Avian and Murine LR8B and Human Apolipoprotein E Receptor 2: Differentially Spliced Products from Corresponding Genes

Brandes, Christian; Novak, Sabine; Stockinger, Walter; Herz, Joachim; Schneider, Wolfgang J.; Nimpf, Johannes

doi:10.1006/geno.1997.4702

Cited by 49 publications

(51 citation statements)

References 23 publications

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“…It is tempting to speculate that these two variants of LRP1b may serve different functions, possibly by mediating different signaling pathways. A similar alternative splicing event within the cytoplasmic tail is known for ApoER2 (4,16).…”

Section: Discussionmentioning

confidence: 69%

Normal Development and Fertility of Knockout Mice Lacking the Tumor Suppressor Gene LRP1b Suggest Functional Compensation by LRP1

Marschang

Brich

Weeber

et al. 2004

Molecular and Cellular Biology

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LRP1b and the closely related LRP1 are large members of the low-density lipoprotein receptor family. At the protein level LRP1b is 55% identical to LRP1, a multifunctional and developmentally essential receptor with roles in cargo transport and cellular signaling. Somatic LRP1b mutations frequently occur in non-small cell lung cancer and urothelial cancers, suggesting a role in the modulation of cellular growth. In contrast to LRP1, LRP1b-deficient mice develop normally, most likely due to its restricted expression pattern and functional compensation by LRP1 or other receptors. LRP1b is expressed predominantly in the brain, and a differentially spliced form is present in the adrenal gland and in the testis. Despite the presence of a potential furin cleavage site and in contrast to LRP1, immunoblotting for LRP1b reveals the presence of a single 600-kDa polypeptide species. Using a yeast two-hybrid approach, we have identified two intracellular proteins, the postsynaptic density protein 95 and the aryl hydrocarbon receptor-interacting protein, that bind to the intracellular domain of LRP1b. In addition, we have found several potential ligands that bind to the extracellular domain. Analysis of LRP1b knockout mice may provide further insights into the role of LRP1b as a tumor suppressor and into the mechanisms of cancer development.The low-density lipoprotein (LDL) receptor family comprises seven closely related receptors in mammals. These receptors share a typical arrangement of ligand-binding domains, epidermal growth factor homology domains, and YWTD propeller domains in their extracellular part and contain a cytoplasmic tail with at least one NPXY motif. Two LDL receptor family members, i.e., the LDL receptor and the LDL receptorrelated protein 1 (LRP1) are widely expressed in nearly all cells, while the pattern of the other members (very low density lipoprotein [VLDL] receptor, apoER2, and megalin) is more restricted. The biological functions of the receptors are highly diverse and include the uptake of lipoproteins and other ligands, the regulation of cell surface proteinase activity, the regulation of Ca 2ϩ homeostasis, and important functions in brain development and neurotransmission. Besides their classical role in receptor-mediated endocytosis, evidence is now accumulating that many of the family members play important roles in signal transduction through adaptor molecules that bind to their cytoplasmic tails (8).Two very large receptors of the LDL receptor family have been well characterized. LRP1 contains 31 ligand-binding repeats and binds a variety of ligands, including apoE-carrying lipoproteins, ␣2-macroglobulin, and proteinases and their inhibitors. A unique feature of LRP1 is the fact that this receptor is cleaved by furin in a late secretory compartment, which results in a carboxyl-terminal 85-kDa fragment and a noncovalently linked 515-kDa subunit. LRP1 can bind numerous ligands and has been implicated in a variety of biological functions, including lipoprotein metabolism, the regulation of the ...

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Section: Discussionmentioning

confidence: 69%

Normal Development and Fertility of Knockout Mice Lacking the Tumor Suppressor Gene LRP1b Suggest Functional Compensation by LRP1

Marschang

Brich

Weeber

et al. 2004

Molecular and Cellular Biology

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“…In these species, the receptor has been given the name LR8B because it is related to the LDL-receptor (LR), it contains eight ligand binding repeats, and it is expressed predominantly in the brain. Subsequent studies have shown that ApoER2 and LR8B are orthologs in humans and birds and that the gene products are differentially spliced (Brandes et al 1997;Clatworthy et al 1999).…”

Section: The Lipoprotein Receptorsmentioning

confidence: 99%

“…One difference relates to the number of ligand-binding repeats in the extracellular domain. LDLR contains seven ligand binding repeats, whereas VLDLR contains eight repeats, and ApoER2 contains seven or eight, depending on the species (Brandes et al 1997;Nimpf and Schneider 1998;Clatworthy et al 1999). The number of ligand-binding repeats and the linear arrangement of the repeats are believed to be important for binding specificity .…”

Section: The Lipoprotein Receptorsmentioning

confidence: 99%

“…The number of ligand-binding repeats and the linear arrangement of the repeats are believed to be important for binding specificity . Alternative splicing of LR8B (ApoER2) in mice and humans produces a receptor containing an additional 59 residues in the cytoplasmic tail that is not present in chicken (Brandes et al 1997). This insert does not disrupt the NPxY internalization motif.…”

Section: The Lipoprotein Receptorsmentioning

confidence: 99%

“…This insert does not disrupt the NPxY internalization motif. There are only five residues that differ between the mouse and human inserts, suggesting an important function for this peptide in mammalian cells (Brandes et al 1997). A specific sequence downstream of the internalization motif in LDLR has been suggested to be important for basolateral targeting of the receptor in hepatocytes (Yokode et al 1992).…”

Section: The Lipoprotein Receptorsmentioning

confidence: 99%

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Avian and Murine LR8B and Human Apolipoprotein E Receptor 2: Differentially Spliced Products from Corresponding Genes

Cited by 49 publications

References 23 publications

Normal Development and Fertility of Knockout Mice Lacking the Tumor Suppressor Gene LRP1b Suggest Functional Compensation by LRP1

Normal Development and Fertility of Knockout Mice Lacking the Tumor Suppressor Gene LRP1b Suggest Functional Compensation by LRP1

Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS

Apolipoprotein E Receptor 2 and Very-Low-Density Lipoprotein Receptor: An Overview

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