LRP5 and LRP6 in development and disease

Abstract

Low-density lipoprotein-related receptors 5 and 6 (LRP5/6) are highly homologous proteins with key functions in canonical Wnt signaling. Alterations in the genes encoding these receptors or their interacting proteins are linked to human diseases and as such they have been a major focus of drug development efforts to treat several human conditions including osteoporosis, cancer, and metabolic disease. Here, we discuss the links between alterations in Lrp5/6 and disease, proteins that interact with them, and insights gained into their function from mouse models. We also highlight current drug development related to Lrp5/6 as well as how the recent elucidation of their crystal structures may allow for further refinement of our ability to target them for therapeutic benefit.

miR-17-92/p38α Dysregulation Enhances Wnt Signaling and Selects Lgr6+ Cancer Stem-like Cells during Lung Adenocarcinoma Progression

“…The coactivator Lrp6 interacts with Lgr6 enhancing the response to Wnt ligands, amplifying the receptors signal (26,27 Fig. 3D and Supplementary Fig.…”

Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases

“…3 In contrast, murine models suggested incomplete functional redundancy between the two receptors. 4 Although both have a crucial role in the regulation of bone mass, 5 LRP6 is closely related to glucose and lipid metabolism signaling pathways [6][7][8] and plays a more important role than LRP5 in developmental processes. 9 The human LRP6 gene (hLRP6), which is located on chromosome 12p13.2, is 150 kb in length and contains 23 exons.…”

Apolipoprotein E Related Co-Morbidities and Alzheimer’s Disease

“…LRP5 is a co-receptor of the Wnt/β-catenin signalling cascade [65] that in health affords protection to the individual from vascular diseases as demonstrated in apoɛ and LRP5 double gene knockout (ApoE -/-LRP5 -/-) mice [66]. Since LRP5 polymorphisms are also being discovered in aggressive PD, this implies that these polymorphisms are contributing to loss of gene function, and thereby predispose individuals to periodontitis [15].…”