Identification of CD109 as part of the TGF‐β receptor system in human keratinocytes

Finnson, Kenneth W.; Tam, Betty; Li, Kai; Marcoux, Anne; Lepage, Pierre; Roy, Stéphane; Bizet, Albane A.; Philip, Anie

doi:10.1096/fj.05-5229fje

Cited by 132 publications

(186 citation statements)

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“…Immunoprecipitation experiments revealed the association of 25 kDa and 180 kDa CD109 complex with TbRI. These results confirmed the report by Finnson et al (2006), which showed that CD109 interacted directly with TbRI, independently of ligand binding. Interestingly, the furinase-resistant CD109 R1273S was not able to associate with TbRI, although the R1273S mutant protein was localized on the cell surface.…”

Section: P-smad2supporting

confidence: 92%

“…As CD109 binds TGF-b1 with high affinity, secreted 180 kDa CD109 may also contribute to negative regulation of TGF-b1 signaling by sequestration of TGF-b1 in the medium. However, inhibition of TGF-b signaling by CD109 can occur independently of ligand sequestration via direct modulation of TbRI activity (Finnson et al, 2006). In this study, we showed that overexpression of 180 kDa soluble CD109 also inhibits TGF-b signaling, suggesting that soluble CD109 can bind to TbRI.…”

Section: P-smad2mentioning

confidence: 60%

“…On the other hand, inhibition of endogenous CD109 processing in HEK293 cells moderately increased the level of Smad2 phosphorylation (Supplementary Figure S2b). CD109 modulates receptor activity by direct interaction with TbRI, independently of ligand binding (Finnson et al, 2006). We found association of 180 kDa and 25 kDa CD109 complex with TbRI by immunoprecipitation experiments, whereas the association of TbRII with CD109 appears to be very weak or non-existent.…”

Section: Secretion Of 180 Kda Cd109 Into the Culture Mediummentioning

confidence: 63%

“…CD109 is expressed on a subset of fetal and adult CD34 þ bone marrow mononuclear cells, mesenchymal stem cell subsets, phytohemagglutinin-activated T lymphoblasts, thrombinactivated platelets, leukemic megakaryoblasts, endothelial cells and some human tumor cell lines (Kelton et al, 1990;Murray et al, 1999;Giesert et al, 2003). Tam et al (2003) and Finnson et al (2006) reported that CD109 was a component of the TGF-b receptor system and that it decreased TGF-b1-induced phosphorylation of R-Smad in human keratinocytes. We recently found that CD109 was upregulated in oral squamous cell carcinoma (SCC), which resulted in a reduction of the TGF-b1-mediated anti-proliferative effect in oral SCC cells .…”

Section: Kip1mentioning

confidence: 99%

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Processing of CD109 by furin and its role in the regulation of TGF-β signaling

et al. 2010

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CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, whose expression is upregulated in squamous cell carcinomas of the lung, esophagus, uterus and oral cavity. CD109 negatively regulates transforming growth factor (TGF)-b signaling in keratinocytes by directly modulating receptor activity. In this study, we further characterized CD109 regulation of TGF-b signaling and cell proliferation. We found that CD109 is produced as a 205 kDa glycoprotein, which is then processed in the Golgi apparatus into 180 kDa and 25 kDa proteins by furin (furinase). 180 kDa CD109 associated with GPI-anchored 25 kDa CD109 on the cell surface and was also secreted into the culture medium. To investigate whether furinase cleavage of CD109 is necessary for its biological activity, we mutated arginine 1273 in the CD109 furinase cleavage motif (amino acid 1270-RRRR-1273) to serine (R1273S). Interestingly, CD109 R1273S neither significantly impaired TGF-b signaling nor affected TGF-b-mediated suppression of cell growth, although it was expressed on the cell surface as a 205 kDa protein. Consistent with this finding, the 180 kDa and 25 kDa CD109 complex, but not CD109 R1273S, associated with the type I TGF-b receptor. These findings indicate that processing of CD109 into 180 kDa and 25 kDa proteins by furin, followed by complex formation with the type I TGF-b receptor is required for the regulation of TGF-b signaling in cancer cells and keratinocytes.

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Section: P-smad2supporting

confidence: 92%

Section: P-smad2mentioning

confidence: 60%

Section: Secretion Of 180 Kda Cd109 Into the Culture Mediummentioning

confidence: 63%

Section: Kip1mentioning

confidence: 99%

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Processing of CD109 by furin and its role in the regulation of TGF-β signaling

et al. 2010

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“…It also forms a complex with TGF-b signaling receptors and negatively regulates TGF-b signaling (Finnson et al 2006). CD109 directs the localization of TGF-b receptors to caveolae and promotes their degradation (Bizet et al 2011) in a process involving Smad7 and Smurf2 (Bizet et al 2012).…”

Section: Cd109mentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

552

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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Brief Report: CD109 Overexpression Ameliorates Skin Fibrosis in a Mouse Model of Bleomycin‐Induced Scleroderma

Vorstenbosch

Alajmi

Winocour

et al. 2013

Arthritis & Rheumatism

Self Cite

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Objective. Transforming growth factor ␤ (TGF␤) is a profibrotic cytokine, and its aberrant function is implicated in several types of fibrotic pathologies including scleroderma (systemic sclerosis [SSc]). Multiple lines of evidence show that increased TGF␤ signaling contributes to progressive fibrosis in SSc by promoting fibroblast activation, excessive extracellular matrix (ECM) deposition, and dermal thickening. We have previously identified CD109 as a TGF␤ coreceptor and have shown that it antagonizes TGF␤ signaling and TGF␤-induced ECM expression in vitro in human keratinocytes and fibroblasts. The aim of the present study was to examine the ability of CD109 to prevent skin fibrosis in a mouse model of bleomycin-induced SSc.Methods. Transgenic mice overexpressing CD109 in the epidermis and their wild-type (WT) littermates were injected with bleomycin in phosphate buffered saline (PBS) or with PBS alone every other day for 21 days or 28 days. Dermal thickness and collagen deposition were determined histologically using Masson's trichrome and picrosirius red staining. In addition, collagen and fibronectin content was analyzed using Western blotting, and activation of TGF␤ signaling was examined by determining phospho-Smad2 and phospho-Smad3 levels using Western blotting and immunohistochemistry.Results. Transgenic mice overexpressing CD109 in the epidermis showed resistance to bleomycininduced skin fibrosis, as evidenced by a significant decrease in dermal thickness, collagen crosslinking, collagen and fibronectin content, and phospho-Smad2/3 levels, as compared to their WT littermates.Conclusion. Our findings suggest that CD109 inhibits TGF␤ signaling and fibrotic responses in experimental murine scleroderma. They also suggest that CD109 regulates dermal-epidermal interactions to decrease extracellular matrix synthesis in the dermis. Thus, CD109 is a potential molecular target for therapeutic intervention in scleroderma.Accumulating evidence indicates that the profibrotic cytokine transforming growth factor ␤ (TGF␤) is a key factor driving the fibrotic process in scleroderma (systemic sclerosis [SSc]). A large number of studies have demonstrated that TGF␤ signaling is dysregulated in scleroderma (1). Cultured SSc fibroblasts display aberrant activation of autocrine TGF␤ signaling and increased TGF␤ receptor levels, leading to elevated extracellular matrix (ECM) synthesis (2). TGF␤ exacerbates fibrosis through deposition and accumulation of ECM not only by promoting the expression of ECM proteins such as type I collagen and fibronectin (3), but also by reducing ECM degradation through decreased synthesis of matrix metalloproteinases and increased expression of protease inhibitors. Despite the lack of success so far with efforts to develop effective anti-TGF␤ therapies to ameliorate fibrosis, strategies to block the production, activation, and intracellular signaling of TGF␤ are increasingly being explored.TGF␤ signaling is transduced by a pair of transmembrane serine/threonine kinases known as TGF␤ receptor ty...

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Identification of CD109 as part of the TGF‐β receptor system in human keratinocytes

Cited by 132 publications

References 50 publications

Processing of CD109 by furin and its role in the regulation of TGF-β signaling

Processing of CD109 by furin and its role in the regulation of TGF-β signaling

Signaling Receptors for TGF-β Family Members

Brief Report: CD109 Overexpression Ameliorates Skin Fibrosis in a Mouse Model of Bleomycin‐Induced Scleroderma

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