Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation

Hum Mol Genet. 2014 Dec 20;23(25):6712-21. doi: 10.1093/hmg/ddu389. Epub 2014 Jul 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Chromogranins
  • Cyclic AMP / metabolism*
  • Enzyme Activation
  • G-Protein-Coupled Receptor Kinase 2 / genetics
  • G-Protein-Coupled Receptor Kinase 2 / metabolism
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Gene Expression Regulation
  • Hippocampus / enzymology
  • Hippocampus / pathology
  • Humans
  • Induced Pluripotent Stem Cells / enzymology
  • Induced Pluripotent Stem Cells / pathology
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neural Stem Cells / enzymology*
  • Neural Stem Cells / pathology
  • Neurofibromatosis 1 / enzymology
  • Neurofibromatosis 1 / genetics*
  • Neurofibromatosis 1 / pathology
  • Neurofibromin 1 / genetics*
  • Neurofibromin 1 / metabolism
  • Neurons / enzymology*
  • Neurons / pathology
  • Primary Cell Culture
  • Protein Kinase C / genetics*
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Signal Transduction
  • ras Proteins / genetics*
  • ras Proteins / metabolism

Substances

  • Chromogranins
  • KRAS protein, human
  • Neurofibromin 1
  • Proto-Oncogene Proteins
  • Cyclic AMP
  • Proto-Oncogene Proteins c-akt
  • protein kinase C zeta
  • Protein Kinase C
  • GRK2 protein, human
  • G-Protein-Coupled Receptor Kinase 2
  • Mitogen-Activated Protein Kinase Kinases
  • Gnas protein, mouse
  • GTP-Binding Protein alpha Subunits, Gs
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins