Abstract
The canonical Wnt/β-catenin signaling plays a fundamental role in regulating embryonic development, injury repair and the pathogenesis of human diseases. In vertebrates, low density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6), the single-pass transmembrane proteins, act as coreceptors of Wnt ligands and are indispensable for Wnt signal transduction. LRP5 and LRP6 are highly homologous and widely co-expressed in embryonic and adult tissues, and they share similar function in mediating Wnt signaling. However, they also exhibit distinct characteristics by interacting with different protein partners. As such, each of them possesses its own unique functions. In this review, we systematically discuss the similarity and divergence of LRP5 and LRP6 in mediating Wnt and other signaling in the context of kidney diseases. A better understanding of the precise role of LRP5 and LRP6 may afford us to identify and refine therapeutic targets for the treatment of a variety of human diseases.
Highlights
Wnt/β-catenin is an evolutionarily conserved developmental signaling that plays a critical role in cell fate determination, organ development, injury repair and the pathogenesis of human diseases (Clevers, 2006; Tan et al, 2014)
In Lrp6 knockout mouse embryo (18.5 days post coitum), macroscopic small cystic kidneys are visible, suggesting a PKD phenotype (Pinson et al, 2000; Wang et al, 2016). These findings indicate that LRP6 plays a pivotal role during early renal development, and that LRP5, while not affecting early renal development, may at least partially contribute to renal cystogenesis after renal maturation by affecting Wnt/β-catenin signaling
Over the last two decades, significant progress has been made in our understanding the role of lipoprotein receptor-related protein -5 or -6 (LRP5/6) in mediating Wnt signaling and other signal pathways
Summary
Wnt/β-catenin is an evolutionarily conserved developmental signaling that plays a critical role in cell fate determination, organ development, injury repair and the pathogenesis of human diseases (Clevers, 2006; Tan et al, 2014). In the Wnt activation state, the binding of Wnt ligands to the seven-pass transmembrane Frizzled (Fzd) receptor and its co-receptors, the low density lipoprotein receptor-related protein -5 or -6 (LRP5/6), leads to dimerization of the two receptors on cell surface and induces conformational changes of these receptors (Nusse and Clevers, 2017). The cytoplasmic tail of LRP5/6 is phosphorylated by several protein kinases, and subsequently recruits Axin and inhibits the activity of GSK3, resulting in the dissociation of the β-catenin destruction complex. There are several structurally unrelated, transmembrane receptor proteins that mediate different Wnt signaling (Grumolato et al, 2010) Both canonical and non-canonical Wnt ligands use common receptors of the Fzd family; they employ different co-receptors. LRP5/6 coreceptors are used for canonical Wnt ligands, whereas non-canonical ligands choose other transmembrane proteins (Garcia de Herreros and Dunach, 2019)
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