CD109‐mediated degradation of TGF‐β receptors and inhibition of TGF‐β responses involve regulation of SMAD7 and Smurf2 localization and function

Bizet, Albane A.; Tran-Khanh, Nicolas; Saksena, Anshuman; Li, Kai; Buschmann, Michael D.; Philip, Anie

doi:10.1002/jcb.23349

Cited by 76 publications

(67 citation statements)

References 29 publications

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“…c High anti-CD109 staining in the TNBC tumors (magnification ×400) signaling [13]. 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 [14]. Thus, CD109 regulates TGF-β receptor endocytosis and degradation to inhibit TGF-β signaling.…”

Section: Discussionmentioning

confidence: 94%

CD109 is a potential target for triple-negative breast cancer

et al. 2014

Tumor Biol.

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The aim of this study is to explore the expression of CD109 in breast cancer stem cells and the relationship between CD109 protein and clinicopathological characteristics of breast cancer. CD44+/CD24- tumor cells (CSCs) were selected by flow cytometry. The protein expression of CD109 was analyzed by immunohistochemistry staining, and the relationship between CD109 and clinicopathological parameters of breast cancer was determined. CD109 positively regulated the proliferation of breast CSCs in vitro, and CD109 protein expression was significantly higher in triple-negative breast cancer (TNBC) compared to non-TNBC (63.78 vs. 3.71 %, P = 0.001). Moreover, CD109 protein expression was related to the histological grade of breast cancer (P = 0.015), whereas age (P = 0.731), tumor size (P = 0.995), clinical stage (P = 0.644), and lymph node metastasis (P = 0.924) were not. In the logistic regression model, histological grade (P = 0.001) and molecular type (P = 0.001) were significantly related to CD109 expression. The patients with high expression of CD109 protein had significantly poorer postoperative disease-specific survival than those with no or low expression of CD109 protein (P = 0.001). In the Cox regression, CD109 was an independent prognostic factor (P = 0.001). CD109 is highly expressed in TNBC and is a potential biomarker for the initiation, progression, and differentiation of breast cancer tumors.

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Section: Discussionmentioning

confidence: 94%

CD109 is a potential target for triple-negative breast cancer

et al. 2014

Tumor Biol.

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“…Soluble CD109 can bind to all 3 isoforms of TGFβ-1/2/3, thus interfering with the activation of TGFβ dependent signaling34. In fact, membrane bound CD109 acts as a co-receptor for TGFβ1 and results in internalization and degradation of TGFβ receptors via binding to Smad73536. Further, CILP inhibits transcriptional activation of matrix genes in NP cells by binding to TGFβ1 and inhibiting the downstream phosphorylation of Smads, thereby promoting disc degeneration37.…”

Section: Discussionmentioning

confidence: 99%

Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus

Matta

Karim

Isenman

et al. 2017

Sci Rep

104

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Degenerative disc disease (DDD) is associated with spinal pain often leading to long-term disability. However, the non-chondrodystrophic canine intervertebral disc is protected from the development of DDD, ostensibly due to its retention of notochordal cells (NC) in the nucleus pulposus (NP). In this study, we hypothesized that secretome analysis of the NC-rich NP will lead to the identification of key proteins that delay the onset of DDD. Using mass-spectrometry, we identified 303 proteins including components of TGFβ- and Wnt-signaling, anti-angiogeneic factors and proteins that inhibit axonal ingrowth in the bioactive fractions of serum free, notochordal cell derived conditioned medium (NCCM). Ingenuity Pathway Analysis revealed TGFβ1 and CTGF as major hubs in protein interaction networks. In vitro treatment with TGFβ1 and CTGF promoted the synthesis of healthy extra-cellular matrix proteins, increased cell proliferation and reduced cell death in human degenerative disc NP cells. A single intra-discal injection of recombinant TGFβ1 and CTGF proteins in a pre-clinical rat-tail disc injury model restored the NC and stem cell rich NP. In conclusion, we demonstrate the potential of TGFβ1 and CTGF to mitigate the progression of disc degeneration and the potential use of these molecules in a molecular therapy to treat the degenerative disc.

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“…CD109 promotes TGF-b receptor internalization and degradation by regulation of SMAD7 and SMURF2 activity in ubiquitin-mediated proteolysis [14,15]. It was also reported that proteolytic processing of CD109 by furin or mesotrypsin is required for its function in cultured cells [16,17].…”

Section: Introductionmentioning

confidence: 92%

CD109 attenuates TGF-β1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells

Zhang

Murakumo

Hagiwara

et al. 2015

Biochemical and Biophysical Research Communications

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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.

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CD109‐mediated degradation of TGF‐β receptors and inhibition of TGF‐β responses involve regulation of SMAD7 and Smurf2 localization and function

Cited by 76 publications

References 29 publications

CD109 is a potential target for triple-negative breast cancer

CD109 is a potential target for triple-negative breast cancer

Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus

CD109 attenuates TGF-β1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells

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