Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras
Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras
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DOI：
10.1093/hmg/ddl023
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发表时间：
2006-04-01
影响因子：
3.5
通讯作者：
Zhong, Y
中科院分区：
文献类型：
--
作者：
Hannan, F;Ho, I;Zhong, Y
I型神经纤维瘤病（NFI）是一种常见的遗传性疾病，可导致神经系统肿瘤，以及人类和动物模型的学习和记忆缺陷。我们确定了一种新的生长因子刺激的腺苷酸环化酶（AC）途径在果蝇脑，这是破坏的突变表皮生长因子受体（EGFR），神经纤维蛋白（NF 1）和Ras，但不是G α（s）。这是首次在后生动物中证明受体酪氨酸激酶（RTK）途径，独立于异源三聚体G蛋白亚基G α（s）发挥作用，可以激活AC。我们还表明，G α（s）是果蝇脑中主要的G α亚型，并定义了第二个AC通路，由血清素和组胺刺激，需要NF 1和G α（s），以及第三个，经典的G α（s）依赖性AC通路，这是由Phe-Met-Arg-Phe-amide（FMRFamide）和多巴胺刺激。使用突变和缺失的人NF 1蛋白（hNF 1）表达的NF 1突变苍蝇，我们表明，Ras激活hNF 1是必不可少的生长因子刺激AC活性。此外，我们证明，在C-末端区域的hNF 1的序列是足够的NF 1/G α（S）-依赖性神经递质刺激AC活动，并为拯救NF 1突变苍蝇的身体大小的缺陷。
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 alpha(s). This is the first demonstration in a metazoan that a receptor tyrosine kinase (RTK) pathway, acting independently of the heterotrimeric G-protein subunit G alpha(s), can activate AC. We also show that G alpha(s) is the major G alpha isoform in fly brains, and define a second AC pathway stimulated by serotonin and histamine requiring NF1 and G alpha(s), as well as a third, classical G alpha(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/G alpha(s)-dependent neurotransmitter stimulated AC activity, and for rescue of body size defects in Nf1 mutant flies.