uPAR / LDLR-family member interaction

Angiogenesis, the formation of new blood vessels from preexisting vasculature, represents a strictly controlled process underlying an equal balance between angiogenic and angiostatic factors (growth factors, proteases, adhesion molecules, etc.). Angiogenesis represents an essential step in tissue remodeling and is involved in many physiological and pathological processes. Throughout the last years, great interest in studying these cellular and molecular mechanisms underlying the angiogenic process has been aroused. In this regard, the pivotal role of the urokinase plasminogen activator system (uPAR:uPA:uPAR) as an integral part of pericellular proteolysis for the purpose of efficient endothelial cell invasion could be ascertained. Besides its proteolytic activity, the uPA / uPAR complex also participates in a great variety of signal transduction pathways by interaction with integrins, G- coupled proteins and (with) up to this point unidentified co-receptors. Focused recycling of uPAR as well as uPAR-associated integrins to the leading edge of migrating endothelial cells upon internalization thereby regulates endothelial cell migration and proliferation in time and space. It was shown that interaction with members of the low-density lipoprotein receptor (LDLR)-related protein (LRP) family is vital to mediate such internalization of the uPA / plasminogen system. Recently, a direct interaction between uPAR and LDLR-family members was reported to be sufficient for uPAR as well as uPAR-associated integrin internalization. However, the LDLR-like protein interaction motif of uPAR has not yet been identified. In silico protein structure prediction and crystal structure analysis revealed a small surface exposed loop in domain 3 of uPAR, which is supposed to bear the LDLR-like protein interaction site. Preliminary data derived from uPAR / LDLR-like protein interaction blocking experiments using a small peptide mimicking this loop completely prevented uPAR as well as uPAR-mediated integrin internalization in endothelial cells. Detailed analyzes of direct uPAR / LDLR-like protein interaction will give clear insights into the regulatory role of uPAR in LDLR-family member-mediated endocytosis of uPAR-complexes including integrin adhesion receptors and the consequences on intracellular signal transduction. As angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression, characterization of a direct interaction motif of uPAR with LDLR-family members may contribute to the development of novel and effective therapeutic strategies.

Angiogenesis, the formation of new blood vessels from preexisting vasculature, represents a strictly controlled process underlying an equal balance between angiogenic and angiostatic factors (growth factors, proteases, adhesion molecules, etc.). Angiogenesis represents an essential step in tissue remodeling and is involved in many physiological and pathological processes. Throughout the last years, great interest in studying these cellular and molecular mechanisms underlying the angiogenic process has been aroused. In this regard, the pivotal role of the urokinase plasminogen activator system (uPAR:uPA:uPAR) as an integral part of pericellular proteolysis for the purpose of efficient endothelial cell invasion could be ascertained. Besides its proteolytic activity, the uPA / uPAR complex also participates in a great variety of signal transduction pathways by interaction with integrins, G-coupled proteins and (with) up to this point unidentified co-receptors. Focused recycling of uPAR as well as uPAR-associated integrins to the leading edge of migrating endothelial cells upon internalization thereby regulates endothelial cell migration and proliferation in time and space. It was shown that interaction with members of the low-density lipoprotein receptor (LDLR)-related protein (LRP) family is vital to mediate such internalization of the uPA / plasminogen system. Recently, a direct interaction between uPAR and LDLR-family members was reported to be sufficient for uPAR as well as uPAR-associated integrin internalization. However, the LDLR-like protein interaction motif of uPAR has not yet been identified. In silico protein structure prediction and crystal structure analysis revealed a small surface exposed loop in domain 3 of uPAR, which is supposed to bear the LDLR-like protein interaction site. Preliminary data derived from uPAR / LDLR-like protein interaction blocking experiments using a small peptide mimicking this loop completely prevented uPAR as well as uPAR-mediated integrin internalization in endothelial cells. Detailed analyzes of direct uPAR / LDLR-like protein interaction now gives clear insights into the regulatory role of uPAR in LDLR-family member-mediated endocytosis of uPAR-complexes including integrin adhesion receptors and the consequences on intracellular signal transduction. As angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression, the characterization of a direct interaction motif of uPAR with LDLR- family members of this project may contribute to the development of novel and effective therapeutic strategies.