The transforming growth factor-β system, a complex pattern of cross-reactive ligands and receptors

Cheifetz, Sela; Weatherbee, James A.; Tsang, Monica; Anderson, John; Mole, John E.; Lucas, Robert A.; Massagué, Joan

doi:10.1016/0092-8674(87)90192-9

Cited by 681 publications

(331 citation statements)

References 29 publications

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“…betaglycan) (14 -16). Nevertheless, betaglycan has a high affinity for all three TGF-␤ isoforms (17)(18)(19), which has been exploited to counteract TGF-␤ signaling by sequestering the ligand using the soluble extracellular ligand binding domain (20,21). Depending on the cell type, betaglycan either enhances (14,15,22) or inhibits TGF-␤ responses (23).…”

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confidence: 99%

Identification of Endoglin in Rat Hepatic Stellate Cells

Meurer

Tihaa

Lahme

et al. 2005

Journal of Biological Chemistry

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Transforming growth factor ␤ (TGF-␤) signaling is mediated by the cell surface TGF-␤ type I (ALK5), type II, and the accessory type III receptors endoglin and betaglycan. Hepatic stellate cells (HSC), the most profibrogenic cell type in the liver, express ALK5, T␤RII, and betaglycan. To monitor the expression of betaglycan in HSC, we used the commercially available antibody sc-6199 in Western blot analysis. This antibody, raised against a peptide mapping at the carboxyl terminus of the human betaglycan, is claimed to be specific for betaglycan, although it is known that the C-terminal domain is highly conserved in type III receptors. Proteins recognized in HSC by sc-6199 did not match the characteristic migration pattern of betaglycan. Moreover, the determined molecular weight (M r 160) and the observed reductant sensitivity after treatment with dithiothreitol resemble those of a closely related type III receptor, endoglin (CD105). Endoglin, a disulfide-linked homodimer, is an accessory component of the TGF-␤ receptor complex and mainly expressed on endothelial cells. The presence of endoglin in HSC of rat liver was confirmed by molecular cloning of the endoglin cDNA and immunocytochemistry. The reactivity of sc-6199 with both auxiliary TGF-␤ receptors (betaglycan and endoglin) from rats was demonstrated by Western blot and immunocytochemical analysis of cells heterologously expressing these proteins. Furthermore, Northern and Western blotting revealed that both betaglycan and endoglin genes are differentially regulated in HSC and in transdifferentiated myofibroblasts (MFB). By surface labeling and immunoprecipitation experiments, we show that endoglin is found in significant amounts exposed at the plasma membrane of HSC and MFB, which is a pivotal prerequisite for binding of and signaling in response to TGF-␤. In conclusion, we hypothesize that TGF-␤ signals in HSC and MFB are tuned by two different interconnected signaling pathways, as it was previously demonstrated for endothelial cells.The transforming growth factor family of growth factors regulates a diverse set of physiologic processes including proliferation, cellular differentiation, apoptosis, and expression of extracellular matrix genes (1-3). Signaling by the three identified mammalian TGF-␤ 1 isoforms TGF-␤1, TGF-␤2, and TGF-␤3 is initiated by binding to the high affinity cell surface receptors, the accessory TGF-␤ type III receptor (T␤RIII) (4), the type II receptor (T␤RII) (5), and type I (6) receptor (T␤RI), of which T␤RII and T␤RI possess intracellular serine/threonine kinase domains. Upon binding of TGF-␤1 or TGF-␤3 to the receptor type II, the liganded receptor dimer associates with and its constitutive active kinase transphosphorylates the type I receptor at the GS domain (7). The active type I receptor in turn phosphorylates and thereby activates the intracellular signal transducers represented by the R-Smad family members 2 and 3 (2, 7, 8).Because TGF-␤2 has a lower affinity for the type II receptor (9, 10), cells sense this ligand by eithe...

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confidence: 99%

Identification of Endoglin in Rat Hepatic Stellate Cells

Meurer

Tihaa

Lahme

et al. 2005

Journal of Biological Chemistry

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“…An example of this is the mammalian T and B cell Ag receptors, in which covalently linked binding chains engage ligand (15), while other receptor chains are required for signaling, but not for ligand binding (16). In other cases, although binding and signaling domains may exist on the same protein, ligand specificity is determined by combinations of multiple receptor chains, as seen in the cytokine (17,18) and TGF-␤ receptor families (19).…”

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Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses

Wyllie

Kiss-Tóth

Visintin

et al. 2000

The Journal of Immunology

245

151

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Members of the Toll-like receptor (TLR) family are components of the mammalian anti-microbial response, signaling with a domain closely related to that of IL-1 receptors. In this report the expression and function of TLR1, a TLR of unknown function, are examined. TLR1 is expressed by monocytes, as demonstrated using a novel mAb. Monocytes also express TLR2. TLR1 transfection of HeLa cells, which express neither TLR1 nor TLR2, was not sufficient to confer responsiveness to several microbial extracts. However, cotransfection of TLR1 and TLR2 resulted in enhanced signaling by HeLa cells to soluble factors released from Neisseria meningitidis relative to the response with either TLR alone. This phenomenon was also seen with high concentrations of some preparations of LPS. The N. meningitidis factors recognized by TLR1/TLR2 were not released by N. meningitidis mutant in the LpxA gene. Although LpxA is required for LPS biosynthesis, because cooperation between TLR1 and TLR2 was not seen with all LPS preparations, the microbial component(s) TLR1/2 recognizes is likely to be a complex of LPS and other molecules or a compound metabolically and chemically related to LPS. The functional IL-1R consists of a heterodimer; this report suggests a similar mechanism for TLR1 and TLR2, for certain agonists. These data further suggest that mammalian responsiveness to some bacterial products may be mediated by combinations of TLRs, suggesting a mechanism for diversifying the repertoire of Toll-mediated responses.

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“…Each ofthese peptides has been cloned, demonstrating that TGF01 is encoded as a 390 amino acid precursor (10), TGFs2 as a 412 amino acid precursor (11,12), and that both have a signal peptide of 20-23 amino acids at the NH2 terminus . The processed 112 amino acid chains of the two peptides share 72% sequence homology and appear to bind equally well to TGFS class III receptors (13), although TGFS1 binds with greater affinity than TGF02 to class I and II receptors (14,15). Interestingly, lymphoid cells appear to possess only class I and II TGF,6 receptors (16), although in vitro, lymphocyte and monocyte responses to TGF01 and 02 appear comparable (6,17,18).…”

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Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta.

Allen

Manthey

Hand

et al. 1990

The Journal of Experimental Medicine

241

131

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Transforming growth factor /3 (TGF (3),t originally isolated from platelets as a 25-kD peptide (1, 2), has been shown to be a product of other inflammatory cells, including lymphocytes (3, 4) and macrophages (5, 6), and to have potent immunomodulatory effects (7). Although five different forms of TGFJ3 have now been characterized (1), only TGF01 and its homologue, TGF02 (8, 9), have thus far been identified in hemopoietic cells (6). Each ofthese peptides has been cloned, demonstrating that TGF01 is encoded as a 390 amino acid precursor (10), TGFs2 as a 412 amino acid precursor (11,12), and that both have a signal peptide of 20-23 amino acids at the NH2 terminus . The processed 112 amino acid chains of the two peptides share 72% sequence homology and appear to bind equally well to TGFS class III receptors (13), although TGFS1 binds with greater affinity than TGF02 to class I and II receptors (14, 15). Interestingly, lymphoid cells appear to possess only class I and II TGF,6 receptors (16), although in vitro, lymphocyte and monocyte responses to TGF01 and 02 appear comparable (6,17,18). The secretion of TGFa peptides by lymphocytes and monocytes only after activation (3-6) implicates these polypeptides in the evolution of immunologic processes, and in recent studies TGFR has been identified in chronic inflammatory tissues (19)(20)(21)(22), including the synovium of rheumatoid arthritis patients (7,22) and in experimentally induced arthritis in rodents (22). To define the role of TGFS in such lesions, we injected natural or recombinant TGF0 directly into the joint cavity of Lewis rats and monitored its effect on cellular recruitment and activation, and on its potential modulation of pathogenic effects. TGF01 and TGF02 were both found to induce synovial erythema, swelling, and leukocyte infiltration . The infiltrating mononuclear cells, activated to express growth factors, likely regulated the pronounced synovial hyperplasia that was apparent within 2-3 d. Based on these observations, it appears that TGF0, released by platelets and inflammatory cells in the arthritic synovium, may directly contribute to the events associated with inflammatory arthropathies.

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The transforming growth factor-β system, a complex pattern of cross-reactive ligands and receptors

Cited by 681 publications

References 29 publications

Identification of Endoglin in Rat Hepatic Stellate Cells

Identification of Endoglin in Rat Hepatic Stellate Cells

Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses

Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta.

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