The LPA₂ receptor PDZ domain affects canonical Wnt signaling in colon cancer cells

Colorectal cancer is the third leading cause of cancer-related deaths worldwide. Aberrant canonical Wnt signaling is a hallmark of this cancer type. It has been reported that LPA is a bioactive lipid that plays different roles in colon cancer by activating its G-protein-coupled receptors, promoting cell proliferation, migration, survival, and angiogenesis. Although it has been reported that LPA activates canonical Wnt signaling, the mechanisms underlying their interaction remain unclear; this study aims to investigate them. As previously reported, LPA receptor expression changes under malignant conditions: while LPA₁ is expressed at high levels and LPA₂ is low in non-malignant 112CoN cells, the opposite occurs in malignant cells, with colon cancer cells showing low LPA₁ levels and high LPA₂ levels. We also observed that both LPA and Wnt-3a induce strong ERK activation in all colon cell lines; these effects are not additive. Additionally, LPA and Wnt-3a stimulate β-catenin transcriptional activity and its phosphorylation at residues S552 and S675, again in a non-additive manner. We further found that LPA₂ and the Wnt effectors Dvl2 and Dvl3 co-precipitate in colon cancer cells, and that the PDZ-interacting motif in the carboxyl terminus of the LPA₂ receptor is critical for their direct interaction. Moreover, expressing a mutated LPA_2-PDZminus receptor inhibited cell migration while increasing proliferation. Remarkably, the LPA_2-PDZminus receptor negatively affected its ability to activate canonical Wnt signaling and unexpectedly, it also impaired the Wnt-3a ligand-induced activation of canonical Wnt signaling in colon cancer cells.