Functional characterization of lysophosphatidic acid receptor 1 mutants identified in rat cancer tissues.

Lysophosphatidic acid (LPA), an extracellular lipid mediator, exerts various cellular effects through activation of LPA receptors, LPA-LPA, in many types of cells including cancer cells. We recently found several missense mutations of Lpar1 in rat cancer tissues. One of these mutations is located at the extracellular tip of the seventh transmembrane domain of LPA, and another three mutations are found within the NPXXY motif in the seventh transmembrane domain. These mutants are designated F295S LPA and P308S, I310T, and Y311H LPA, respectively. Here, we examined the functions of these LPA mutants. Compared with wild-type (WT) LPA, F295S, P308S, and I310T LPA showed decreased maximal responses in inhibition of cAMP formation, Ca mobilization, and cytoskeletal changes. Y311H LPA failed to show LPA-induced cellular responses. However, these LPA mutants were internalized in response to LPA exposure. Finally, while WT and F295S LPA showed a similar, broad distribution throughout the cell, P308S, I310T, and Y311H LPA displayed a restricted cellular distribution and co-localized with the endoplasmic reticulum. These data suggest that the LPA mutants perturb LPA signaling in cancer tissues.