Abstract
How Wnt signalling including canonical and non-canonical pathways are initiated at the cell surface is not completely understood. Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. Importantly, through direct binding to Frz, LRP5/6 are able to prevent Frz-regulated non-canonical pathway activation and further non-canonical pathway-mediated tumour metastasis. Knockdown of endogenous LRP5/6 promotes otherwise-nonaggressive tumour cells to migrate in vitro, whereas a soluble recombinant protein of LRP6 ectodomain suppresses migration and metastasis of otherwise-aggressive tumour cells in vitro and in vivo. Furthermore, the expression level of membrane LRP5/6 correlates inversely with metastasis in mouse and human breast cancer. Our study suggests a previously unrecognized mode of receptor interaction, revealing the mechanism of LRP5/6 in inhibition of non-canonical pathway, and a possible clinical use of the LRP6 ectodomain to impede metastasis.
Highlights
How Wnt signalling including canonical and non-canonical pathways are initiated at the cell surface is not completely understood
The current view is that the close proximity of LRP5/6 and Frz coupled by canonical Wnt ligand binding to E1-4 of LRP5/6 and amino-terminal cysteine-rich domain (CRD) of Frz is needed for canonical pathway activation[2,9]
Immunoprecipitation (IP)/western blot (WB) analysis revealed that full-length LRP6 interacted with Frz[8], and this interaction was not affected by sequestration of Wnt ligands with co-transfected soluble form of Frz8-CRD (Fig. 1b)
Summary
How Wnt signalling including canonical and non-canonical pathways are initiated at the cell surface is not completely understood. Through direct binding to Frz, LRP5/6 are able to prevent Frz-regulated non-canonical pathway activation and further non-canonical pathway-mediated tumour metastasis. Dkk[1] promotes the internalization of LRP5/6 via binding with Dkk[1] receptor Kremen, making LRP5/6 unavailable for Wnt reception and inhibiting the canonical pathway[12]. Components of non-canonical pathways including planar cell polarity (PCP) and Wnt/Ca2 þ pathways have been implicated in directly promoting the invasiveness of diverse forms of cancer[13,14,15]. The non-canonical Wnt5a can promote normal cell motility as well as tumour metastasis through the activation PCP/JNK or Ca2 þ /PKC signalling cascade[16,17,18]. Noncanonical pathways are involved in cancer development through promoting tumour cell motility
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