ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and β-catenin translocation

Maretzky, Thorsten; Reiß, Karina; Ludwig, Andreas; Buchholz, Julian; Scholz, Felix; Proksch, E.; Strooper, Bart De; Hartmann, Dieter; Säftig, Paul

doi:10.1073/pnas.0500918102

Cited by 616 publications

(625 citation statements)

References 40 publications

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“…One representative out of three experiments is shown described previously. 24 Whereas release of sFasL was not diminished in ADAM17 À/À , ADAM9 À/À , and ADAM15 À/À MEFs compared to wild-type cells, the generation of sFasL was almost completely abolished in ADAM10-deficient MEFs (Figure 3a). The reduced capacity to generate sFasL was confirmed by immunoblot in two independent ADAM10-deficient cell lines (Figure 3b).…”

Section: Resultsmentioning

confidence: 96%

“…Our analyses of an uncleavable human FasL mutant (Supplementary Figure 1) showed that the release of sFasL was completely abrogated in human and murine cells, indicating that despite the loose cleavage specificity the protease susceptible region is located within this region. ADAM10 has been implicated before in the shedding of different substrates including CD44, 37 amphiregulin, 38 N-cadherin, 21 E-cadherin 24 and the neuronal adhesion molecule L1. 39 For some of these substrates, ADAM10 is responsible for both the constitutive and the inducible shedding.…”

Section: Discussionmentioning

confidence: 99%

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ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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“…ADAM-10 contributes to E-cadherin shedding [88,89]. The subsequent release of soluble E-cadherin in the extracellular milieu leads to the abrogation of cell-cell contacts, thereby facilitating cell migration.…”

Section: Adams and Adamtss In Cell Proliferation And Apoptosismentioning

confidence: 99%

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

et al. 2008

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A disintegrin and metalloproteinases (ADAMs) are a recently discovered family of proteins that share the metalloproteinase domain with matrix metalloproteinases (MMPs). Among this family, structural features distinguish the membrane-anchored ADAMs and the secreted ADAMs with thrombospondin motifs referred to as ADAMTSs. By acting on a large panel of membrane-associated and extracellular substrates, they control several cell functions such as adhesion, fusion, migration and proliferation. The current review addresses the contribution of these proteinases in the positive and negative regulation of cancer progression as mainly mediated by the regulation of growth factor activities and integrin functions.

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“…Proteolytic cleavage of the E-cadherin ectodomain, resulting in release of an 80 kDa ectodomain fragment, was first reported in mammary tissue and linked to metalloproteinase activity [78]. Subsequent studies have identified matrix metalloproteinases (MMP)-3 and -7 as well as a disintegrin and metalloproteinase (ADAM)-10 as E-cadherin ectodomain sheddases in mammary cells and keratinocytes [79][80][81]. Recent data from our laboratories have shown that aggregation of Furthermore, our results show a significant elevation in the levels of sE-cad in ascites from women with ovarian cancer (mean 12.24 +/-5.31 ug/ml) compared with ascites from women with ovarian hyperstimulation syndrome or benign ovarian cysts (mean 2.06 +/-1.87 ug/ml) [82].…”

Section: Regulation Of E-cadherin In Ovarian Tumorsmentioning

confidence: 99%

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

165

172

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The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

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ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and β-catenin translocation

Cited by 616 publications

References 40 publications

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

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