From outside to inside and back again: the lysophosphatidic acid-CCN axis in signal transduction.

CCN1 and CCN2 are matricellular proteins that are transcriptionally induced by various stimuli, including growth factors. CCN proteins act to facilitate signaling events involving extracellular matrix proteins. Lysophosphatidic acid (LPA) is a lipid that activates G protein-coupled receptors (GPCRs), enhancing proliferation, adhesion, and migration in many types of cancer cells. Our group previously reported that LPA induces production of CCN1 protein in human prostate cancer cell lines within 2-4 h. In these cells, the mitogenic activity of LPA is mediated by LPA Receptor 1 (LPAR1), a GPCR. There are multiple examples of the induction of CCN proteins by LPA, and by the related lipid mediator sphingosine-1-phosphate (S1P), in various cellular models. The signaling pathways responsible for LPA/S1P-induced CCN1/2 typically involve activation of the small GTP-binding protein Rho and the transcription factor YAP. Inducible CCNs can potentially play roles in downstream signal transduction events required for LPA and S1P-induced responses. Specifically, CCNs secreted into the extracellular space can facilitate the activation of additional receptors and signal transduction pathways, contributing to the biphasic delayed responses typically seen in response to growth factors acting via GPCRs. In some model systems, CCN1 and CCN2 play key roles in LPA/S1P-induced cell migration and proliferation. In this way, an extracellular signal (LPA or S1P) can activate GPCR-mediated intracellular signaling to induce the production of extracellular modulators (CCN1 and CCN2) that in turn initiate another round of intracellular signaling.