 403. [Abstract] [Full Text] [PDF]
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 P.-P. Kuang, M. Joyce-Brady, X.-H. Zhang, J.-C. Jean, and R. H. Goldstein Fibulin-5 gene expression in human lung fibroblasts is regulated by TGF-beta and phosphatidylinositol 3-kinase activity Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1412 - C1421. [Abstract] [Full Text] [PDF]
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 F. Poobalarahi, C. F. Baicu, and A. D. Bradshaw Cardiac myofibroblasts differentiated in 3D culture exhibit distinct changes in collagen I production, processing, and matrix deposition Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2924 - H2932. [Abstract] [Full Text] [PDF]
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 J. Gauldie, M. Kolb, K. Ask, G. Martin, P. Bonniaud, and D. Warburton Smad3 Signaling Involved in Pulmonary Fibrosis and Emphysema Proceedings of the ATS, November 1, 2006; 3(8): 696 - 702. [Abstract] [Full Text] [PDF]
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 J. Seoane Escaping from the TGF{beta} anti-proliferative control Carcinogenesis, November 1, 2006; 27(11): 2148 - 2156. [Abstract] [Full Text] [PDF]
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G. Ge and D. S. Greenspan BMP1 controls TGF{beta}1 activation via cleavage of latent TGF{beta}-binding protein J. Cell Biol., October 9, 2006; 175(1): 111 - 120. [Abstract] [Full Text] [PDF]
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S. Pegorier, L. A. Wagner, G. J. Gleich, and M. Pretolani Eosinophil-Derived Cationic Proteins Activate the Synthesis of Remodeling Factors by Airway Epithelial Cells J. Immunol., October 1, 2006; 177(7): 4861 - 4869. [Abstract] [Full Text] [PDF]
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S. A. Illman, K. Lehti, J. Keski-Oja, and J. Lohi Epilysin (MMP-28) induces TGF-{beta} mediated epithelial to mesenchymal transition in lung carcinoma cells J. Cell Sci., September 15, 2006; 119(18): 3856 - 3865. [Abstract] [Full Text] [PDF]
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 Q. Lu, E. O. Harrington, H. Jackson, N. Morin, C. Shannon, and S. Rounds Transforming growth factor-beta1-induced endothelial barrier dysfunction involves Smad2-dependent p38 activation and subsequent RhoA activation J Appl Physiol, August 1, 2006; 101(2): 375 - 384. [Abstract] [Full Text] [PDF]
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C. Neurohr, S. L. Nishimura, and D. Sheppard Activation of Transforming Growth Factor-beta by the Integrin {alpha}vbeta8 Delays Epithelial Wound Closure Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 252 - 259. [Abstract] [Full Text] [PDF]
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J. Araya, S. Cambier, A. Morris, W. Finkbeiner, and S. L. Nishimura Integrin-Mediated Transforming Growth Factor-{beta} Activation Regulates Homeostasis of the Pulmonary Epithelial-Mesenchymal Trophic Unit Am. J. Pathol., August 1, 2006; 169(2): 405 - 415. [Abstract] [Full Text] [PDF]
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A. J. Ottaviano, L. Sun, V. Ananthanarayanan, and H. G. Munshi Extracellular Matrix-Mediated Membrane-Type 1 Matrix Metalloproteinase Expression in Pancreatic Ductal Cells Is Regulated by Transforming Growth Factor-{beta}1. Cancer Res., July 15, 2006; 66(14): 7032 - 7040. [Abstract] [Full Text] [PDF]
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S. Arandjelovic, C. L. Van Sant, and S. L. Gonias Limited Mutations in Full-length Tetrameric Human {alpha}2-Macroglobulin Abrogate Binding of Platelet-derived Growth Factor-BB and Transforming Growth Factor-beta1 J. Biol. Chem., June 23, 2006; 281(25): 17061 - 17068. [Abstract] [Full Text] [PDF]
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 J. Lin, S. R. Patel, M. Wang, and G. R. Dressler The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor {beta}/Activin Signaling in Renal Epithelia Mol. Cell. Biol., June 15, 2006; 26(12): 4577 - 4585. [Abstract] [Full Text] [PDF]
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C.-L. Chen, S. S. Huang, and J. S. Huang Cellular Heparan Sulfate Negatively Modulates Transforming Growth Factor-beta1 (TGF-beta1) Responsiveness in Epithelial Cells J. Biol. Chem., April 28, 2006; 281(17): 11506 - 11514. [Abstract] [Full Text] [PDF]
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A. Miyamoto, R. Lau, P. W. Hein, J. M. Shipley, and G. Weinmaster Microfibrillar Proteins MAGP-1 and MAGP-2 Induce Notch1 Extracellular Domain Dissociation and Receptor Activation J. Biol. Chem., April 14, 2006; 281(15): 10089 - 10097. [Abstract] [Full Text] [PDF]
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 S. S. Cheon, Q. Wei, A. Gurung, A. Youn, T. Bright, R. Poon, H. Whetstone, A. Guha, and B. A. Alman Beta-catenin regulates wound size and mediates the effect of TGF-beta in cutaneous healing FASEB J, April 1, 2006; 20(6): 692 - 701. [Abstract] [Full Text] [PDF]
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H. Aoki, H. Ohnishi, K. Hama, T. Ishijima, Y. Satoh, K. Hanatsuka, A. Ohashi, S. Wada, T. Miyata, H. Kita, et al. Autocrine loop between TGF-beta1 and IL-1beta through Smad3- and ERK-dependent pathways in rat pancreatic stellate cells Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1100 - C1108. [Abstract] [Full Text] [PDF]
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A. C. Newby Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates Cardiovasc Res, February 15, 2006; 69(3): 614 - 624. [Abstract] [Full Text] [PDF]
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Y. Asano, H. Ihn, K. Yamane, M. Jinnin, and K. Tamaki Increased Expression of Integrin {alpha}v{beta}5 Induces the Myofibroblastic Differentiation of Dermal Fibroblasts Am. J. Pathol., February 1, 2006; 168(2): 499 - 510. [Abstract] [Full Text] [PDF]
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Y. Asano, H. Ihn, K. Yamane, M. Jinnin, Y. Mimura, and K. Tamaki Increased Expression of Integrin {alpha}v{beta}3 Contributes to the Establishment of Autocrine TGF-{beta} Signaling in Scleroderma Fibroblasts J. Immunol., December 1, 2005; 175(11): 7708 - 7718. [Abstract] [Full Text] [PDF]
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 M. Dziadzio, R. E. Smith, D. J. Abraham, C. M. Black, and C. P. Denton Circulating levels of active transforming growth factor {beta}1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score Rheumatology, December 1, 2005; 44(12): 1518 - 1524. [Abstract] [Full Text] [PDF]
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E.-S. Akool, A. Doller, R. Muller, P. Gutwein, C. Xin, A. Huwiler, J. Pfeilschifter, and W. Eberhardt Nitric Oxide Induces TIMP-1 Expression by Activating the Transforming Growth Factor {beta}-Smad Signaling Pathway J. Biol. Chem., November 25, 2005; 280(47): 39403 - 39416. [Abstract] [Full Text] [PDF]
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L. Fontana, Y. Chen, P. Prijatelj, T. Sakai, R. Fassler, L. Y. Sakai, and D. B. Rifkin Fibronectin is required for integrin {alpha}v{beta}6-mediated activation of latent TGF-{beta} complexes containing LTBP-1 FASEB J, November 1, 2005; 19(13): 1798 - 1808. [Abstract] [Full Text] [PDF]
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 K. Janssens, P. ten Dijke, S. Janssens, and W. Van Hul Transforming Growth Factor-{beta}1 to the Bone Endocr. Rev., October 1, 2005; 26(6): 743 - 774. [Abstract] [Full Text] [PDF]
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R. D. Wang, J. L. Wright, and A. Churg Transforming Growth Factor-{beta}1 Drives Airway Remodeling in Cigarette Smoke-Exposed Tracheal Explants Am. J. Respir. Cell Mol. Biol., October 1, 2005; 33(4): 387 - 393. [Abstract] [Full Text] [PDF]
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 L. A. Jaeger, A. K. Spiegel, N. H. Ing, G. A. Johnson, F. W. Bazer, and R. C. Burghardt Functional Effects of Transforming Growth Factor {beta} on Adhesive Properties of Porcine Trophectoderm Endocrinology, September 1, 2005; 146(9): 3933 - 3942. [Abstract] [Full Text] [PDF]
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 F. Clotman, P. Jacquemin, N. Plumb-Rudewiez, C. E. Pierreux, P. Van der Smissen, H. C. Dietz, P. J. Courtoy, G. G. Rousseau, and F. P. Lemaigre Control of liver cell fate decision by a gradient of TGF{beta} signaling modulated by Onecut transcription factors Genes & Dev., August 15, 2005; 19(16): 1849 - 1854. [Abstract] [Full Text] [PDF]
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C. Colarossi, Y. Chen, H. Obata, V. Jurukovski, L. Fontana, B. Dabovic, and D. B. Rifkin Lung Alveolar Septation Defects in Ltbp-3-Null Mice Am. J. Pathol., August 1, 2005; 167(2): 419 - 428. [Abstract] [Full Text] [PDF]
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S. Cambier, S. Gline, D. Mu, R. Collins, J. Araya, G. Dolganov, S. Einheber, N. Boudreau, and S. L. Nishimura Integrin {alpha}v{beta}8-Mediated Activation of Transforming Growth Factor-{beta} by Perivascular Astrocytes: An Angiogenic Control Switch Am. J. Pathol., June 1, 2005; 166(6): 1883 - 1894. [Abstract] [Full Text] [PDF]
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R. Mazzieri, V. Jurukovski, H. Obata, J. Sung, A. Platt, E. Annes, N. Karaman-Jurukovska, P.-E. Gleizes, and D. B. Rifkin Expression of truncated latent TGF-{beta}-binding protein modulates TGF-{beta} signaling J. Cell Sci., May 15, 2005; 118(10): 2177 - 2187. [Abstract] [Full Text] [PDF]
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 B. L. Granger, M. L. Flenniken, D. A. Davis, A. P. Mitchell, and J. E. Cutler Yeast wall protein 1 of Candida albicans Microbiology, May 1, 2005; 151(5): 1631 - 1644. [Abstract] [Full Text] [PDF]
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Y. Mimura, H. Ihn, M. Jinnin, Y. Asano, K. Yamane, and K. Tamaki Constitutive Thrombospondin-1 Overexpression Contributes to Autocrine Transforming Growth Factor-{beta} Signaling in Cultured Scleroderma Fibroblasts Am. J. Pathol., May 1, 2005; 166(5): 1451 - 1463. [Abstract] [Full Text] [PDF]
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D. B. Rifkin Latent Transforming Growth Factor-{beta} (TGF-{beta}) Binding Proteins: Orchestrators of TGF-{beta} Availability J. Biol. Chem., March 4, 2005; 280(9): 7409 - 7412. [Full Text] [PDF]
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F. Debacq-Chainiaux, C. Borlon, T. Pascal, V. Royer, F. Eliaers, N. Ninane, G. Carrard, B. Friguet, F. de Longueville, S. Boffe, et al. Repeated exposure of human skin fibroblasts to UVB at subcytotoxic level triggers premature senescence through the TGF-{beta}1 signaling pathway J. Cell Sci., February 15, 2005; 118(4): 743 - 758. [Abstract] [Full Text] [PDF]
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Y. Sugano, T. Anzai, T. Yoshikawa, Y. Maekawa, T. Kohno, K. Mahara, K. Naito, and S. Ogawa Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction Cardiovasc Res, February 1, 2005; 65(2): 446 - 456. [Abstract] [Full Text] [PDF]
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 M. J. Burton, R. L. Bailey, D. Jeffries, D. C. W. Mabey, and M. J. Holland Cytokine and Fibrogenic Gene Expression in the Conjunctivas of Subjects from a Gambian Community Where Trachoma Is Endemic Infect. Immun., December 1, 2004; 72(12): 7352 - 7356. [Abstract] [Full Text] [PDF]
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G. D. Young and J. E. Murphy-Ullrich The Tryptophan-rich Motifs of the Thrombospondin Type 1 Repeats Bind VLAL Motifs in the Latent Transforming Growth Factor-{beta} Complex J. Biol. Chem., November 12, 2004; 279(46): 47633 - 47642. [Abstract] [Full Text] [PDF]
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 S.S. Prime, M. Pring, M. Davies, and I.C. Paterson TGF-{beta} SIGNAL TRANSDUCTION IN ORO-FACIAL HEALTH AND NON-MALIGNANT DISEASE (PART I) Critical Reviews in Oral Biology & Medicine, November 1, 2004; 15(6): 324 - 336. [Abstract] [Full Text] [PDF]
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K. Koli, F. Wempe, A. Sterner-Kock, A. Kantola, M. Komor, W.-K. Hofmann, H. von Melchner, and J. Keski-Oja Disruption of LTBP-4 function reduces TGF-{beta} activation and enhances BMP-4 signaling in the lung J. Cell Biol., October 11, 2004; 167(1): 123 - 133. [Abstract] [Full Text] [PDF]
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