Human Molecular Genetics Advance Access originally published online on March 2, 2006
Human Molecular Genetics 2006 15(7):1087-1098; doi:10.1093/hmg/ddl023
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Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA, 2New York Medical College, Valhalla, NY 10595, USA, 3Graduate Program in Genetics and 4Graduate Program in Neurobiology and Behavior, State University of New York at Stonybrook, NY 11794, USA, 5Biophysics and Physiology, University of California, Irvine, CA 92697, USA and 6Cologne Center for Genetics and Institute for Genetics, University of Cologne, 50674 Cologne, Germany
* To whom correspondence should be addressed. Tel: +1 5163678811; fax: +1 5163678000. Email: zhongyi{at}cshl.edu
Received December 8, 2005; Accepted February 7, 2006
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 G
s. This is the first demonstration in a metazoan that a receptor tyrosine kinase (RTK) pathway, acting independently of the heterotrimeric G-protein subunit Gs, can activate AC. We also show that Gs is the major G isoform in fly brains, and define a second AC pathway stimulated by serotonin and histamine requiring NF1 and Gs, as well as a third, classical Gs-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/Gs-dependent neurotransmitter stimulated AC activity, and for rescue of body size defects in Nf1 mutant flies.
The authors wish it to be known that, in their opinion, the first three authors should be considered as joint First Authors.
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