Architecture of the large membrane-bound mucins

Desseyn, Jean‐Luc; Tétaert, Daniel; Gouyer, Valérie

doi:10.1016/j.gene.2007.12.014

Cited by 66 publications

(62 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mucins are heavily glycosylated proteins found in the mucus layer or at the cell surface of many epitheliums (16). There are two structurally distinct families of mucins, secreted and membrane-bound forms.…”

mentioning

confidence: 99%

A Binding Domain on Mesothelin for CA125/MUC16

Kaneko

Gong

Zhang

et al. 2009

Journal of Biological Chemistry

160

165

View full text Add to dashboard Cite

Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296 -359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296 -359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.

show abstract

mentioning

confidence: 99%

A Binding Domain on Mesothelin for CA125/MUC16

Kaneko

Gong

Zhang

et al. 2009

Journal of Biological Chemistry

160

165

View full text Add to dashboard Cite

show abstract

“…It has been speculated that the EGF-like domain of MUC4 specific domains plays a role in the above receptor-ligand interactions (42,43). Meanwhile, the other unique domains present in the MUC4 mucin but not found in other membranebound mucins are NIDO, AMOP, and vWD domains (44). Although there is no direct evidence in the literature yet, the homology and evolution analysis hints at a role for both NIDO and AMOP domain in cell-cell interaction and adhesion to the extracellular matrix (45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic cancer counterattack: MUC4 mediates Fas-independent apoptosis of antigen-specific cytotoxic T lymphocyte

et al. 2014

View full text Add to dashboard Cite

Tumor-associated MUC4 mucin has considerable potential as an immunotherapy target for pancreatic cancer. In previous studies, we developed dendritic cell (DC) vaccines which elicited MUC4 antigen-specific cytotoxic T lymphocyte (MS-CTL) response against tumor cells in vitro. Due to the observation that MS-CTL apoptotic rate increased significantly when co-cultured with MUC4+ tumor cells compared with T2 cells, we investigated whether high expression levels of MUC4 in pancreatic cancer cells would have an effect on the significant increase of apoptosis rate of MS-CTLs. First, the adverse influence of regulatory T cells (Tregs) was eliminated by CD8+ T lymphocyte sorting before the induction of MS-CTLs. Then, we constructed clonal MUC4-knockdown HPAC pancreatic cancer sublines with different MUC4 expression for co-incubation system. By utilizing appropriate control to rule out the possible apoptosis-induced pathway of intrinsic activated cell-autonomous death (ACAD) and analogous antigen-dependent apoptosis of CTL (ADAC) in our study system, further analysis of the effect of MUC4 membrane-expression, supernatants and blockade of CTL surface Fas receptor on MS-CTL apoptosis was carried out. The results demonstrated that the level of MUC4 membrane expression strongly positively correlated with MS-CTL apoptosis and the influence of supernatants and Fas-blockade did not significantly correlate with MS-CTL apoptosis. This evidence suggested that there may be a novel counterattack pathway of pancreatic cancer cells, which is a MUC4-mediated, cell contact-dependent and Fas-independent process, to induce CTL apoptosis. Therefore, further exploration and understanding of the potential counterattack mechanisms is beneficial to enhance the efficacy of MUC4 specific tumor vaccines.

show abstract

“…[131,[221][222][223][224][225][226][227][228][229][230][231] Mindestens 21 Gene für Mucine sind identifiziert worden (MUC1, 2, 3A, 3B, 4, 5AC, 5B, 6-9, 11-13 und 15-21 -man beachte, dass MUC15 und MUC18 keine Tandemwiederholungen aufweisen). Diese sind bezüglich ihrer Sequenzen nicht verwandt, doch ist ihnen gemeinsam, dass sie sich wiederholende Motive enthalten, die reich an Ser/Thr/Pro-Resten sind und große Mengen O-Glycane tragen.…”

Section: O-glycane In Den Mucinen Von Schleimhautgewebeunclassified

Das Tn‐Antigen – strukturell einfach und biologisch komplex

Otto

Cummings

2011

Angewandte Chemie

View full text Add to dashboard Cite

Die Glycoproteine tierischer Zellen enthalten vielfältige Glycanstrukturen, die co‐ und/oder posttranslational an die Proteine angeheftet werden. Mehr als zwanzig verschiedene Bindungsarten von Glycanen an Proteine sind bekannt, doch sind N‐Glycane (gebunden an Asn) und O‐Glycane (gebunden an Ser/Thr) die häufigsten. Ein abnormes O‐Glycan, das bei Krebs und anderen menschlichen Erkrankungen auftritt, ist das Tn‐Antigen. Es hat eine einfache Struktur, bestehend aus einem N‐Acetyl‐D‐galactosamin, das α‐glycosidisch an einen Serin‐ oder Threoninrest gebunden ist. Das Tn‐Antigen war eines der ersten Glycokonjugate, die chemisch synthetisiert wurden. Es wird normalerweise von einer spezifischen Galactosyltransferase, der T‐Synthase, im Golgi‐Apparat modifiziert. Die Expression aktiver T‐Synthase hängt vom molekularen Chaperon Cosmc ab, dessen Gen auf dem X‐Chromosom liegt. Genmutationen, die die Funktion von T‐Synthase, Cosmc oder anderen an der O‐Glycosylierung beteiligten Faktoren beeinträchtigen, können zur Expression des Tn‐Antigens führen. Da dieses bei einer Reihe von Krankheiten auftritt, besteht großes Interesse, es für die Entwicklung von Impfstoffen und anderen therapeutischen Ansätzen zu nutzen.

show abstract

Architecture of the large membrane-bound mucins

Cited by 66 publications

References 57 publications

A Binding Domain on Mesothelin for CA125/MUC16

A Binding Domain on Mesothelin for CA125/MUC16

Pancreatic cancer counterattack: MUC4 mediates Fas-independent apoptosis of antigen-specific cytotoxic T lymphocyte

Das Tn‐Antigen – strukturell einfach und biologisch komplex

Contact Info

Product

Resources

About