PHLPP1 splice variants differentially regulate AKT and PKCα signaling in hippocampal neurons: characterization of PHLPP proteins in the adult hippocampus

P>Pleckstrin homology and leucine rich repeat protein phosphatases (PHLPPs) are a novel class of potent protein kinase B (AKT) inhibitors that have been intensely investigated in relation to AKT activity in cancer. Currently, our understanding of the role of PHLPP1 alpha in the central nervous system is limited. In this study, we characterized PHLPP protein expression and target kinases in the adult hippocampus. We directly verify PHLPP1 alpha inhibits AKT in hippocampal neurons and demonstrate a novel role for PHLPP1 beta/SCOP, to promote AKT activation. PHLPP1 alpha expression changes dramatically in the hippocampus during development, constituting the most abundant PHLPP protein in adult neurons. Further, while all PHLPP proteins could be observed in the cytosolic fraction, only PHLPP1 alpha could be localized to the nucleus. The results provide unique evidence for a divergence in the function of PHLPP1 alpha and PHLPP1 beta/SCOP, and suggest that PHLPP1 alpha plays a major role in regulating AKT signaling in neurons.