Cloning of a novel member of the low-density lipoprotein receptor family

Hey, P.; Twells, Rebecca C.J.; Phillips, Michael; Nakagawa, Yusuke; Brown, S. D.; Kawaguchi, Yoshihiko; Cox, Roger; Xie, Guochun; Dugan, Valarie; Hammond, Holly A.; Metzker, Michael L.; Todd, John A.; Hess, J. Fred

doi:10.1016/s0378-1119(98)00311-4

Cited by 201 publications

(154 citation statements)

References 42 publications

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“…Mutants for arrow contained extra bands of denticles that were more prominent in the midline, causing the denticle stripes to look like arrows. Elimination of maternal and zygotic arrow resulted in a phenotype identical to that of wg mutants, and molecular cloning revealed that Arrow is homologous to LRP5 and LRP6 (Wehrli et al 2000), which had been cloned as members of the LDLR family Hey et al 1998). With the evidence that the Lrp6 mouse mutant phenotypically resembles a composite of several Wnt mutants (Pinson et al 2000), that LRP5 and LRP6 display critical roles in Wnt/b-catenin signaling in Xenopus (Tamai et al 2000), and that Wnt1 can bridge a complex formation between the extracellular domains of FZD and LRP6 (Tamai et al 2000), LRP5/6 and Arrow were established as coreceptors for the Wnt/b-catenin pathway.…”

Section: Lrp5/6 and Arrowmentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

495

411

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Frizzled and LRP5/6 are Wnt receptors that upon activation lead to stabilization of cytoplasmic b-catenin. In this study, we review the current knowledge of these two families of receptors, including their structures and interactions with Wnt proteins, and signaling mechanisms from receptor activation to the engagement of intracellular partners Dishevelled and Axin, and finally to the inhibition of b-catenin phosphorylation and ensuing b-catenin stabilization.T he Wnt/b-catenin pathway, or canonical Wnt pathway as it is often referred to, is an ancient and conserved signaling cascade involving b-catenin acting as a transcriptional coactivator (Logan and Nusse 2004). The pathway is best understood when considered in a two-state model of OFF (without Wnt) and ON (with Wnt). In the OFF state, cytoplasmic b-catenin is constitutively targeted for degradation by two multidomain scaffolding proteins, Axin and Adenomatous polyposis coli (APC), which facilitate the amino-terminal phosphorylation of b-catenin via the kinases GSK3 and CKIa. Phosphorylated b-catenin is recognized by the E3 ubiquitin ligase b-Trcp and is thus ubiquitinated and degraded by the proteasome, thereby maintaining low levels of free b-catenin in the cytoplasm and nucleus (MacDonald et al. 2009). In the ON state, a Wnt ligand binds to the seven-pass transmembrane receptor Frizzled (FZD) and the single-pass low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) ). The Wnt-FZD -LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of b-catenin phosphorylation and thus ensuing b-catenin stabilization. The rise of cytoplasmic and nuclear levels of b-catenin levels promotes b-catenin partnering with the TCF/ LEF transcription factors for activation of Wntresponsive gene expression.Wnt/b-catenin signaling controls cell proliferation and differentiation and is a key regulatory mechanism for stem cells. As such, mutations in the Wnt pathway cause many diseases including cancer (Clevers 2006). All of the above "core" Wnt/b-catenin signaling components are present in vertebrates and the well-studied fruit fly Drosophila and are also encoded in sequenced genomes of radial symmetric Cnidarians Hydra magnipapillata and Nematostella vectensis (Guder et al. 2006) and of the primitive metazoan sponge Amphimedon queenslandica

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Section: Lrp5/6 and Arrowmentioning

confidence: 99%

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

MacDonald

2012

Cold Spring Harbor Perspectives in Biology

495

411

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“…122 A gene encoding a novel transmembrane protein has been identified by sequence analysis of the IDDM4 locus. 123 This gene, termed low-density lipoprotein receptor related protein (LRP5), encodes a protein that contains conserved sequences, characteristic of the low-density lipoprotein receptor family. LRP5 is in close proximity to the two markers, D11S1917 and H0570PolyA, and the exon encoding the signal peptide of LPR-5 is only 3 kb downstream the H0570polyA marker.…”

Section: Iddm2-the Insulin Gene (Ins) Regionmentioning

confidence: 99%

Genetics of type 1 diabetes mellitus

2002

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“…Wnt signaling inhibits adipogenesis (28,29), and polymorphisms in pathway components are associated with an increased risk for the development of diabetes (30,31), obesity (32), and hyperlipidemia (33,34). In addition, the Lrp5 coreceptor was originally identified as a candidate gene in the IDDM4 locus with linkage to insulin-dependent diabetes mellitus (35,36), and mice globally deficient for Lrp5 are glucose intolerant and exhibit increased plasma cholesterol levels when fed a high-fat diet (37,38).…”

mentioning

confidence: 99%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Frey

Ellis

et al. 2015

Molecular and Cellular Biology

120

104

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fThe Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of ␤-catenin and thereby induce the expression of key enzymes required for fatty acid ␤-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. Wnt signaling regulates nearly all aspects of osteoblast function, from initial fate specification (1) to the control of osteoclast differentiation (2). In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3, 4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5-7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9, 10) likely due to an increase in the number of mineralizing osteoblasts (11).Like other metabolically active cells, osteoblasts require a supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix (12). When energy input fails to meet demand, normal bone accrual ceases, a phenomenon that is evident clinically by the arrest of longitudinal bone growth and osteopenia observed in undernourished children and adults (13, 14). Therefore, osteoblasts must possess mechanisms to acquire and regulate the utilization of fuel macromolecules, as well as the ability to communicate energy needs with other tissues.Recent studies have delineated a role for the osteoblast in a bone-pancreas endocrine loop that contributes to the regulation of glucose metabolism, as well as bone acquisition. Insulin receptor signaling in the osteoblast regulates the activity of the osteogenic transcription factor Runx2 and is required for the attainment of a mature phenotype as well as normal postnatal bone acquisition (15). In addition, insulin actions regulate the production and bioavailability of osteocalcin (15, 16), a bone-derived hormone that in ...

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Cloning of a novel member of the low-density lipoprotein receptor family

Cited by 201 publications

References 42 publications

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

Frizzled and LRP5/6 Receptors for Wnt/ -Catenin Signaling

Genetics of type 1 diabetes mellitus

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

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