Abstract
Wnt signaling plays crucial roles in development and tissue homeostasis, and its dysregulation leads to various diseases, notably cancer. Wnt/β-catenin signaling is initiated when the glycoprotein Wnt binds to and forms a ternary complex with the Frizzled and low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Despite being identified as a Wnt co-receptor over 20 years ago, the molecular mechanisms governing how LRP6 senses Wnt and transduces downstream signaling cascades are still being deciphered. Due to its role as one of the main Wnt signaling components, the dysregulation or mutation of LRP6 is implicated in several diseases such as cancer, neurodegeneration, metabolic syndrome and skeletal disease. Herein, we will review how LRP6 is activated by Wnt stimulation and explore the various regulatory mechanisms involved. The participation of LRP6 in other signaling pathways will also be discussed. Finally, the relationship between LRP6 dysregulation and disease will be examined in detail.
Highlights
Wnt signaling has crucial roles in development and tissue homeostasis (Nusse and Clevers, 2017)
B-cell CLL/lymphoma 9 protein (BCL9) is phosphorylated at the T172 residue by cyclin dependent kinase 1 (CDK1), and phosphorylated BCL9 inhibits LRP6 degradation thereby acting as a positive regulator of Wnt/STOP signaling (Chen et al, 2018)
These data suggest that LRP6 phosphorylation-mediated Wnt signaling can be transduced in a β-catenin-independent manner (Figure 5D)
Summary
Wnt signaling has crucial roles in development and tissue homeostasis (Nusse and Clevers, 2017). Similar to Dab, long-term treatment of Wnt3a (6–8 h) induces phosphorylation of adaptor related protein complex 2 subunit mu 1 (AP2M1) through AP2-associated kinase 1 (AAK1), and phosphorylated AP2M1 activates clathrin-mediated LRP6 internalization, once again leading to negative regulation of Wnt/β-catenin signaling (Agajanian et al, 2019). B-cell CLL/lymphoma 9 protein (BCL9) is phosphorylated at the T172 residue by cyclin dependent kinase 1 (CDK1), and phosphorylated BCL9 inhibits LRP6 degradation thereby acting as a positive regulator of Wnt/STOP signaling (Chen et al, 2018) These data suggest that LRP6 phosphorylation-mediated Wnt signaling can be transduced in a β-catenin-independent manner (Figure 5D). N-myc downstream regulated gene-1 protein (NDRG1) interacts with LRP6 and suppresses LRP6mediated Wnt signaling activation, resulting in inhibition of breast cancer metastasis (Liu et al, 2012). GSK3β activity and expression of inflammatory marker genes are increased in the brains of LRP6+/− mice (Abe et al, 2013)
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