The Neurofibromatosis 1 Gene Product Neurofibromin Regulates Pituitary Adenylate Cyclase-Activating Polypeptide-Mediated Signaling in Astrocytes

摘要: Individuals with the neurofibromatosis 1 (NF1)-inherited tumor predisposition syndrome develop low-grade astrocytomas. The NF1 suppressor gene product neurofibromin exhibits GTPase-activating activity (GAP) toward RAS, such that loss of expression leads to high levels activated RAS and increased cell proliferation. Previous work has demonstrated Nf1 inactivation in astrocytes proliferation vitro vivo, accompanied by pathway activation. Studies on mutant Drosophila have suggested might also regulate cAMP signaling. Because intracellular profound effects astrocyte growth control, we sought determine contribution regulation. In this report, demonstrate results reduced generation response PACAP attenuated calcium influx Rap1 Based differential forskolin dibutyryl-cAMP Nf1-/- astrocytes, likely functions at level adenylyl cyclase Last, reintroduction a fragment containing residues sufficient for restoring RAS-GAP function cells resulted only partial restoration neurofibromin-mediated These positively influences activation regulatory targets expands role