Zinc signaling is mediated by the zinc sensing receptor, ZnR, recently suggested to be the same receptor as G‐protein coupled receptor 39, GPR39. However, it is unknown if GPR39 is mediating Zn2+‐dependent signaling in prostate and salivary tissue where changes in zinc concentrations are frequent and of physiological significance. Here, we show that GPR39 is mediating Zn2+‐dependent Ca2+ responses and is regulating activity of MAP and PI3 pathways in prostate cancer cells, PC3, and ductal salivary gland cells, HSY. We next ask whether ZnR/GPR39 interacts with other GPCR family members. We find that endogenous ZnR/GPR39 activity is regulated by the expression and activity of another cation sensing GPCR, the Ca2+‐sensing receptor (CaSR). Although CaSR is not activated by Zn2+, co‐expression of CaSR and ZnR/GPR39 synergistically enhances Ca2+ responses in PC3 and HSY cells. Silencing of the CaSR using siRNA or a dominant negative construct reduces the Zn2+‐dependent signaling. Importantly, overexpression of GPR39 in HEK293 cells is sufficient to trigger Zn2+‐dependent responses. Nevertheless, application of the CaSR agonist spermine, at concentration below its threshold, enhanced Zn2+‐dependent Ca2+ response. Our results suggest that the CaSR interacts with ZnR/GPR39 and thereby regulates its activity. Finally, we show that in PC3 cells ZnR/GPR39 is required for mediating the Zn2+‐dependent activation of MAPK and PI3K, pathways leading to enhanced cell growth. Importantly, Zn2+‐dependent activation of ZnR/GPR39 also enhances the expression of the Ca2+‐binding protein S100A4 that is linked to invasion of prostate cancer cells. J. Cell. Physiol. 229: 868–877, 2014. © 2013 Wiley Periodicals, Inc.