May P, Woldt E, Matz RL, Boucher P.. The LDL receptor-related protein (LRP) family: an old family of proteins with new physiological functions. Ann Med 39: 219-228

Universität Freiburg, Medizinische Klinik II/Zentrum für Neurowissenschaften, Freiburg, Germany.
Annals of Medicine (Impact Factor: 3.89). 02/2007; 39(3):219-28. DOI: 10.1080/07853890701214881
Source: PubMed


The low-density lipoprotein (LDL) receptor is the founding member of a family of seven structurally closely related transmembrane proteins (LRP1, LRP1b, megalin/LRP2, LDL receptor, very low-density lipoprotein receptor, MEGF7/LRP4, LRP8/apolipoprotein E receptor2). These proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins. While currently available data suggest that the role of the LDL receptor is limited to the regulation of cholesterol homeostasis by receptor-mediated endocytosis of lipoprotein particles, there is growing experimental evidence that the other members of the gene family have additional physiological functions as signal transducers. In this review, we focus on the latest discovered functions of two major members of this family, LRP1 and megalin/LRP2, and on the newly elucidated physiological role of a third member of the family, MEGF7/LRP4, which can also function as a modulator of diverse signaling pathways during development.

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    • "Responsible membrane proteins in the Wnt signaling pathway, however, are not fully elucidated in chondrocyte differentiation. The low-density lipoprotein receptor (LDLR)-related protein 4 (LRP4) is a transmembrane protein and a member of the LDLR family [4]. In osteoblasts, LRP4 is a receptor for Wnt signaling inhibitors of Dkk1, Sost, and Sostdc1 (Wise), and reduces Wnt/bcatenin signaling during bone development [5] [6]. "
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    ABSTRACT: Endochondral ossification is an essential step for skeletal development, which requires chondrocyte differentiation in growth cartilage. The low-density lipoprotein receptor-related protein 4 (LRP4), a member of LDLR family, is an inhibitor for Wnt signaling, but its roles in chondrocyte differentiation remain to be investigated. Here we found by lasercapture microdissection that LRP4 expression was induced during chondrocyte differentiation in growth plate. In order to address the roles, we overexpressed recombinant human LRP4 or knocked down endogenous LRP4 by lentivirus in mouse ATDC5 chondrocyte cells. We found that LRP4 induced gene expressions of extracellular matrix proteins of type II collagen (Col2a1), aggrecan (Acan), and type X collagen (Col10a1), as well as production of total proteoglycans in ATDC5 cells, whereas LRP4 knockdown had opposite effects. Interestingly, LRP4-knockdown reduced mRNA expression of Sox9, a master regulator for chondrogenesis, as well as Dkk1, an extracellular Wnt inhibitor. Analysis of Wnt signaling revealed that LRP4 blocked the Wnt/β-catenin signaling activity in ATDC5 cells. Finally, the reduction of these extracellular matrix productions by LRP4-knockdown was rescued by a β-catenin/TCF inhibitor, suggesting that LRP4 is an important regulator for extracellular matrix productions and chondrocyte differentiation by suppressing Wnt/β-catenin signaling.
    Full-text · Article · Aug 2014 · Biochemical and Biophysical Research Communications
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    • "LDLa is a cysteine-rich repeat domain that plays a central role in metabolism of mammalian cholesterol, especially during the receptor protein binds LDL [67]. It enters the cell by endocytosis [68]. Successive cysteine-rich repeats of ~ 40 residues are located at the amino-terminus of this multi-domain membrane protein. "
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    ABSTRACT: Background Cysticercosis remains a major neglected tropical disease of humanity in many regions, especially in sub-Saharan Africa, Central America and elsewhere. Owing to the emerging drug resistance and the inability of current drugs to prevent re-infection, identification of novel vaccines and chemotherapeutic agents against Taenia solium and related helminth pathogens is a public health priority. The T. solium genome and the predicted proteome were reported recently, providing a wealth of information from which new interventional targets might be identified. In order to characterize and classify the entire repertoire of protease-encoding genes of T. solium, which act fundamental biological roles in all life processes, we analyzed the predicted proteins of this cestode through a combination of bioinformatics tools. Functional annotation was performed to yield insights into the signaling processes relevant to the complex developmental cycle of this tapeworm and to highlight a suite of the proteases as potential intervention targets. Results Within the genome of this helminth parasite, we identified 200 open reading frames encoding proteases from five clans, which correspond to 1.68% of the 11,902 protein-encoding genes predicted to be present in its genome. These proteases include calpains, cytosolic, mitochondrial signal peptidases, ubiquitylation related proteins, and others. Many not only show significant similarity to proteases in the Conserved Domain Database but have conserved active sites and catalytic domains. KEGG Automatic Annotation Server (KAAS) analysis indicated that ~60% of these proteases share strong sequence identities with proteins of the KEGG database, which are involved in human disease, metabolic pathways, genetic information processes, cellular processes, environmental information processes and organismal systems. Also, we identified signal peptides and transmembrane helices through comparative analysis with classes of important regulatory proteases. Phylogenetic analysis using Bayes approach provided support for inferring functional divergence among regulatory cysteine and serine proteases. Conclusion Numerous putative proteases were identified for the first time in T. solium, and important regulatory proteases have been predicted. This comprehensive analysis not only complements the growing knowledge base of proteolytic enzymes, but also provides a platform from which to expand knowledge of cestode proteases and to explore their biochemistry and potential as intervention targets. Electronic supplementary material The online version of this article (doi: 10.1186/1471-2164-15-428) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2014 · BMC Genomics
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    • "Of the 4 putative targets of miR-143 which have been reported previously to be up-regulated in SNEB, LRP2 is involved in lipid metabolism and is of particular interest because the metabolism of lipids is altered during SNEB [51,52]. LRP2 is implicated in lipid metabolism through its role as a receptor for sterols, steroid hormones bound to carrier proteins [53] like lipoproteins [54] and apolipoprotein M of liver [55-57]. A study of miRNA based modulation of obesity also reported LRP2 as a putative target of miR-130a, with roles in lipid metabolism [58]. "
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