Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras.
Neurofibromatosis type I (NFI) is a common genetic disorder that causes nervous system tumors, and learning and memory defects in humans, and animal models. We identify a novel growth factor stimulated adenylyl cyclase (AC) pathway in the Drosophila brain, which is disrupted by mutations in the epidermal growth factor receptor (EGFR), neurofibromin (NF1) and Ras, but not Galpha(s). This is the first demonstration in a metazoan that a receptor tyrosine kinase (RTK) pathway, acting independently of the heterotrimeric G-protein subunit Galpha(s), can activate AC. We also show that Galpha(s) is the major Galpha isoform in fly brains, and define a second AC pathway stimulated by serotonin and histamine requiring NF1 and Galpha(s), as well as a third, classical Galpha(s)-dependent AC pathway, which is stimulated by Phe-Met-Arg-Phe-amide (FMRFamide) and dopamine. Using mutations and deletions of the human NF1 protein (hNF1) expressed in Nf1 mutant flies, we show that Ras activation by hNF1 is essential for growth factor stimulation of AC activity. Further, we demonstrate that sequences in the C-terminal region of hNF1 are sufficient for NF1/Galpha(s)-dependent neurotransmitter stimulated AC activity, and for rescue of body size defects in Nf1 mutant flies.
Hannan
Frances
F
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Ho
Ivan
I
Tong
James Jiayuan
JJ
Zhu
Yinghua
Y
Nurnberg
Peter
P
Zhong
Yi
Y
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D049628:Body Size / Q000235:genetics; D004330:Drosophila; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D018377:Neurotransmitter Agents; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism* / Q000494:pharmacology
D020690:GTPase-Activating Proteins; D006133:Growth Substances; D025542:Neurofibromin 1; D018377:Neurotransmitter Agents; D019204:GTP-Binding Proteins; D018631:ras Proteins; D000262:Adenylyl Cyclases