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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Key words: Transforming growth factor-ß, Activation, Sensor
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Introduction |
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The components and assembly of the sensor |
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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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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.
|
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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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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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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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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References |
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