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

ABSTRACT: 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? 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? inhibits AKT in hippocampal neurons and demonstrate a novel role for PHLPP1?/SCOP, to promote AKT activation. PHLPP1? 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? could be localized to the nucleus. The results provide unique evidence for a divergence in the function of PHLPP1? and PHLPP1?/SCOP, and suggest that PHLPP1? plays a major role in regulating AKT signaling in neurons.

SUBMITTER: Jackson TC

PROVIDER: S-EPMC3730267 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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

Jackson Travis C TC Verrier Jonathan D JD Semple-Rowland Susan S Kumar Ashok A Foster Thomas C TC

Journal of neurochemistry 20100928 4

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 PHLPP1α 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 PHLPP1α inhibits AKT in hippocampal neurons and demonstrate a novel role ...[more]

PMID: 20819118

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Project description:Severe loss of cholinergic neurons in the basal forebrain nuclei and of noradrenergic neurons in the locus coeruleus are almost invariant histopathological hallmarks of Alzheimer's disease. However, the role of these transmitter systems in the spectrum of cognitive dysfunctions typical of the disease is still unclear, nor is it yet fully known whether do these systems interact and how. Selective ablation of either neuronal population, or both of them combined, were produced in developing animals to investigate their respective and/or concurrent contribution to spatial learning and memory, known to be severely affected in Alzheimer's disease. Single or double lesions were created in 4-8 days old rats by bilateral intraventricular infusion of two selective immunotoxins. At about 16 weeks of age, the animals underwent behavioural tests specifically designed to evaluate reference and working memory abilities, and their brains were later processed for quantitative morphological analyses. Animals with lesion to either system alone showed no significant reference memory deficits which, by contrast, were evident in the double-lesioned subjects. These animals could not adopt an efficient search strategy on a given testing day and were unable to transfer all relevant information to the next day, suggesting deficits in acquisition, storage and/or recall. Only animals with single noradrenergic or double lesions exhibited impaired working memory. Interestingly, ablation of cholinergic afferents to the hippocampus stimulated a robust ingrowth of thick fibres from the superior cervical ganglion which, however, did not appear to have contributed to the observed cognitive performance. Ascending cholinergic and noradrenergic afferents to the hippocampus and neocortex appear to be primarily involved in the regulation of different cognitive domains, but they may functionally interact, mainly at hippocampal level, for sustaining normal learning and memory. Moreover, these transmitter systems are likely to compensate for each other, but apparently not via ingrowing sympathetic fibres.

Dataset Information

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

Publications

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

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