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The glycosylphosphatidylinositol (GPI)‐anchored protein cluster of differentiation 109 (CD109) is expressed on many human cell types and modulates the transforming growth factor β (TGF‐β) signaling network. CD109 belongs to the alpha‐macroglobulin family of proteins, known for their protease‐triggered conformational changes. However, the effect of proteolysis on CD109 and its conformation are unknown. Here, we investigated the interactions of CD109 with proteases. We found that a diverse selection of proteases cleaved peptide bonds within the predicted bait region of CD109, inducing a conformational change that activated the thiol ester of CD109. We show CD109 was able to conjugate proteases with this thiol ester and decrease their activity toward protein substrates, demonstrating that CD109 is a protease inhibitor. We additionally found that CD109 has a unique mechanism whereby its GPI‐anchored macroglobulin 8 (MG8) domain dissociates during its conformational change, allowing proteases to release CD109 from the cell surface by a precise mechanism and not unspecific shedding. We conclude that proteolysis of the CD109 bait region affects both its structure and location, and that interactions between CD109 and proteases may be important to understanding its functions, for example, as a TGF‐β co‐receptor. [ABSTRACT FROM AUTHOR]

CD109 is a glycosylphosphatidylinositol‐anchored glycoprotein and a member of the α2‐macroglobulin/C3,C4,C5 family of thioester‐containing proteins first identified as being expressed on blood cells, including activated T cells and platelets, and a subset of CD34 + bone marrow cells containing megakaryocyte progenitors. Although CD109 carries the biallelic platelet‐specific alloantigen Gov, the physiological functions or roles of CD109 in human disease remain largely unknown. It was recently demonstrated that CD109 is expressed in many malignant tumors, including various squamous cell carcinomas and adenocarcinomas, and plays a role as a multifunctional coreceptor. CD109 reportedly associates with transforming growth factor (TGF)‐β receptors and negatively regulates TGF‐β signaling in keratinocytes. Additionally, CD109 is potentially related to signal transducer and activator of transcription‐3 signaling and aberrant cell proliferation. In this review, we describe recent evidence of CD109‐specific significance in malignant tumors shown in mouse models and human tissues. Furthermore, we discuss the physiological functions of CD109 in vitro and in vivo, including results of phenotype analyses of CD109‐deficient mice exhibiting epidermal hyperplasia and osteopenia. [ABSTRACT FROM AUTHOR]

Cluster of differentiation (CD) 109 is a glycosylphosphatidylinositol- anchored cell surface glycoprotein and a co-receptor for transforming growth factor β. The expression of CD109 has been detected in squamous cell carcinoma of the lung, esophagus, skin and gallbladder. The aim of the present study was to evaluate CD109 expression in penile squamous cell carcinoma (PSCC). CD109 expression in PSCC tumor and adjacent tissues from 45 specimens in tissue microarrays was examined by immunohistochemical analyses. In addition, 3 fresh surgical samples of PSCC were collected and examined for their CD109 mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence staining. CD109 transcription and expression were significantly higher in the PSCC tissues compared with adjacent normal penile tissues, and its expression was restricted to squamous cells. However, CD109 expression level was not associated with the PSCC differentiation grade. These results suggest that CD109 may be associated with the pathogenesis of PSCC, and may therefore be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

CD109 is a glycosylphosphatidylinositol-anchored cell surface protein that is frequently detected in squamous cell carcinomas. CD109 is a negative regulator of TGF-β1 signaling in human keratinocytes, and the N-terminal fragment of CD109 secreted from cells after cleavage by the furin protease is important for modulating TGF-β1 signaling. Previously, we found that CD109 is expressed in human glioblastoma cells; however, the role of CD109 in glioblastoma cells is not established. Here, we describe the effects of CD109 in human glioblastoma cell lines. Three glioblastoma cell lines, SK-MG-1, U251MG and MG178, were tested and CD109 overexpression attenuated TGF-β1 signaling and enhanced EGF signaling in SK-MG-1, but not in U251MG or MG178. The N-terminal CD109 fragment in SK-MG-1 was hyperglycosylated compared with that in MG178 or U251MG. The conditioned medium of CD109-overexpressing SK-MG-1, containing the secreted N-terminal CD109, had a negative effect on TGF-β1 signaling in wild-type SK-MG-1 and MG178, whereas it did not show any effect on EGF signaling. In addition, cell surface CD109 interacts with EGF receptor in SK-MG-1 overexpressing CD109, and exhibited enhanced cell migration and invasion. These findings suggest that CD109 attenuates TGF-β1 signaling and enhances EGF signaling in SK-MG-1 cells and that the membrane-anchored CD109 may play major roles in the EGF signaling pathway. [ABSTRACT FROM AUTHOR]

Excessive extracellular matrix deposition that occurs in many fibrotic skin disorders such as hypertrophic scarring and scleroderma is often associated with hypoxia. CD109 is a novel TGF- β co-receptor and TGF- β antagonist shown to inhibit TGF- β-induced extracellular matrix protein production in vitro. We examined whether CD109 is able to regulate extracellular matrix deposition under low oxygen tension in vivo using transgenic mice overexpressing CD109 in the epidermis. By creating dorsal bipedicle skin flaps with centrally located excisional wounds in these mice and their wild-type littermates, we generated a novel murine hypoxic wound model. Mice were sacrificed on 7 or 14 days post-wounding, and tissues were harvested for histological and biochemical analysis. Hypoxic wounds in both transgenic and wild-type mice showed increased levels of HIF-1 α and delayed wound closure, validating this model in mice. Hypoxic wounds in CD109 transgenic mice demonstrated decreased collagen type 1 and fibronectin expression, and reduced dermal thickness on day 7 post-wounding as compared to those in wild-type mice and to non-hypoxic control wounds. These results suggest that CD109 decreases extracellular matrix production and fibrotic responses during hypoxic wound healing. Manipulating CD109 levels may have potential therapeutic value for the treatment of fibrotic skin disorders associated with poor oxygen delivery. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)-β is an important cytokine that negatively regulates keratinocyte proliferation. Deregulation of TGF-β signalling has been reported in psoriasis, where despite increased expression of TGF-β, psoriatic keratinocytes continue to hyperproliferate. Recently, we have identified CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein, as a novel co-receptor and negative regulator of TGF-β signalling. In the current work, we demonstrate that release of CD109 from the cell surface or the addition of CD109 protein results in downregulation of TGF-β signalling and TGF-β receptor expression in human keratinocytes. Moreover, these effects are associated with an increase in phospho-STAT3 levels, enhanced total STAT3 and Bcl-2 expression and an increase in cell growth and survival, suggesting that released/soluble CD109 is able to induce molecular changes that are known to occur in psoriasis. Analysis of CD109 expression in psoriasis patients reveals that CD109 protein expression is markedly decreased in psoriatic epidermis as compared to adjacent uninvolved skin. In contrast, CD109 mRNA expression is unchanged in psoriatic plaques in comparison with normal skin. This raises a possibility that CD109 protein release is enhanced in psoriatic keratinocytes. Furthermore, psoriatic epidermis displays decreased expression of TGF-β receptors, consistent with the results obtained in vitro in keratinocytes with CD109 release or addition of CD109 recombinant protein. Together our findings suggest that aberrant CD109 release from the cell surface in human keratinocytes may induce molecular changes that are usually observed in psoriasis and may explain TGF-β receptor downregulation and decrease in TGF-β signalling in psoriasis. [ABSTRACT FROM AUTHOR]

Abstract: Transforming growth factor-β (TGF-β) is implicated in numerous pathological disorders, including cancer and mediates a broad range of biological responses by signaling through the type I and II TGF-β receptors. Internalization of these receptors via the clathrin-coated pits pathway facilitates SMAD-mediated signaling, whereas internalization via the caveolae pathway is associated with receptor degradation. Thus, molecules that modulate receptor endocytosis are likely to play a critical role in regulating TGF-β action. We previously identified CD109, a GPI-anchored protein, as a TGF-β co-receptor and a negative regulator of TGF-β signaling. Here, we demonstrate that CD109 associates with caveolin-1, a major component of the caveolae. Moreover, CD109 increases binding of TGF-β to its receptors and enhances their internalization via the caveolae. In addition, CD109 promotes localization of the TGF-β receptors into the caveolar compartment in the presence of ligand and facilitates TGF-β-receptor degradation. Thus, CD109 regulates TGF-β receptor endocytosis and degradation to inhibit TGF-β signaling. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. [Copyright &y& Elsevier]

Bladder cancer is one of the most common malignant diseases. Since a high-rate of recurrence is a serious problem for early stage urothelial carcinomas, new strategies for the management of recurrent urothelial carcinomas have been explored. CD109 is a glycosylphosphatidylinositol-anchored glycoprotein and is expressed in various cancer tissues, mainly squamous cell carcinomas. CD109 negatively controls transforming growth factor (TGF)-β/Smad signaling in vitro. In this study, we analyzed the clinical significance of CD109 expression in bladder cancer using immunohistochemistry. Of 156 urothelial carcinoma tissues, 69.9% were positive for CD109, whereas CD109 was not expressed in seven normal bladder epithelia. CD109 expression was significantly higher in non-muscle-invasive (pTa+pT1) or low-grade (G1+G2) tumors than in muscle-invasive (pT2-4) or high-grade (G3) tumors, and was associated with cancer-specific survival. Simultaneous immunostaining of CD109 and phosphorylated Smad2 showed an inverse immunoreactivity relationship between the two, suggesting that CD109 inhibits TGF-β/Smad signaling in tumor tissues. Interestingly, CD109 was found to be highly expressed in the basal layer of non-invasive urothelial carcinomas, and the expression pattern was similar to that of CD44, a marker of cancer stem cells. These findings suggest that CD109 is involved in bladder tumorigenesis and is a potential target for cancer immunotherapy. [ABSTRACT FROM AUTHOR]