title: Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation.
abstract: Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder in which affected individuals are prone to learning, attention and behavioral problems. Previous studies in mice and flies have yielded conflicting results regarding the specific effector pathways responsible for NF1 protein (neurofibromin) regulation of neuronal function, with both cyclic AMP (cAMP)- and RAS-dependent mechanisms described. Herein, we leverage a combination of induced pluripotent stem cell-derived NF1 patient neural progenitor cells and Nf1 genetically engineered mice to establish, for the first time, that neurofibromin regulation of cAMP requires RAS activation in human and mouse neurons. However, instead of involving RAS-mediated MEK/AKT signaling, RAS regulation of cAMP homeostasis operates through the activation of atypical protein kinase C zeta, leading to GRK2-driven Gαs inactivation. These findings reveal a novel mechanism by which RAS can regulate cAMP levels in the mammalian brain.
authors: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Corina
authors: C
authors: Anastasaki
authors: Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA gutmannd@neuro.wustl.edu.
authors: David H
authors: DH
authors: Gutmann
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002864:Chromogranins; D000242:Cyclic AMP / Q000378:metabolism*; D004789:Enzyme Activation; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000201:enzymology* / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D061251:Primary Cell Culture; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D002864:Chromogranins; D000242:Cyclic AMP; D054769:G-Protein-Coupled Receptor Kinase 2; D019205:GTP-Binding Protein alpha Subunits, Gs; D020929:Mitogen-Activated Protein Kinase Kinases; D025542:Neurofibromin 1; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000099221:Protein Kinase C zeta; C117307:KRAS protein, human; C496567:GRK2 protein, human; C498642:Gnas protein, mouse