Stem Cells, Vol. 15, No. 3, 190-197,
May 1997
© 1997 AlphaMed Press
TGF-ß Latency: Biological Significance and Mechanisms of Activation
Pierre-Emmanuel Gleizes,
John S. Munger,
Irene Nunes,
John G. Harpel,
Roberta Mazzieri,
Irene Noguera,
Daniel B. Rifkin
Department of Cell Biology and Kaplan Cancer Center and the Raymond and Beverly Sackler Foundation Laboratory, New York University Medical Center, New York, New York, USA
Key Words. Growth factor • Transforming growth factor-ß • Latent TGF-ß binding protein (LTBP ) • Extracellular matrix • Bioavailability • Proteases
Dr. Pierre-Emmanuel Gleizes, Department of Cell Biology, NYU Medical Center, 550 First Avenue, New York, NY 10016, USA.
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Abstract
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Transforming growth factor (TGF-)ß is secreted as a latent complex in which the mature growth factor remains associated with its propeptide. In order to elicit a biological response, the cytokine must be released from the latent complex, a process termed latent TGF-ß activation or TGF-ß formation. Although latent TGF-ß activation is a critical step in the regulation of its activity, little is known about the molecular mechanisms that lead to the production of active TGF-ß. In this article, we present an overview of the data available on this topic, and we propose a tentative model for the mechanism of TGF-ß formation based upon the observations with different cell systems and on recent findings on the structure of the latent TGF-ß complex.
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Introduction
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Transforming growth factor (TGF-ß), a generic name that refers to five structurally related growth factors, is unusual among the known cytokines as it is secreted as a latent complex and is found primarily in a latent form in vivo. When referring to a cytokine, the word "latency" describes a condition in which a molecule is maintained in an inactive state in a reversible manner. Latency is one mechanism to control growth factor activity; it prevents the cytokine from eliciting a response until conversion to the active form and may also allow the cytokine to circulate and reach its target cell. Like most members of the TGF-ß superfamily [1], which also includes Müllerian inhibitory substance, decapentaplegic, activins, inhibins and bone morphogenic proteins, the TGF-ß isoforms are synthesized as dimeric precursor proproteins that are cleaved during secretion to yield mature cytokines. However, mature TGF-ß remains associated with its propeptide through noncovalent interactions, creating a latent complex from which TGF-ß must be released to elicit its biological activity [2]. This process is called latent TGF-ß activation or TGF-ß formation. Although most studies on the regulation of TGF-ß action have focused on TGF-ß transcription and translation, latency appears to be a critical step in the control of TGF-ß activity, as enhanced TGF-ß expression does not always correlate with increased levels of active TGF-ß [3]. The generation of transgenic mice overexpressing TGF-ß can require the use of a mutated cDNA encoding a constitutively active form of the growth factor as overexpression of latent TGF-ß does not always result in a detectable phenotype [4]. In addition, latent TGF-ß activation can be induced independently of transcription [5]. Latency also regulates TGF-ß bioavailability and may limit its diffusion from the secreting cell, thus modulating the autocrine and paracrine actions of the growth factor [6].
The approaches employed to study TGF-ß formation have yielded several insights: A) in vitro experiments with purified latent TGF-ß have defined physicochemical conditions and enzymes that directly activate the latent complex; B) tissue culture studies have identified a set of molecules involved in TGF-ß formation and provided insight into the regulation of this process, and C) development of immunocytochemical techniques that discriminate between latent and active TGF-ß has permitted the examination of latent TGF-ß activation in vivo. In parallel, the characterization of latent TGF-ß structure has enhanced our understanding of TGF-ß formation at the molecular level.
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Biological Functions of TGF-ß
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TGF-ß1, -ß2, and -ß3 are found in mammals. Recent information on the functions of TGF-ß1 and TGF-ß3 in vivo has been gained from the targeted deletions for each of the corresponding genes in mice. Knock-out of TGF-ß1 gene does not yield any gross embryonic abnormality, but newborn mice exhibit lethal multifocal inflammation, starting three weeks after birth [7]. Therefore, TGF-ß1 appears as an essential regulator of the immune system. When crossed into mice bearing the severe combined immunodeficiency mutation to avoid this inflammatory disorder, the targeted deletion of TGF-ß1 gene does not result in the premature death of the animals, indicating that inflammation is not secondary to any other fatal defect [8]. Furthermore, fifty percent of TGF-ß1-/- fetuses die around 10.5 dpc due to abnormal development of the yolk sac, characterized by defective vasculogenesis and/or anemia [9]. The anemia is due to a reduced number of erythroid cells in the yolk sac, which suggests a role for TGF-ß1 in hematopoiesis. Such a role is also suggested by the recent report that TGF-ß1-null mice lack Langerhans' epithelial cells [10]. The phenotype of mice lacking TGF-ß3 is different, as these animals are born with cleft palate and die within a few hours, showing the requirement for TGF-ß3 for normal embryonic development [11].
These observations complement numerous reports showing direct or indirect involvement of TGF-ß in processes such as wound healing, angiogenesis, hematopoiesis, mammary gland development, bone metabolism, and skin formation as well as in multiple pathologies such as inflammatory and fibrotic diseases and tumor development [12]. The role of TGF-ß in fibrosis may be related to its positive effect on extracellular matrix (ECM) production; TGF-ß both enhances the synthesis of ECM components (fibronectin, collagen type I, biglycan) and downregulates the proteolytic activities responsible for ECM catabolism. The growth of most cell types in vitro is negatively regulated by TGF-ß. This is mirrored in vivo by a link between hyperproliferative disorders and either the loss of TGF-ß expression or the inactivation of TGF-ß receptors [13]. TGF-ß1 also belongs to the cytokine network that regulates hematopoiesis, and was shown to be a negative growth regulator for normal and leukemic bone marrow cells and fetal liver cells in vitro [14]. Overexpression of TGF-ß1 in transgenic mice can result in abnormal phenotypes, indicating that deregulation in the control of TGF-ß latency can have severe consequences [15-18].
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TGF-ß is Secreted as a Latent Complex
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TGF-ß1 cDNA encodes a 392 amino acid polypeptide that dimerizes through disulfide bonds while in the secretion pathway. The precursor molecule is cleaved in the Golgi apparatus at position 279 after a diarginine motif, presumably by a furine-type protease [19, 20]. The C-terminal fragment (amino acids 280-392), which constitutes mature TGF-ß1, remains associated with its N-terminal propeptide, also called the latency-associated peptide (LAP) or ß1-LAP, through noncovalent interactions. ß1-LAP dimerization is stabilized by two interchain disulfide bonds at cyteines 223 and 225. Three asparagines at positions 82, 136 and 176 are N-glycosylated in ß1-LAP. Interestingly, two of these carbohydrate moieties contain mannose 6-phosphate [21], a sugar rarely found on extracellular proteins and which normally functions as a signal for lysosomal targeting by mannose 6-phosphate receptors. How latent TGF-ß1 avoids transport to lysosomes is not understood. This may involve association with a chaperon protein along the secretion pathway; alternatively, the mannose 6-phosphate residues may be shielded from the mannose 6-phosphate receptors in the Golgi apparatus. However, both recombinant and platelet latent TGF-ß1 can interact with the insulin-like growth factor II/mannose 6-phosphate receptor. The structure of mature TGF-ß2 has been solved by x-ray crystallography [22, 23], but few data are available regarding LAP structure or the molecular basis of its interaction with TGF-ß [24]. It is noteworthy that although mature TGF-ß1, -ß2, and -ß3 are highly homologous, the sequences of the corresponding propeptides are more divergent. Differences in LAP:TGF-ß interactions may account, in part, for certain functional differences between TGF-ß isoforms.
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The Interaction between LAP and TGF-ß Can Be Disrupted by Physicochemical and Enzymatic Treatments
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The TGF-ß:LAP interaction can be disrupted in vitro by physicochemical treatments that take advantage of the greater resistance to denaturing conditions of mature TGF-ß compared to LAP [25, 26]. Heat (80°C for 10 min), acidic or basic pH, chaotropes, or detergents promote latent TGF-ß activation. Heat and acidic pH are commonly used to activate latent TGF-ß in biological samples and to evaluate the total amount of TGF-ß (active and latent). It is not clear whether any of these conditions that trigger TGF-ß formation are physiologically relevant. The activation of latent TGF-ß by osteoclasts during bone resorption may be linked to the acidification (pH < 3) of the osteoclast pericellular space [27, 28]. Latent TGF-ß can be activated in vitro upon oxidation with free radicals and reactive oxygen species [29], conditions which are reproduced in irradiated tissues in vivo. Using immunocytochemistry with antibodies specifically recognizing active TGF-ß, Barcellos-Hoff and coworkers have shown that the level of active TGF-ß1 increases rapidly in mammary glands upon irradiation [30].
Two enzymatic processes that yield active TGF-ß have been reported. First, latent TGF-ß is activated upon treatment of the inactive complex with glycosidases (endoglycosidase-F, sialidase, neuraminidase, N-glycanase) [31]. This result stresses the role of carbohydrates in the stability of latent TGF-ß. A recent report by Schultz-Cherry and Hinshaw suggests that the influenza virus activates latent TGF-ß through a membrane-bound neuraminidase [32]. Sialidase release by macrophages could also participate in latent TGF-ß activation by these cells. Second, latent TGF-ß activation can be observed upon proteolytic degradation of LAP. Lyons and coworkers have shown that the serine proteases plasmin and cathepsin D release TGF-ß from the latent complex, apparently through cleavage of LAP in its N-terminal region [33, 34]. As discussed below, the action of proteases, especially plasmin, is thought to be central to the release of TGF-ß from the latent complex.
Finally, latent TGF-ß activation can occur through direct interaction with thrombospondin-1 (TSP-1). TSP-1 is an adhesive protein that binds to cell surfaces and ECM and is present at high concentration in platelet alpha-granules. From a study performed with synthetic peptides, it appears that this nonenzymatic activation involves interaction of the type I (properdin-like) domains of TSP-1 with latent TGF-ß [35]. Mature TGF-ß forms a complex with TSP-1 in which the cytokine remains active. Addition of TSP-1 to cultures of endothelial cells also yields active TGF-ß [36]. These observations have been recently extended in part to thrombospondin-2 [37].
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Latent TGF-ß Forms a Complex with the Latent TGF-ß Binding Protein (LTBP)
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Most cultured cell types release latent TGF-ß as a larger complex, designated large latent complex, which in addition to TGF-ß and LAP includes a 120-240 kDa glycoprotein called the latent TGF-ß binding protein (LTBP) [38]. To date, cDNAs of three related LTBPs have been cloned: human and rat LTBP-1 [39, 40], human and bovine LTBP-2 [41, 42], and mouse LTBP-3 [43]. LTBP associates through disulfide bonds with LAP during secretion. Alternative splicing and proteolytic cleavage yield different forms of LTBP in distinct cell types. A study of latent TGF-ß1 secretion by erythroleukemic cells has suggested a role for LTBP in the proper processing and secretion of latent TGF-ß1 [44]. This observation may reflect an ability of LTBP to mask LAP mannose 6-phosphate residues within the large latent complex, a hypothesis currently under investigation. However, some cell types, such as rat osteoblasts, secrete latent TGF-ß lacking LTBP [45]. LTBP is composed primarily of two kinds of cysteine-rich domains: EGF-like repeats, most of which are calcium-binding, and eight-cysteine domains, originally described in LTBP. We and Saharinen et al. have recently shown that covalent binding of LTBP-1 to latent TGF-ß1 is mediated by the third eight-cysteine domain, which presumably forms two disulfide bonds with the cysteine 33 pair in LAP dimer [46, 47]. The function of the other eight-cysteine domains remains unknown, though they may participate in other protein-protein interactions.
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The LTBP Addresses Latent TGF-ß to the ECM
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The structure of LTBP is similar to that of fibrillin, an extracellular protein found in elastic fibers, and is reminiscent of other ECM proteins like MAGP, nidogene and fibulin. As in these other proteins, a central stretch of multiple tandem epidermal growth factor-like domains confers to LTBP a rod-like shape, as verified by electron microscopy (P-E. Gleizes, D. Keene and D.B. Rifkin, unpublished data). Accordingly, LTBP is incorporated into the ECM, when expressed by cells in culture, either by itself or as part of the large latent complex. LTBP participates in the regulation of latent TGF-ß bioavailability by addressing it to the ECM [48]. In cells producing the large latent TGF-ß complex, LTBP and latent TGF-ß colocalize to ECM ([49], R. Mazzieri, unpublished results). Dallas and coworkers have shown that LTBP-1 is associated with fibrillar structures in cultures of fetal rat calvarial cells as well as in rat bone and cartilages in vivo, suggesting a structural role for LTBP-1 in ECM [50]. Also in vivo, LTBP-2 has been localized to elastin-associated microfibrils [41]. As revealed by immunofluorescence and immunoelectron microscopy, LTBP-1 colocalizes with fibronectin ([49], R. Mazzieri, unpublished data), although no direct association of the two molecules has been shown. Indeed, LTBP partners in the microfibrillar structure remain to be established. Also, it is not clear whether LTBP can self-polymerize to form microfibrils, or whether it merely decorates preformed structures. LTBP-1 incorporation into the ECM requires participation of the N-terminal portion of the molecule, as shown either with deletion mutants or with antibodies to various domains of LTBP-1 [47, 51]. Two different cDNAs encoding LTBP-1 have been identified: one gives rise to a short form (LTBP-1S), and the second produces a longer form (LTBP-1L), which has an N-terminal extension and is more efficiently incorporated into ECM when overexpressed in COS cells [52].
LTBP-1 associated with the ECM cannot be recovered using detergents or denaturing agents, indicating that it is stabilized by covalent crosslinking. Our laboratory has recently shown that LTBP-1 is a substrate for transglutaminase and that this enzyme ensures covalent association of LTBP-1 with the ECM [51]. Transglutaminase catalyzes formation of isopeptide bonds between glutamine [gamma]-carboxamide groups and lysine [epsilon]-amino groups. Although devoid of a signal sequence, transglutaminase is found in the extracellular milieu and mediates crosslinking between ECM components such as plasminogen, fibronectin, nidogen, and vitronectin. Matrix-bound LTBP or large latent complex is freed from isolated ECM in vitro upon treatment with plasmin, mast cell chymase, or leukocyte elastase, all of which cleave LTBP [48, 51, 53]. A putative protease-sensitive region, rich in proline and basic residues (amino acids 413-506 in LTBP-1S) and located at the C-terminus of the region required for association to ECM, may be the site of cleavage by these serine proteases [39, 48]. Although proteolytic release of LTBP or large latent complex from ECM by cells has not been demonstrated, this mechanism is assumed to be essential for TGF-ß activation as discussed below. Because there are several LTBPs with distinct tissue distributions, the bioavailability of the TGF-ß isoforms in specific organs may be regulated in part by the formation of different large latent complexes.
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Mechanisms of Latent-TGF-ß Activation
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A number of papers have reported latent TGF-ß activation in various cell systems. For example, TGF-ß formation is stimulated by retinoic acid or fibroblast growth factor-2 in endothelial cell cultures [54, 55], endotoxin and bleomycin with macrophages [56], vitamin D3 with chondrocytes, and glucocorticoids with osteoblasts [5]. However, few experiments have characterized the mechanism of activation. The most studied activation system has been the coculture of endothelial cells and smooth muscle cells or pericytes [57, 58]. Although these cell types constitutively produce large latent TGF-ß, no active TGF-ß is detected in their conditioned medium. However, when placed together, endothelial cells and smooth muscle cells (or pericytes) rapidly yield active TGF-ß. Examination of this system has stressed the role of plasmin, as TGF-ß formation is blocked by plasmin inhibitors or depletion of plasminogen, the plasmin zymogen [57]. Plasminogen is converted to plasmin by the urokinase type plasminogen activator (u-PA) on the cell surface, a mechanism which requires binding of u-PA to a specific receptor. Addition of neutralizing antibodies to u-PA to the coculture also blocks release of TGF-ß. TGF-ß formation in this system is a self-regulated mechanism, as TGF-ß upregulates synthesis of the plasminogen activator inhibitor PAI-1, which in turn decreases latent TGF-ß activation by inhibiting u-PA. Apo(a), the apolipoprotein that is found in lipoprotein(a) [Lp(a)], is structurally homologous with plasminogen and can function as a competitive inhibitor of plasminogen conversion. Through inhibition of plasmin generation, Lp(a) decreases the formation of TGF-ß, which derepresses the growth and proliferation of smooth muscle cells in vitro [59, 60]. Recently, Grainger and coworkers have shown that TGF-ß formation is decreased in transgenic mice expressing Apo(a), concomitant with lower plasmin generation [61, 62]. These mice also develop artherosclerotic lesions, which involves proliferation and migration of vascular smooth muscle cells. These are the first data to suggest a role for plasmin in latent TGF-ß activation in vivo.
Latent TGF-ß is likely to be activated on the cell surface where plasmin is protected from inhibitors. As mentioned above, targeting of the latent complex to the cell surface might be enhanced by the interaction of LAP with the mannose 6-phosphate/insulin-like growth factor II (IGF-II) receptor. Indeed, an excess of mannose 6-phosphate added to endothelial cell/smooth muscle cell cocultures inhibits activation, which suggests the involvement of this receptor and of LAP mannose 6-phosphate residues in the activation process [63]. Similarly, it has been suggested that the mannose 6-phosphate receptor/IGF-II receptor participates in TGF-ß formation in cocultures of fat-storing cells and sinusoidal endothelial cells [64].
The smooth muscle cell/endothelial cell coculture system has permitted the identification of other components of the activation pathway. The first is LTBP, as demonstrated by decreased TGF-ß formation in the presence of an excess of LTBP-1 or antibodies to this molecule [65]. The second is transglutaminase, as neutralizing antibodies to and inhibitors of transglutaminase block latent TGF-ß activation [54]. As LTBP and transglutaminase are both involved in the incorporation of latent TGF-ß into the ECM, it is possible that the sequestration of latent TGF-ß in the ECM is a necessary step in TGF-ß formation in this system. This hypothesis is supported by recent experiments showing that antibodies to the N-terminal domain of LTBP-1, which block LTBP-1 reactivity with transglutaminase in vitro and LTBP-1 incorporation into ECM by cells, also inhibit latent TGF-ß activation [51].
How can these different observations be integrated into an activation scheme? After secretion, the large latent complex is incorporated into the ECM through crosslinking of LTBP by transglutaminase (Fig. 1). Following incorporation into ECM, TGF-ß formation probably requires addressing of the large latent complex to the cell surface, and therefore its release from the ECM by a protease. This proteolytic step results in the truncation of LTBP, which may in turn expose novel regions of LAP. LAP would then become available for binding to the cell surface through the mannose 6-phosphate/IGF-II receptor as well as become more sensitive to a second proteolytic cleavage by plasmin, releasing TGF-ß. As mentioned before, intact LTBP may mask the mannose 6-phosphate residues in LAP, preventing latent TGF-ß from binding to the mannose 6-phosphate/IGF-II receptor. Also, it has been observed that latent TGF-ß is less susceptible to plasmin activation when associated with LTBP in the large latent complex. Therefore, although not directly required for latency, LTBP may prevent latent TGF-ß from interacting inappropriately with components of the activation pathway. It is noteworthy that in this working hypothesis, two proteolytic steps are required: first, to release the latent complex from ECM and expose the mannose 6-phosphate residues, and second, to cleave LAP and liberate TGF-ß. Whether these two steps are performed by plasmin is unclear, and other proteases might be involved. The need for the two cell types in this activation scheme remains to be explained. Endothelial and smooth muscle cells might cooperate by providing sufficient levels of the different components necessary to this mechanism. For example, endothelial cells may provide u-PA, which smooth muscle cells produce in low amount, whereas smooth muscle cells appear to be richer in cell surface mannose 6-phosphate/IGF-II receptors than endothelial cells [66].
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Figure 1. A model for latent TGF-ß activation. ECM: extracellular matrix protein; M6P-R: mannose 6-phosphate/IGF-II receptor; Plasm: plasmin; Plasmgn: plasminogen; TGase: transglutaminase; TGF-Rs: TGF-ß serine/threonine kinase receptors.
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Other activation systems have been described, although in less detail. TGF-ß formation by endotoxin-stimulated macrophages has the same requirements as the coculture system, suggesting a similar activation mechanism [56]. However, it is likely that several pathways can lead to the release of active TGF-ß. Mice with targeted deletions of the plasminogen or plasminogen activator genes do not display any phenotype reminiscent of TGF-ß knock-out mice, suggesting that plasmin is dispensable for latent TGF-ß activation in vivo. Plasmin-independent TGF-ß formation has also been observed in cells in culture [67, 68]. Other proteases, such as cathepsin D, may substitute for plasmin in the cleavage of LAP, whereas mast cell chymase, leukocyte elastase and thrombin can release LTBP from the ECM. Nonenzymatic mechanisms, such as activation by thrombospondins, must also be taken into account; this might occur, for example, in adrenocortical cells stimulated with adrenocorticotropic hormone [37]. Finally, TGF-ß formation can also occur independent of the interaction with the mannose 6-phosphate/IGF-II receptor, as observed with endothelial cells treated with retinoic acid [69] or with human osteoblast-like cells [70].
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Perspectives
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From the study of the coculture system, latent TGF-ß activation appears as a multistep mechanism. Each step may represent a regulatory level, which translates into a tight control of TGF-ß formation. Although the past years have brought insight into the components and the regulation of latent TGF-ß activation, the sequence of this mechanism is still hypothetical. In particular, the exact relationship between incorporation of the large latent complex into the ECM and activation remains unclear. Also, nothing is known of the fate of the latent complex after its association with the ECM: whether it is released, whether it binds to the mannose 6-phosphate/IGF-II receptor or to another molecule on the cell surface, and what is the final step of activation. Some of the answers may be found by focusing on the role of LTBP in this process. Study of the structural relationship between LTBP and latent TGF-ß should permit validation of the hypothesis that LTBP masks domains of latent TGF-ß involved in activation. Identification of putative molecules interacting with LTBP may help unravel new components of the activation pathway. Recently, functional domains of LTBP-1 have been characterized; this allows the design of new molecular tools to assess some aspects of the mechanism of TGF-ß formation through a genetic analysis. For example, overexpression of mutants of LTBP defective for association with the ECM might act in a dominant negative fashion in cells synthesizing the large latent complex, resulting in loss of latent TGF-ß targeting to the ECM. Such an approach would allow a direct study of the role of ECM in TGF-ß formation. Moreover, genetic analysis can be carried out in transgenic animals to reveal insight into the mechanisms of TGF-ß activation in vivo, for which very few data are available. As with LTBP, more structural and functional information on LAP and its association with TGF-ß is required to understand the mechanism underlying the formation and breakdown of latent TGF-ß.
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Acknowledgments
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This research was supported by NIH grants CA 23753 (Daniel B. Rifkin), EY 06537 (Irene Noguera), T32GM 07238 (Irene Noguera), T32GM 07308 NIGMS to John G. Harpel, a fellowship from the Association pour la Recherche contre le Cancer (ARC) (Pierre-Emmanuel Gleizes), and a Clinical Associate Physician award (John S. Munger).
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References
|
|---|
-
Massague J. The transforming growth factor-beta family. Annu Rev Cell Biol 1990;6:597-641.
-
Lawrence DA. Identification and activation of latent transforming growth factor beta. Methods Enzymol 1991;198:327-336.[Medline]
-
Theodorescu D, Bergsma D, Man MS et al. Cloning and overexpression of TGF-ß1 cDNA in a mammary adenocarcinoma: in vitro and in vivo effects. Growth Factors 1991;5:305-316.[Medline]
-
Pierce D Jr, Johnson MD, Matsui Y et al. Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. Genes Dev 1993;7:2308-2317.[Abstract/Free Full Text]
-
Boulanger J, Reyes-Moreno C, Koutsilieris M. Mediation of glucocorticoid receptor function by the activation of latent transforming growth factor-ß1 in MG-63 human osteosarcoma cells. Int J Cancer 1995;61:692-697.[Medline]
-
Arrick BA, Lopez AR, Elfman F et al. Altered metabolic and adhesive properties and increased tumorigenesis associated with increased expression of transforming growth factor ß1. J Cell Biol 1992;118:715-726.[Abstract/Free Full Text]
-
Kulkarni AB, Huh CG, Becker D et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 1993;90:770-774.[Abstract/Free Full Text]
-
Diebold RJ, Eis MJ, Yin M et al. Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci USA 1995;92:12215-12219.[Abstract/Free Full Text]
-
Dickson MC, Martin JS, Cousins FM et al. Defective hematopoiesis and vasculogenesis in transforming growth factor-ß1 knock out mice. Development 1995;121:1845-1854.[Abstract]
-
Borkowski TA, Letterio JJ, Farr AG et al. A role for endogenous transforming growth factor ß1 in Langherans cell biology: the skin of transforming growth factor ß1 null mice is devoid of epidermal Langherans cells. J Exp Med 1996;184:2417-2422.[Abstract/Free Full Text]
-
Proetzel G, Pawlowski SA, Wiles MV et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet 1995;11:409-414.[Medline]
-
Roberts AB, Sporn MB. The transforming growth factor-ßs. In: Roberts AB, Sporn MB, eds. Peptide Growth Factors and Their Receptors. I. New York: Springer-Verlag, 1990:419-472.
-
Glick AB, Lee MM, Darwiche N et al. Targeted deletion of the TGF-ß1 gene causes rapid progression to squamous cell carcinoma. Genes Dev 1994;8:2429-2440.[Abstract/Free Full Text]
-
Sachs L. The control of hematopoiesis and leukemia: from basic biology to the clinic. Proc Natl Acad Sci USA 1996;93:4742-4749.[Abstract/Free Full Text]
-
Zhou L, Dey CR, Wert SE et al. Arrested lung morphogenesis in transgenic mice bearing an SP-C-TGF-beta 1 chimeric gene. Dev Biol 1996;175:227-238.[Medline]
-
Sellheyer K, Bickenbach JR, Rothnagel JA et al. Inhibition of skin development by overexpression of transforming growth factor beta 1 in the epidermis of transgenic mice. Proc Natl Acad Sci USA 1993;90:5237-5241.[Abstract/Free Full Text]
-
Sanderson N, Factor V, Nagy P et al. Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci USA 1995;92:2572-2576.[Abstract/Free Full Text]
-
Galbreath E, Kim SJ, Park K et al. Overexpression of TGF-beta 1 in the central nervous system of transgenic mice results in hydrocephalus. J Neuropath Exp Neurol 1995;54:339-349.[Medline]
-
Gentry LE, Nash BW. The pro-domain of pre-pro-transforming growth factor beta 1 when independently expressed is a functional binding protein for the mature growth factor. Biochemistry 1990;29:6851-6857.[Medline]
-
Dubois CM, Laprise MH, Blanchette F et al. Processing of transforming growth factor beta 1 precursor by human furin convertase. J Biol Chem 1995;270:10618-10624.[Abstract/Free Full Text]
-
Purchio AF, Cooper JA, Brunner AM et al. Identification of mannose 6-phosphate in two asparagine-linked sugar chains of recombinant transforming growth factor-beta 1 precursor. J Biol Chem 1988;263:14211-14215.[Abstract/Free Full Text]
-
Daopin S, Piez KA, Ogawa Y et al. Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily. Science 1992;257:369-373.[Abstract/Free Full Text]
-
Schlunegger MP, Grutter MG. An unusual feature revealed by the crystal structure at 2.2. Å resolution of human transforming growth factor-beta 2. Nature 1992;358:430-434.[Medline]
-
McMahon GA, Dignam JD, Gentry LE. Structural characterization of the latent complex between transforming growth factor beta 1 and beta 1-latency-associated peptide. Biochem J 1996;313:343-351.
-
Brown PD, Wakefield LM, Levinson AD et al. Physicochemical activation of recombinant latent transforming growth factor-betas 1, 2, and 3. Growth Factors 1990;3:35-43.[Medline]
-
Lawrence DA, Pircher R, Jullien P. Conversion of a high molecular weight latent ß-TGF from chicken embryo fibroblasts into a low molecular weight active ß-TGF under acidic conditions. Biochem Biophys Res Commun 1985;133:1026-1034.[Medline]
-
Oreffo R, Mundy G, Seyedin S et al. Activation of the bone-derived latent TGF-beta complex by isolated osteoclasts. Biochem Biophys Res Commun 1989;158:817-822.[Medline]
-
Bonewald LF, Mundy GR. Role of transforming growth factor beta in bone remodeling: a review. Connect Tissue Res 1989;23:201-208.[Medline]
-
Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-ß1. Mol Endocrinol 1996; 10:1079-1083.
-
Barcellos-Hoff MH, Derynck R, Tsang ML et al. Transforming growth factor-beta activation in irradiated murine mammary gland. J Clin Invest 1994;93:892-899.
-
Miyazono K, Heldin CH. Role for carbohydrate structures in TGF-beta 1 latency. Nature 1989;338:158-160.[Medline]
-
Schultz-Cherry S, Hinshaw VS. Influenza virus neuraminidase activates latent transforming growth factor ß. J Virol 1996;70:8624-8629.[Abstract]
-
Lyons RM, Gentry LE, Purchio AF et al. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol 1990;110:1361-1367.[Abstract/Free Full Text]
-
Lyons RM, Keski-Oja J, Moses HL. Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol 1988;106:1659-1665.[Abstract/Free Full Text]
-
Schultz-Cherry S, Lawler J, Murphy-Ullrich JE. The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-ß. J Biol Chem 1994;269:26783-26788.[Abstract/Free Full Text]
-
Schultz-Cherry S, Murphy-Ullrich JE. Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism. J Cell Biol 1993;122:923-932.[Abstract/Free Full Text]
-
Souchelnitskiy S, Chambaz EM, Feige JJ. Thrombospondins selectively activate one of the two latent forms of transforming growth factor-ß present in adrenocortical cell-conditioned medium. Endocrinology 1995;136:5118-5126.[Abstract]
-
Miyazono K, Hellman U, Wernstedt C et al. Latent high molecular weight complex of transforming growth factor ß1. J Biol Chem 1988;263:6407-6415.[Abstract/Free Full Text]
-
Kanzaki T, Olofsson A, Moren A et al. TGF-ß1 binding protein: a component of the large latent complex of TGF-ß1 with multiple repeat sequences. Cell 1990;61:1051-1061.[Medline]
-
Tsuji T, Okada F, Yamagushi K et al. Molecular cloning of the large subunit of transforming growth factor type ß masking protein and expression of the mRNA in various rat tissues. Proc Natl Acad Sci USA 1990;87:8835-8839.[Abstract/Free Full Text]
-
Gibson MA, Hatzinikolas G, Davis EC et al. Bovine latent transforming growth factor beta 1-binding protein 2: molecular cloning, identification of tissue isoforms, and immunolocalization to elastin-associated microfibrils. Mol Cell Biol 1995;15:6932-6942.[Abstract]
-
Moren A, Olofsson A, Stenman G et al. Identification and characterization of LTBP-2, a novel latent transforming growth factor-beta-binding protein. J Biol Chem 1994;269:32469-32478.[Abstract/Free Full Text]
-
Yin W, Smiley E, Germiller J et al. Isolation of a novel latent transforming growth factor-beta binding protein gene (LTBP-3). J Biol Chem 1995;270:10147-10160.[Abstract/Free Full Text]
-
Miyazono K, Olofsson A, Colosetti P et al. A role of the latent TGF-beta 1-binding protein in the assembly and secretion of TGF-beta 1. EMBO J 1991;10:1091-1101.[Medline]
-
Dallas SL, Park-Snyder S, Miyazono K et al. Characterization and autoregulation of latent transforming growth factor ß (TGFß) complexes in osteoblast-like cell lines: production of a latent complex lacking the latent TGFß-binding protein. J Biol Chem 1994;269:6815-6822.[Abstract/Free Full Text]
-
Gleizes P-E, Beavis RC, Mazzieri R et al. Identification and characterization of an eight-cysteine repeat of the latent transforming growth factor-ß binding protein-1 (LTBP-1) that mediates bonding to the latent transforming growth factor-ß1. J Biol Chem 1996;271:29891-29896.[Abstract/Free Full Text]
-
Saharinen J, Taipale J, Keski-Oja J. Association of the small latent transforming growth factor-ß with an eight cysteine repeat of protein LTBP-1. EMBO J 1996;15:245-253.[Medline]
-
Taipale J, Miyazono K, Heldin CH et al. Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol 1994;124:171-181.[Abstract/Free Full Text]
-
Taipale J, Saharinen J, Hedman K et al. Latent transforming growth factor-ß1 and its binding protein are components of extracellular matrix fibrils. J Histochem Cytochem 1996;44:875-889.[Abstract]
-
Dallas SL, Miyazono K, Skerry TM et al. Dual role for the latent transforming growth factor-beta binding protein in storage of latent TGF-beta in the extracellular matrix and as a structural matrix protein. J Cell Biol 1995;131:539-549.[Abstract/Free Full Text]
-
Nunes I, Gleizes P-E, Metz CN et al. Latent TGF-ß binding protein domains involved in activation and transglutaminase-dependent crosslinking of latent TGF-ß. J Cell Biol 1997; 136:1151-1163.[Abstract/Free Full Text]
-
Olofsson A, Ichijo H, Moren A et al. Efficient association of an amino-terminally extended form of human latent transforming growth factor-ß binding protein with the extracellular matrix. J Biol Chem 1995;270:31294-31297.[Abstract/Free Full Text]
-
Taipale J, Lohi J, Saharinen J et al. Human mast cell chymase and leukocyte elastase release latent transforming growth factor-beta 1 from the extracellular matrix of cultured human epithelial and endothelial cells. J Biol Chem 1995;270:4689-4696.[Abstract/Free Full Text]
-
Kojima S, Kiyomitsu N, Rifkin DB. Requirement for transglutaminase in the activation of latent transforming growth factor-ß in bovine endothelial cells. J Cell Biol 1993;121:439-448.[Abstract/Free Full Text]
-
Flaumenhaft R, Abe M, Mignatti P et al. Basic fibroblast growth factor-induced activation of latent transforming growth factor beta in endothelial cells: regulation of plasminogen activator activity. J Cell Biol 1992;118:901-909.[Abstract/Free Full Text]
-
Nunes I, Shapiro RL, Rifkin DB. Characterization of latent TGF-beta activation by murine peritoneal macrophages. J Immunol 1995;155:1450-1459.[Abstract]
-
Sato Y, Rifkin DB. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-ß1-like molecule by plasmin during coculture. J Cell Biol 1989;109:309-315.[Abstract/Free Full Text]
-
Antonelli-Orlidge A, Saunders K, Smith S et al. An activated form of transforming growth factor beta is produced by co-cultures of endothelial cells and pericytes. Proc Natl Acad Sci USA 1989;86:4544-4548.[Abstract/Free Full Text]
-
Kojima S, Harpel P, Rifkin D. Lipoprotein (a) inhibits the generation of transforming growth factor beta: an endogenous inhibitor of smooth muscle cell migration. J Cell Biol 1991;113:1439-1445.[Abstract/Free Full Text]
-
Grainger DJ, Kirschenlohr HL, Metcalfe JC et al. Proliferation of human smooth muscle cells promoted by lipoprotein(a). Science 1993;260:1655-1658.[Abstract/Free Full Text]
-
Grainger DJ, Kemp PR, Liu AC et al. Activation of transforming growth factor-ß is inhibited in transgenic apolipoprotein(a) mice. Nature 1994;370:460-462.[Medline]
-
Lawn RM, Pearle AD, Kunz LL et al. Feedback mechanism of focal vascular lesion formation in transgenic apolipoprotein(a) mice. J Biol Chem 1996;271:31367-31371.[Abstract/Free Full Text]
-
Dennis P, Rifkin, DB. Cellular activation of latent transforming growth factor beta requires binding to the cation-independent mannose-6-phosphate/insulin-like growth factor type II receptor. Proc Natl Acad Sci USA 1991;88:580-584.[Abstract/Free Full Text]
-
de Bleser PJ, Jannes P, van Buul-Offers SC et al. Insulinlike growth factor-II/mannose 6-phosphate receptor is expressed on CCl4-exposed rat fat-storing cells and facilitates activation of latent transforming growth factor-beta in cocultures with sinusoidal endothelial cells. Hepatology 1995;21:1429-1437.[Medline]
-
Flaumenhaft R, Abe M, Sato Y et al. Role of the latent TGF-beta binding protein in the activation of latent TGF-beta by co-cultures of endothelial and smooth muscle cells. J Cell Biol 1993;120:995-1002.[Abstract/Free Full Text]
-
Nunes I, Munger JS, Harpel JG et al. Structure and activation of the large latent transforming growth factor-ß complex. Int J Obes 1996;20(suppl 3):S4-S8.
-
Nunes I, Kojima S, Rifkin DB. Effects of endogenously activated transforming growth factor-beta on growth and differentiation of retinoic acid-treated HL-60 cells. Cancer Res 1996;56:495-499.[Abstract/Free Full Text]
-
Bizik J, Felnerova D, Grofova M et al. Active transforming growth factor-ß in human melanoma cell lines: no evidence for plasmin-related activation of latent TGF-ß. J Cell Biochem 1996;62:113-122.[Medline]
-
Kojima S, Rifkin DB. Mechanism of retinoid-induced activation of latent transforming growth factor-ß in bovine endothelial cells. J Cell Physiol 1993;155:323-332.[Medline]
-
Oursler MJ, Riggs BL, Spelsberg TC. Glucocorticoid-induced activation of latent transforming growth factor-beta by normal human osteoblast-like cells. Endocrinology 1993;133:2187-2196.[Abstract]
accepted for publication February 19, 1997.
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Abstract
Introduction
