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External Domain (external + domain)
Selected AbstractsInteraction of KLRG1 with E-cadherin: New functional and structural insightsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2008Stephan Rosshart Abstract The killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed by memory T cells and NK cells in man and mice. It is frequently used as a cell differentiation marker and members of the cadherin family are ligands for KLRG1. The present study provides new insights into the interaction of mouse KLRG1 with E-cadherin. Firstly, we demonstrate that co-engagement of KLRG1 and CD3/TCR in a spatially linked manner was required for inhibition arguing against the notion that KLRG1-ligation per se transmits inhibitory signals. Secondly, experiments with T cells carrying Y7F-mutant KLRG1 molecules with a replacement of the tyrosine residue to phenylalanine in the single ITIM indicated that the inhibitory activity of KLRG1 is counteracted to some degree by increased interaction of KLRG1+ T cells with E-cadherin expressing target cells. Thirdly, we demonstrate that deletion of the first or the second external domain of E-cadherin abolished reactivity in KLRG1-reporter cell assays. Finally, we made the intriguing observation that KLRG1 formed multimeric protein complexes in T cells in addition to the previously described mono- and dimeric molecules. [source] Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissuesHISTOPATHOLOGY, Issue 5 2009Juan Carlos Martinez Aims:, Delta-like ligand 4 (DLL4) is one of five known Notch ligands in mammals and interacts predominantly with Notch 1. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a ,brake' on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. This action was believed to occur only in vascular development, raising hopes that DLL4 could be a specific drug target for controlling vessel growth in tumours and other pathological conditions. Our aim was to pursue this by raising a monoclonal antibody to the internal domain of DLL4 and assess its distribution in normal and malignant tissues in comparison with antibodies against the external domain of DLL4. Methods and results:, The anti-DLL4 monoclonal antibody was raised using conventional mouse hybridoma techniques. The antibody has been fully characterized by Western blotting and transfectant immunostaining. It has also been comprehensively compared with other antibodies against both the internal and external domains of DLL4. The antigen is widely expressed on human tissues not only on endothelium but also on epithelium and stromal cells. Indeed, in our comprehensive survey only pulmonary alveoli failed to express DLL4. Of a wide range of malignancies, most also expressed DLL4 on tumour cells with a predominantly cytoplasmic pattern, although a number also displayed nuclear positivity. Conclusions:, Contrary to previous beliefs, DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. These findings raise many interesting possibilities for further study of DLL4 and its potential as a therapeutic target. [source] The role of platelet-derived growth factor in a murine model of crescentic nephritisNEPHROLOGY, Issue 3 2000La Haseley SUMMARY Platelet-derived growth factor (PDGF) is a major mesenchymal cell mitogen, with an established role in the pathogenesis of experimental mesangial proliferative nephritis. The role of PDGF in experimental models of crescentic glomerulonephritis is not well defined. To study the role of PDGF in glomerular crescent formation, we induced a model of crescentic glomerulonephritis in transgenic mice expressing high concentrations of the soluble external domain of the PDGF, receptor (PDGF-R,). Crescentic nephritis was induced by the intraperitoneal injection of antibody to whole rabbit glomeruli. At day 7 of disease, biopsies of transgenic and wild-type mice were evaluated for crescent frequency, crescent area, and thickness of crescent cell layer. In situ hybridization was performed to evaluate the expression of both PDGF B-chain and PDGFR, mRNA within crescents. Delivery of soluble receptor to the urinary space was evaluated by Western blotting. Crescent frequency did not differ between wild type and transgenic mice. However, crescent area quantified by computer image analysis was significantly reduced in transgenic mice (P < 0.015). Transgenic biopsies displayed predominantly crescents composed of two cell layers (P = 0.03 compared with wild type), whereas wild-type biopsies had significantly more crescents composed of four or more cell layers (P = 0.04). Both PDGF B-chain and PDGF-R, mRNA were detected within crescents in a heterogeneous fashion. Soluble receptor was detectable in the urine of all transgenic diseased mice. We conclude that PDGF plays a role in modulating crescent size and development in our murine model of crescentic nephritis. [source] Imaging with radiolabelled monoclonal antibody (MUJ591) to prostate-specific membrane antigen in staging of clinically localized prostatic carcinoma: comparison with clinical, surgical and histological stagingBJU INTERNATIONAL, Issue 9 2005Vinod Nargund OBJECTIVE To evaluate the reliability of prostate scintigraphy using a radiolabelled antibody (MUJ591) raised against the external domain of prostate-specific membrane antigen (PSMA) in the staging of early prostate cancer. PATIENTS AND METHODS This was a prospective study of 16 patients who had radical retropubic prostatectomies (median PSA 9.75 ng/mL). All patients underwent PSMA imaging using MUJ591 radiolabelled with 99mTc using a photo-reduction technique. RESULTS The findings of prostate imaging and histology were identical in seven patients. Scans showed understaging and overstaging in six and three patients, respectively. CONCLUSIONS PSMA scintigraphy using 99mTc-labelled MUJ591 identifies the presence of prostate cancer, but is not sensitive in delineating micro-invasion of the capsule, seminal vesicles or bladder neck. As in other studies it seems to be useful in detecting prostate bed recurrence and distant micrometastasis. [source] Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissuesHISTOPATHOLOGY, Issue 5 2009Juan Carlos Martinez Aims:, Delta-like ligand 4 (DLL4) is one of five known Notch ligands in mammals and interacts predominantly with Notch 1. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a ,brake' on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. This action was believed to occur only in vascular development, raising hopes that DLL4 could be a specific drug target for controlling vessel growth in tumours and other pathological conditions. Our aim was to pursue this by raising a monoclonal antibody to the internal domain of DLL4 and assess its distribution in normal and malignant tissues in comparison with antibodies against the external domain of DLL4. Methods and results:, The anti-DLL4 monoclonal antibody was raised using conventional mouse hybridoma techniques. The antibody has been fully characterized by Western blotting and transfectant immunostaining. It has also been comprehensively compared with other antibodies against both the internal and external domains of DLL4. The antigen is widely expressed on human tissues not only on endothelium but also on epithelium and stromal cells. Indeed, in our comprehensive survey only pulmonary alveoli failed to express DLL4. Of a wide range of malignancies, most also expressed DLL4 on tumour cells with a predominantly cytoplasmic pattern, although a number also displayed nuclear positivity. Conclusions:, Contrary to previous beliefs, DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. These findings raise many interesting possibilities for further study of DLL4 and its potential as a therapeutic target. [source] | ||||||||||