Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras

Hannan, F., Ho, I., Tong, J. J., Zhu, Y., Nurnberg, P., Zhong, Y. (April 2006) Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras. Hum Mol Genet, 15 (7). pp. 1087-98. ISSN 0964-6906 (Print)

URL: https://www.ncbi.nlm.nih.gov/pubmed/16513807
DOI: 10.1093/hmg/ddl023

Abstract

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.

Item Type: Paper
Uncontrolled Keywords: Adenylate Cyclase metabolism Animals Animals Genetically Modified Body Size genetics Drosophila Enzyme Activation GTP-Binding Proteins metabolism GTPase-Activating Proteins metabolism Gene Deletion Gene Expression Regulation Growth Substances metabolism pharmacology Humans Models Biological Mutation Neurofibromin 1 genetics metabolism pharmacology Neurotransmitter Agents Protein Structure Tertiary Signal Transduction genetics ras Proteins metabolism pharmacology
Subjects: diseases & disorders > cancer
organism description > animal > insect > Drosophila
diseases & disorders > mental disorders > genetic disorders
organism description > animal behavior > memory
diseases & disorders > congenital hereditary genetic diseases > neurofibromatosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Zhong lab
Depositing User: CSHL Librarian
Date: 1 April 2006
Date Deposited: 15 Dec 2011 15:40
Last Modified: 13 Apr 2018 21:10
PMCID: PMC1866217
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22809

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