Figure 8. A schematic model shows that PIP5K1α acts on two parallel signaling pathways.

The model depicts PIP5K1α acts on two parallel pathways. PIP5K1α is the key kinase responsible for generation of PIP2. In turns, PIP2 serves as a precursor molecule required for PI3K activity and generation of PIP3, thus PIP5K1α acts upstream of PI3K/AKT as illustrated in our previous reported studies (Semenas et al., 2014) and the data presented in this study. Here we revealed a new mechanism by which AR-V7 cooperates with PIP5K1α and CDK1 to promote growth and invasion of PCa cells. AR-V7 physically interacts with PIP5K1α and CDK1 predominantly in the nucleus through formation of protein complexes. In PCa cells with PTEN mutations, AR-V7 is able to increase activity of pAKT. ISA-2011B blocks deregulated PIP5K1α/AKT activity and disrupt AR-V7/CDK1/PIP5K1α complexes in the nuclear and cytoplasmic compartment of PTEN-negative cells. The effect of ISA-2011B on AR may be mediated through CDK1, which is an upstream regulator and co-factor of both AR and AR-V7. The combination of ISA-2011B and enzalutamide synergistically inhibits deregulated AR and AR-V7 pathways in PCa cells.