Proc Amer Assoc Cancer Res, Volume 46, 20054499 Lysophosphatidic acid (LPA) is a well characterized growth and survival factor for cancer cells in culture. This study details the identification of two G-protein coupled receptors, OSGPR78 and OSGPR114 as novel lysophosphatidic acid (LPA) receptors. OSGPR78 and OSGPR114, when expressed in a yeast-based reporter assay, are activated by multiple analogs of LPA, including myristoyl, palmitoyl, oleoyl, stearoyl and polyunsaturated LPA analogs. Similarly, when expressed in mammalian cells, the receptors also respond to the same LPA analogs. Pertussis toxin sensitivity of the effects of LPA activation of OSGPR114 expressed in CHO cells suggests a coupling to Gi/o proteins. Amino acid homologies of OSGPR114 and OSGPR78 demonstrate no obvious similarity with the known LPA G-protein coupled receptors LPA1-3. The expression of these novel LPA receptors in normal human tissues, cancer cell lines and in tumor samples has been characterized using fluorogenic real-time PCR. In normal tissues, OSGPR114 was expressed at the highest levels in areas such as the lung, kidney, leukocytes and ovary, whereas OSGPR78 was found to be expressed at high levels in almost every tissue studied. Several cancer cell lines have been identified which express OSGPR78 or OSGPR114 as the predominant LPA receptor and both receptors are widely expressed in human tumor samples. Furthermore, in cell lines shown to express OSGPR114 or OSGPR78, small interfering RNA oligonucleotides (siRNA) designed to specifically knockdown OSGPR114 and OSGPR78 expression induced a growth-inhibitory and pro-apoptotic phenotype in cells maintained in full serum. In summary, we demonstrate that OSGPR78 and OSGPR114 are novel LPA activated G-protein coupled receptors. Initial evidence suggests that OSGPR114 and OSGPR78, like the known LPA receptors (LPA1-3 and gpr23), are involved in mediating the proliferation and survival effects of LPA on cancer cells in culture.