Recent studies suggest that lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA₁, LPA₂, or LPA₃ may play a role in the development of several types of cancers, including colorectal cancer. However, the specific receptor subtype(s) and their signal-transduction pathways responsible for LPA-induced cancer cell proliferation have not been fully elucidated. We show by specific RNA interference (RNAi) that LPA₂ and LPA₃ but not LPA₁ are targets for LPA-induced proliferation of HCT116 and LS174T colon cancer cells. We determined that LPA-induced colon cancer cell proliferation requires the β-catenin signaling pathway, because knockdown of β-catenin by RNAi abolished LPA-induced proliferation of HCT116 cells. Moreover, LPA activates the main signaling events in the β-catenin pathway: phosphorylation of glycogen synthase kinase 3β (GSK3β), nuclear translocation of β-catenin, transcriptional activation of T cell factor (Tcf)/lymphoid-enhancer factor (Lef), and expression of target genes. Inhibition of conventional protein kinase C (cPKC) blocked the effects, suggesting its involvement in LPA-induced activation of the β-catenin pathway. Thus, LPA₂ and LPA₃ signal the proliferation of colon cancer cells through cPKC-mediated activation of the β-catenin pathway. These results link LPA and its GPCRs to cancer through a major oncogenic signaling pathway.