The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning.
The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning.
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DOI：
10.1371/journal.pgen.1002281
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发表时间：
2011-09
期刊：
影响因子：
4.5
通讯作者：
Skoulakis EM
中科院分区：
文献类型：
--
作者：
Gouzi JY;Moressis A;Walker JA;Apostolopoulou AA;Palmer RH;Bernards A;Skoulakis EM
Anaplastic Lymphoma Kinase (Alk) is a Receptor Tyrosine Kinase (RTK) activated in several cancers, but with largely unknown physiological functions. We report two unexpected roles for the Drosophila ortholog dAlk, in body size determination and associative learning. Remarkably, reducing neuronal dAlk activity increased body size and enhanced associative learning, suggesting that its activation is inhibitory in both processes. Consistently, dAlk activation reduced body size and caused learning deficits resembling phenotypes of null mutations in dNf1, the Ras GTPase Activating Protein-encoding conserved ortholog of the Neurofibromatosis type 1 (NF1) disease gene. We show that dAlk and dNf1 co-localize extensively and interact functionally in the nervous system. Importantly, genetic or pharmacological inhibition of dAlk rescued the reduced body size, adult learning deficits, and Extracellular-Regulated-Kinase (ERK) overactivation dNf1 mutant phenotypes. These results identify dAlk as an upstream activator of dNf1-regulated Ras signaling responsible for several dNf1 defects, and they implicate human Alk as a potential therapeutic target in NF1. Neurofibromatosis-1 (NF1) syndrome is a common (1/3,000 births) genetic disorder affecting multiple organ systems, including the nervous system. Its clinical features include short stature, learning disabilities, and several types of benign and malignant tumors. NF1 is caused by mutations that inactivate the NF1 gene, a crucial negative regulator of Ras signaling. Although unregulated Ras signaling is a hallmark of NF1, the specific Ras signaling pathways responsible for disease development remain largely unknown. The Drosophila and human Nf1 genes are highly conserved; and, as in patients, mutant flies are smaller than usual and present deficient learning. Here, we identified the Drosophila Receptor Tyrosine Kinase dAlk as a negative regulator of organismal growth and olfactory learning. We show that excessive dAlk activation results in growth and learning defects similar to those of Nf1 mutants. Genetic suppression studies and pharmacological inhibition indicate dAlk as a critical upstream activator of Nf1-regulated neuronal Ras/ERK signals that contribute to size determination and learning. Importantly, our results strongly suggest that Alk represents a novel, highly specific, and promising therapeutic target in human NF1.
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影响因子：
34.7
作者：
Lee, Yong-Seok;Silva, Alcino J.
通讯作者：
Silva, Alcino J.
ERK信号传导的神经纤维素调节调节GABA释放和学习。
影响因子：
64.5
作者：
Cui Y;Costa RM;Murphy GG;Elgersma Y;Zhu Y;Gutmann DH;Parada LF;Mody I;Silva AJ
通讯作者：
Silva AJ
影响因子：
4
作者：
Gouzi, JY;Moog-Lutz, C;Brunet-de Carvalho, N
通讯作者：
Brunet-de Carvalho, N
影响因子：
3.3
作者：
Kunugi, H.;Hashimoto, R.;Saitoh, O.
通讯作者：
Saitoh, O.
影响因子：
9.2
作者：
Brogiolo, W;Stocker, H;Hafen, E
通讯作者：
Hafen, E