Gq protein-coupled receptors (GqPCRs) regulate multiple cellular processes, including proliferation and differentiation. In a previous study, we found that the GqPCR for gonadotropin-releasing hormone (GnRH) actually induces apoptosis through PKC-dependent AKT inactivation and JNK activation in prostate cancer cells. However, the molecular details of this regulation remain elusive. Therefore, we decided to elucidate the molecular mechanism governing this apoptosis. We first undertook to examine how general this phenomenon is. In a screen of panel of cell lines, we found that PKC activation results in the reduction of AKT in about 50% cell lines, and it correlates nicely with JNK activation and in some cases with apoptosis. JNK activation is a key step for this type of apoptosis, which is mediated by two signaling branches downstream of PKC that converge at the level of MLK3. One branch consists of c-Src activation of the JNK cascade, and the second involves reduction of AKT activity that alleviates its inhibitory effect on MLK3 to allow the flow of the c-Src signal to JNK. Another crucial step of this process is PKC-induced AKT inactivation. We identified a PKC-regulated PP2A switch, which turns off PI3K/AKT signaling pathway upon PKC activation. At unstimulated state, PP2A binds with PI3K to maintain its basal activity. Upon PKC activation, PP2A catalytic subunit is detached from the PI3K and binds to IGBP1 (α4), which recruits AKT as a substrate and thereby inactivates it. Our results present a general mechanism that mediates a GqPCR-induced, death receptor-independent, apoptosis in physiological as well as cancer-related systems.