Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The type-1 receptor sorLA/LR11, a member of the Vps10p-domain receptor family that also contains domains characterizing members of the LDL (low-density lipoprotein) receptor family, has been shown to induce increased uPAR (urokinase receptor) expression as well as enhanced migration and invasion activities in smooth muscle cells in the presence of PDGF-BB (platelet-derived growth factor-BB). Here we show that sorLA interacts with both components of the plasminogen activating system and PDGF-BB similarly to LRP1 (LDL receptor-related protein/alpha2-macroglobulin receptor), which is an important clearance receptor with established functions in controlling uPAR expression as well as PDGF-BB signalling. In contrast with LRP1, sorLA does not interact with alpha2-macroglobulin, which is a binding protein for several growth factors, including PDGF-BB. By using LRP1-deficient cells transfected with sorLA, we demonstrate that sorLA-bound ligand is internalized at a much lower rate than LRP1-bound ligand, and that sorLA is inefficient in regulating cell surface uPAR expression, which depends on rapid internalization of the ternary complex between urokinase-type plasminogen activator, its type-1 inhibitor, and uPAR. Thus, although overlapping with regard to binding profiles, sorLA is substantially less efficient as a clearance receptor than LRP1. We propose that sorLA can divert ligands away from LRP1 and thereby inhibit both their clearance and signalling events mediated by LRP1.
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PMID:The mosaic receptor sorLA/LR11 binds components of the plasminogen-activating system and platelet-derived growth factor-BB similarly to LRP1 (low-density lipoprotein receptor-related protein), but mediates slow internalization of bound ligand. 1505 42

Low-density lipoprotein receptor family members (LRs) play a key role in the catabolism of many membrane-associated proteins, such as complexes between proteinases and their receptors, in addition to being involved in lipoprotein metabolism as suspected by the hitherto well-established functions of low-density lipoprotein receptor, in a variety of tissues. Recent studies using receptor-deficient or -overexpressing animals and cells have suggested that certain LRs are important regulators of the migration (and proliferation) of vascular smooth muscle cells (SMCs). LR expression is markedly induced in intimal or medial SMCs during the formation of atherosclerotic lesions. Because LRs can modulate the activity of the urokinase-type plasminogen activator (uPA) receptor and possibly of the platelet-derived growth factor (PDGF) receptor, LRs may influence the migration of SMCs through functional modulation of these membrane receptors. Therefore, SMC migration may be regulated by time-restricted expression of LRs. In agreement with the concept of functional interaction between LRs and membrane signaling receptors, a negative regulator of uPA receptor protein catabolism, LR11, has been identified. Statins modulate the PDGF-induced migration of intimal SMCs via the LR11/uPA receptor cascade. Selective modification of the LRs/uPA receptor/PDGF receptor systems in SMCs may be important for suppression of atherosclerotic plaque formation as well as for preventing intimal thickening after angioplasty.
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PMID:Modulation of smooth muscle cell migration by members of the low-density lipoprotein receptor family. 1657 89

LR11 (also called SorLA or SORL1), a member of the LDL receptor family, was originally discovered in 1996 from genes specifically expressed in the intimal smooth muscle cells of atherosclerotic plaques. The soluble form of LR11 (sLR11) as well as the membrane-bound form plays a key role in the phenotype conversion of medial smooth muscle cells into intimal smooth muscle cells through the activation of urokinase receptor/integrin-mediated intracellular pathways. The levels of sLR11 in serum or CSF are increased in patients with atherosclerotic diseases, Alzheimer's disease or malignant diseases including acute leukemias. The recently developed ELISA system using two specific antibodies against LR11 made it possible to measure sLR11 quantitatively and stably for many samples. Thus, a novel clinical examination is expected to detect the pathological immature cells important for the pathophysiology of the above diseases. The soluble receptor-based clinical approach, together with basic studies about the structure-function relationship, may shed light on the development of novel target therapy against pathological immature cells in the science fields of so far independently categorized diseases.
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PMID:[Novel biomarker for pathological immature cells--soluble form of LR11]. 2277 76