Tumor-Endothel-Marker 5 (TEM5), ein membranständiger G-Protein-gekoppelter-Rezeptor, wird in Endothelzellen bei physiologischer und tumorassoziierter Angiogenese hochreguliert. In dieser Arbeit werden extrazelluläre Fragmente von TEM5 charakterisiert. Mehrere neue Fragmente, darunter ein TEM5-N60-Fragment, wurden gefunden. Es entsteht durch Abspaltung (shedding) an der Zellmembran durch die membranständige MMP14 und lösliches Thrombin. Die Spaltstellen beider Proteasen im Volllängenprotein wurden in enger Nachbarschaft zu einem kryptischen RGD-Motiv gefunden. Das RGD-Motiv wird freigelegt und TEM5-N60 kann über mithilfe dessen antagonistisch oder agonistisch auf Integrin αvß3 wirken. Lösliches TEM5-N60 hemmt einerseits die Endothelzellmigration auf αvß3-Liganden. Immobilisiert vermittelt TEM5-N60 andererseits aber Endothelzelladhäsion. TEM5-N60 birgt Potenzial als Marker für Angiogenesebildgebung oder antiangiogene Therapien.      «

Tumor-Endothel-Marker 5 (TEM5), ein membranständiger G-Protein-gekoppelter-Rezeptor, wird in Endothelzellen bei physiologischer und tumorassoziierter Angiogenese hochreguliert. In dieser Arbeit werden extrazelluläre Fragmente von TEM5 charakterisiert. Mehrere neue Fragmente, darunter ein TEM5-N60-Fragment, wurden gefunden. Es entsteht durch Abspaltung (shedding) an der Zellmembran durch die membranständige MMP14 und lösliches Thrombin. Die Spaltstellen beider Proteasen im Volllängenprotein wu...     »

Tumor endothelial marker (TEM) 5 is a membrane-bound protein and is a member of the family of adhesion g-protein-coupled-receptors. It is upregulated in endothelial cells during physiological and tumorassociated angiogenesis. TEM5 is potentially a new target-molecule for antiangiogenic therapy. In this work proteolytic processing of the extracellular domain of TEM5 was studied and some new fragments were identified and characterised. Importantly TEM5-N60, a novel N-terminal 60kDa functional fragment, was found. This fragment is shed from the membrane by membrane-bound metallomatrixprotease 14 (MMP14) as well as by the soluble serin protease Thrombin. Here, cleavage sites of Thrombin and MMP14 were identified in close approximity of a cryptic RGD-motif. Interestingly, this study shows that the RGD-motif ist decrypted by TEM5 cleavage. Depending whether TEM5-N60 is immobilized or soluble it acts as an agonist or an antagonist of the αvß3-integrin. It is shown that soluble TEM5-N60 inhibits endothelial migration upon a layer of the αvß3-ligand Vitronectin, but not of other integrins. However, when immobilized, TEM5-N60 mediates adhesion of endothelial cells. A monoclonal antibody binding to TEM5 can suppress this adhesion. This work provides new insights into the biology of the extracellular processes of TEM5, wich could be important in planning or design of diagnostic and prognostic markers. Furthermore with TEM5-N60 a new interesting soluble fragments was identified, which bears a potential as a molecular marker or tracer itself.      «

Tumor endothelial marker (TEM) 5 is a membrane-bound protein and is a member of the family of adhesion g-protein-coupled-receptors. It is upregulated in endothelial cells during physiological and tumorassociated angiogenesis. TEM5 is potentially a new target-molecule for antiangiogenic therapy. In this work proteolytic processing of the extracellular domain of TEM5 was studied and some new fragments were identified and characterised. Importantly TEM5-N60, a novel N-terminal 60kDa functional frag...     »