Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras
Autor: | James Jiayuan Tong, Frances Hannan, Peter Nürnberg, Ivan Shun Ho, Yi Zhong, Yinghua Zhu |
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Rok vydání: | 2006 |
Předmět: |
congenital
hereditary and neonatal diseases and abnormalities GTPase-activating protein Biology medicine.disease_cause Models Biological Article Receptor tyrosine kinase Animals Genetically Modified Adenylyl cyclase chemistry.chemical_compound GTP-Binding Proteins Heterotrimeric G protein Genetics medicine Animals Body Size Humans Growth Substances Molecular Biology Genetics (clinical) Neurotransmitter Agents Mutation Neurofibromin 1 GTPase-Activating Proteins fungi General Medicine Protein Structure Tertiary Cell biology Enzyme Activation Gene Expression Regulation chemistry ras Proteins Cancer research biology.protein Drosophila Signal transduction Tyrosine kinase Gene Deletion Adenylyl Cyclases Signal Transduction |
Zdroj: | Human Molecular Genetics. 15:1087-1098 |
ISSN: | 1460-2083 0964-6906 |
DOI: | 10.1093/hmg/ddl023 |
Popis: | 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. |
Databáze: | OpenAIRE |
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