Departments of Internal Medicine and Pathology, Yale School of Medicine, New Haven, Connecticut 06520-8019
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ABSTRACT |
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Transforming
growth factor (TGF)- is a multifunctional peptide growth factor with
a wide range of potential effects on growth, differentiation,
extracellular matrix deposition, and the immune response. General
TGF-
signaling pathways have been described in detail over the last
several years, but factors that determine the nature of the TGF-
response are poorly understood. In particular, signaling pathways that
specifically mediate the matrix effects of TGF-
have received little
attention, although they will be important therapeutic targets in the
treatment of pathological fibrosis. This themes article focuses on
TGF-
signaling and highlights potential points for generating
matrix-specific responses.
fibrosis; extracellular matrix; transforming growth factor-
receptors; Smads
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INTRODUCTION |
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TRANSFORMING GROWTH FACTOR (TGF)-
is one of the most powerful and widely distributed profibrogenic
mediators in the body. It regulates not only deposition of the
extracellular matrix (ECM) as part of the normal response to tissue
injury but also pathological fibrosis. Alterations in TGF-
homeostasis are important in fibrotic diseases of multiple tissues. In
addition to influencing the quantity and composition of the ECM,
TGF-
has an astonishing range of other potential effects depending
on the cellular and environmental context, including control of growth
and differentiation and modulation of the immune response.
General TGF- signaling pathways from receptors to nucleus have been
described in detail over the last several years and are surprisingly
simple and direct (18). In contrast, factors that determine the nature of the TGF-
response are poorly understood, and
signaling pathways that specifically mediate the matrix effects of
TGF-
have received little attention. Because TGF-
has so many
potential functions, unraveling the subtleties of its signaling pathways is critical to the understanding of its role in disease and
the development of effective therapies.
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TGF-![]() |
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TGF- enhances fibrogenesis and remodeling in normal healing
after tissue injury. It is also an important mediator of multiple fibrotic diseases and syndromes, including pulmonary fibrosis, liver
fibrosis, chronic pancreatitis, scleroderma, and renal
glomerulosclerosis, and it has a significant role in the fibrotic
complications of radiation therapy, chemotherapy, and organ
transplantation (2). There are three lines of evidence
that TGF-
has a causal role in pathological fibrosis: 1)
TGF-
levels are increased in diseased organs and are often
specifically localized to fibrotic areas; 2) administration
of exogenous TGF-
to laboratory animals leads to the development of
fibrosis in some organs; and 3) anti-TGF-
therapies
lessen experimentally induced fibrosis.
The causal link between TGF- and fibrosis has been demonstrated
particularly clearly for lung, kidney, and liver. In fibrotic diseases
of all three tissues, regions of increased matrix show increased
expression of TGF-
, especially the isoform TGF-
1 (2, 19), and delivery of exogenous TGF-
1 by various means to
these tissues results in severe fibrosis in experimental animals
(22, 23). Also, there are now multiple reports that the
therapeutic administration of TGF-
binding proteins, including
neutralizing antibodies, soluble TGF-
receptors, and the
proteoglycan decorin, ameliorates experimental fibrosis (6, 28,
30, 35). Perhaps most exciting is the report that intratracheal
administration of an adenovirus expressing the TGF-
signaling
inhibitor Smad7 prevents bleomycin-induced lung fibrosis in mice
(16). These studies definitively establish TGF-
as a
primary mediator in pathological fibrosis, although in transgenic
models of TGF-
overexpression fibrosis occurs in some but not all
tissues, and the significance of local (autocrine and paracrine) versus
circulating TGF-
remains unknown.
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THE EFFECTS OF TGF-![]() |
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TGF- alters the normal balance between ECM synthesis and
degradation, inducing an increase in synthesis of matrix components and
a parallel decrease in overall ECM proteolytic activity. This results
in net fibrogenesis, although it is important to note that the
composition as well as quantity of ECM change in response to TGF-
.
Nowhere is this more evident than in the liver, where the increase in
fibrillar collagens and electron-dense matrix obliterates the
sinusoidal fenestrae, resulting in clinical liver disease. It is also
important to note that, although the ECM is generally composed of
proteins, proteoglycans, and glycans, its specific composition varies
among cell and tissue types, reflecting their specialized functions;
the effects of TGF-
on a given ECM may result from cell-specific
signaling pathways. Likewise, the term fibrogenesis is an
oversimplification and encompasses a variety of changes that
potentially involve multiple signaling pathways, direct and indirect,
including the upregulation of other profibrogenic cytokines.
In increasing ECM synthesis, TGF- upregulates the fibrillar and, to
a lesser extent, nonfibrillar collagens, other matrix components
including fibronectin and tenascin, the basement membrane components
laminin and entactin, and membrane proteoglycans including perlecan and
biglycan (2). In the liver, TGF-
induces the production
of the EIIIA splice variant of fibronectin by sinusoidal endothelial
cells, contributing to the activation of fibrogenic hepatic stellate
cells (10). TGF-
also alters the number and variety of
integrins expressed on some cells, potentially enhancing their adhesion
to the ECM (7).
TGF- regulates the expression of many proteins responsible for
matrix degradation. Although the effect of TGF-
on matrix metalloproteinases (MMPs) is mixed, it clearly upregulates protease inhibitors, most notably the tissue inhibitors of metalloproteinases (TIMPs). Additionally, TGF-
induces expression of plasminogen activator inhibitor (PAI)-1. This results in decreased conversion of
plasminogen to plasmin, a protease that directly degrades matrix components and activates MMPs.
One final effect of TGF- that warrants mention is its ability to
increase its own expression and generate potent autocrine loops. The
combination of continued TGF-
overproduction and highly proliferative cells is characteristic of some fibrotic conditions and
may be essential to the development of chronic, progressive fibrosis.
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TGF-![]() |
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In the decade since the cloning of the first TGF- receptors, a
simple and general signaling pathway from ligand to transcription has
become clear (Fig. 1). Latent TGF-
undergoes activation and in turn activates its receptors, the activated
receptors phosphorylate and assemble cytoplasmic Smad proteins, and
Smad complexes move to the nucleus as transcriptional regulators
(18).
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TGF- is synthesized as a prohormone. Although it undergoes cleavage
in the Golgi into an amino terminal latency-associated protein and a
mature TGF-
fragment, the two remain associated, bind to various
latent TGF-
binding proteins, and are secreted as a latent complex.
Latent TGF-
can be activated through multiple mechanisms potentially
involving integrin-
v
6, mannose-6-phosphate receptors, plasmin,
MMPs 2 and 9, and thrombospondin-1 (18).
Once activated, TGF- signals through a complex of two related but
structurally and functionally distinct serine-threonine kinase
receptors, called type I (T
RI) and type II (T
RII). Binding of the
homodimeric TGF-
to T
RII enables the formation and stabilization of type I/type II receptor complexes, most likely heterotetramers. The
T
RII kinase then phosphorylates T
RI in a glycine- and serine-rich juxtamembrane region called the GS box. This is the critical event in
TGF-
signaling and serves as the initiation point for downstream events.
A third TGF- receptor, betaglycan or T
RIII, is a proteoglycan
coreceptor that binds TGF-
with high affinity through its core. In
many cells, it enhances signaling by increasing the affinity of
TGF-
, especially TGF-
2, for the kinase receptors. We have recently determined, however, that in LLC-PK1 cells,
betaglycan competes with T
RI for T
RII binding, inhibiting
signaling (O. Eickelberg, M. Centrella, M. Kashgarian, and R. G. Wells, unpublished observations). Betaglycan is lost in one cell type,
hepatic stellate cells, when they adopt a fibrogenic,
TGF-
-responsive phenotype, although the significance of this to
fibrogenic signaling is not known (31). In addition to
betaglycan, several other receptor-associated proteins with unclear
functions have recently been described (18).
The family of Smad proteins, with three distinct subfamilies, comprises
the cytoplasmic TGF- signaling machinery. The receptor-activated Smads for TGF-
, Smad2 and Smad3, are phosphorylated by T
RI on carboxy-terminal SSXS sequences. These phosphorylated Smads then form
heteromeric complexes with the co-Smad, Smad4, and move into the
nucleus. The inhibitory Smads, represented in TGF-
signaling by
Smad7, lack the carboxy-terminal phosphorylation motif of Smad2 and
Smad3 but interact with T
RI and the receptor-activated Smads, inhibiting the pathway. Of note, Smad7 expression is induced by TGF-
, enabling rapid downregulation of the TGF-
response
(15).
Smad complexes, once translocated to the nucleus, can regulate
transcription in several ways. Smad3 and Smad4, but notably not Smad2,
bind directly to DNA via a GC-rich consensus sequence called a Smad
binding element. Several TGF--induced matrix proteins, including
collagen VII and PAI-1, as well as the inhibitory Smad7, have copies of
this consensus sequence in their promoter regions. Smads (in particular
Smad2, which cannot itself bind to DNA) also cooperate with other
transcription factors, including activator protein (AP-1), simian
virus 40 promoter factor 1 (Sp1), and transcription factor muE3
(TFE3). TFE3 and a Smad3/4 complex, for example, do not
physically interact but bind to adjacent sites in the PAI-1 gene
promoter, enabling its upregulation in response to TGF-
(9). Activated Smads in the nucleus can also interact with transcriptional coactivators, including CREB binding protein (CBP) and
p300, or corepressors, including TG-interacting factor, c-Ski, and
SnoN, for both activation and inhibition of transcription (18).
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SPECIFICITY IN SIGNALING: MATRIX-SPECIFIC PATHWAYS? |
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Why do different cells respond to TGF- in different ways?
Ultimately, the answer is context: the makeup of the surrounding environment and the specific intracellular signaling apparatus. Within
this framework, however, the details are poorly understood. There has
been no systematic study of TGF-
signaling in fibrogenesis, and,
although TGF-
induction of PAI-1 expression is well described, signaling pathways for other matrix proteins are still incomplete, particularly in pathological fibrosis. Recent studies addressing TGF-
pathways to fibrogenesis are highlighted below, as are points in the TGF-
pathway with the potential to generate response specificity.
TGF- levels, isoforms, and activation.
The three major TGF-
isoforms,
1,
2, and
3, have similar
biological effects in vitro. They have highly different expression patterns, however, and the phenotypes of their knockout mice are distinct. TGF-
1-null mice either die in utero because of defects in
vasculogenesis and hematopoiesis or die shortly after birth of
overwhelming inflammatory infiltration of multiple organs; TGF-
2-
and -
3-null mice have multiple, although different and nonoverlapping, developmental abnormalities (18). The
genes for the three isoforms have differentially regulated promoters, suggesting that expression in time and space rather than biological activity may be responsible for the observed effects of individual isoforms. Additionally, TGF-
2 requires betaglycan for high-affinity binding to the receptors, so betaglycan expression is an important determinant of TGF-
2 activity. It is notable, however, that TGF-
1 is often the major isoform in fibrosis, and it is possible that it has
biological effects in vivo that differ from
2 and
3. The
contribution of inflammation to fibrosis is not well understood and is
debated; it may be that the dominant role of TGF-
in inflammation is
important to its role in fibrosis.
TGF- receptors.
Although fibrosis is associated with increased levels of active
TGF-
, fibrogenic cells are also primed to respond differently to
TGF-
from nonfibrogenic cells. Differences in cellular signaling could occur at several points, beginning with T
RI and T
RII. Mutations in a region of T
RI between the transmembrane domain and
the GS box eliminate some, but not all, TGF-
responses:
Ser172 and Thr176 are required for
TGF-
-mediated growth inhibition but not PAI-1 and fibronectin
upregulation (20). These residues are not known to be
phosphorylated, and the mechanisms by which they modulate TGF-
signaling are unclear. Phosphorylation of Ser165, which is
also proximal to the GS box, has different effects on growth inhibition
and matrix induction compared with apoptosis (24), but
again the mechanism is unknown. In the type II receptor, Thr315 (which is not autophosphorylated) is required for
TGF-
-mediated growth inhibition but not matrix induction
(12). Differential autophosphorylation of the kinase
region of T
RII chimeras modulates TGF-
-mediated growth inhibition
(13); it would be intriguing to test these phosphorylation
sites for their effects on matrix responses.
Smads.
The Smads are likely to play a central role in the generation of
response specificity. As noted above, it has been hypothesized that the
degree of activation of the cytoplasmic signaling machinery determines
the nature of the effects of TGF-; studies in Xenopus demonstrate that the transcriptional response to the TGF-
superfamily member activin varies with the levels of activated Smads
(33). Differences between Smad2 and Smad3 function are
also likely to be important. Although the two are grouped together as
TGF-
-specific receptor-activated Smads, Smad2 is unable to bind DNA
directly, and Smad2 and Smad3 are antagonistic in some systems,
suggesting that their relative levels might determine the biological
response (11). In support of this, there is now a report
that Smad2 and Smad3 are expressed in distinct patterns in maturing
chondrocytes according to their state of differentiation
(21). Additionally, we and others have noted that Smad2
activation is decreased compared with Smad3 activation as hepatic
stellate cells in culture become fibrogenic (Ref. 5 and
unpublished data).
Transcription factors and activators.
In the end, signaling specificity comes down to distinct nuclear
events. The multiple known and potential interactions between Smads,
other transcription factors, and transcriptional coactivators and
corepressors provide multiple possible branch points in TGF- signaling, and there are already several examples of matrix-specific responses generated by the expression of specific nuclear factors. At
an AP-1 site in the human collagenase I (MMP-1) promoter, there is
cooperation between c-Jun/c-Fos and Smad3 and Smad4 in inducing TGF-
-mediated transcription (34). In the
PAI-1 gene, Smad3/4 complexes cooperate with the
transcription factor TFE3 to regulate transcription (9).
Novel regulatory elements may also be important in fibrogenesis;
induction of a 30-kDa nuclear protein and its binding to a newly
described promoter element during hepatic stellate cell activation is
important in TIMP-1 upregulation (26). There are several
known corepressors (TGIF, c-Ski, and SnoN) that recruit histone
deacetylase; interestingly, histone deacetylase inhibitors blunt matrix production by hepatic stellate cells
(17), raising the possibility that the expression of
corepressors modulates fibrogenesis.
Cross-talk with other pathways.
There are now many examples of interactions between MAPK pathways and
TGF- signaling, raising the possibility that cross-talk between
mitogenic and TGF-
signaling pathways leads to a coordinate response. As described above, TGF-
-mediated fibronection but not PAI-1 induction in one cell line is dependent on JNK
(8); studies on collagenase I upregulation demonstrate
that Smad and JNK signaling pathways converge at AP-1 sites
(34). MAPKs, in response to such growth factors as
hepatocyte growth factor (HGF) and epidermal growth factor
(EGF), phosphorylate internal sites on Smad2 and induce its
nuclear translocation (4), although the range of
functional effects of this cross-talk is not known. It may be relevant,
however, that HGF overexpression led to a reduction in experimental
fibrosis in a rat model (27).
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SIGNALING SPECIFICITY: THERAPEUTICS AND PERSPECTIVES |
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The recent description of general TGF- signaling pathways
provides an exciting point from which to explore TGF-
signaling in
fibrogenesis. In the future, it will be important to examine proteoglycan and TIMP upregulation by TGF-
and to determine whether there are broad pathways that regulate the matrix effects of TGF-
. The multifunctional nature of TGF-
implies that the design of antifibrosis therapies will require a detailed understanding of specific signaling pathways so that the beneficial effects of TGF-
,
including antimitogenesis, are maintained during long-term treatment.
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ACKNOWLEDGEMENTS |
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I am grateful to Dr. O. Eickelberg for comments on the manuscript.
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FOOTNOTES |
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I receive support from the Yale Liver Center (DK-34989) and the National Institute of Diabetes and Digestive and Kidney Diseases (DK-02290 and DK-56016).
Address for reprint requests and other correspondence: R. G. Wells, Depts. of Internal Medicine and Pathology, Yale School of Medicine, P.O. Box 208019, New Haven, CT 06520-8019 (E-mail: rebecca.wells{at}yale.edu).
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