An Evolutionary Conserved Role for Anaplastic Lymphoma Kinase in Behavioral Responses to Ethanol

Lasek, Amy W.; Lim, Jana P.; Kliethermes, Christopher L.; Berger, Karen H.; Joslyn, Geoff; Brush, Gerry; Xue, Liquan; Robertson, Margaret; Moore, Monica; Vranizan, Karen; Morris, Stephan W.; Schuckit, Marc A.; White, R.; Heberlein, Ulrike

doi:10.1371/journal.pone.0022636

Cited by 98 publications

(122 citation statements)

References 55 publications

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“…A more detailed analysis of Alk knockout mice revealed an increase in the number of hippocampal progenitor cells in the brain and an enhanced performance in a test of novel object recognition. Another strain of such mice manifested increased ethanol consumption compared with heterozygous controls (6). These observations thus suggest that ALK may contribute to behavioral control in adult mice.…”

Section: Introductionmentioning

confidence: 79%

ALKoma: A Cancer Subtype with a Shared Target

2012

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Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that is currently the focus of much attention in oncology. ALK is rendered oncogenic as a result of its fusion to NPM1 in anaplastic large cell lymphoma, to TPM3 or TPM4 in inflammatory myofibroblastic tumor, to EML4 in non–small cell lung carcinoma, and to VCL in renal medullary carcinoma. It is also activated as a result of missense mutations in neuroblastoma and anaplastic thyroid cancer. Whereas these various tumors arise in different organs, they share activated ALK, and a marked clinical efficacy with ALK inhibitors has already been shown for some of the tumors with ALK fusions. One of such compound, crizotinib, is now approved in the United States for the treatment of lung cancer positive for ALK rearrangement. I propose that tumors carrying abnormal ALK as an essential growth driver be collectively termed “ALKoma.” Significance: ALK acquires transforming ability through gene fusion or missense mutation in a wide range of human cancers. Some of these cancers, which I propose be collectively referred to as “ALKoma,” may all be effectively treated with small compounds or antibodies targeted to activated ALKs. Cancer Discov; 2(6); 495–502. © 2012 AACR.

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Section: Introductionmentioning

confidence: 79%

ALKoma: A Cancer Subtype with a Shared Target

2012

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“…Each species in the OR1 clade except D. melanogaster contained a single ortholog, which is named AAEL001915 in A. aegypti. Our phylogeny indicated that OR1 also grouped with two other clades: the IR and homologs of human anaplastic lymphoma kinase (ALK), which in D. melanogaster is implicated in development, learning, and ethanol sensitivity (18,19) (Fig. 1A).…”

Section: Significancementioning

confidence: 99%

Ovary ecdysteroidogenic hormone requires a receptor tyrosine kinase to activate egg formation in the mosquito Aedes aegypti

Vogel

Brown

Strand

2015

Proc. Natl. Acad. Sci. U.S.A.

116

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Mosquitoes are major disease vectors because most species must feed on blood from a vertebrate host to produce eggs. Blood feeding by the vector mosquito Aedes aegypti triggers the release of two neurohormones, ovary ecdysteroidogenic hormone (OEH) and insulin-like peptides (ILPs), which activate multiple processes required for egg formation. ILPs function by binding to the insulin receptor, which activates downstream components in the canonical insulin signaling pathway. OEH in contrast belongs to a neuropeptide family called neuroparsins, whose receptor is unknown. Here we demonstrate that a previously orphanized receptor tyrosine kinase (RTK) from A. aegypti encoded by the gene AAEL001915 is an OEH receptor. Phylogenetic studies indicated that the protein encoded by this gene, designated AAEL001915, belongs to a clade of RTKs related to the insulin receptor, which are distinguished by an extracellular Venus flytrap module. Knockdown of AAEL001915 by RNAi disabled OEH-mediated egg formation in A. aegypti. AAEL001915 was primarily detected in the mosquito ovary in association with follicular epithelial cells. Both monomeric and dimeric AAEL001915 were detected in mosquito ovaries and transfected Drosophila S2 cells. Functional assays further indicated that OEH bound to dimeric AAEL001915, which resulted in downstream phosphorylation of Ak strain transforming factor (Akt). We hypothesize that orthologs of AAEL001915 in other insects are neuroparsin receptors.insect | vector | reproduction | mosquito | oogenesis

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“…The powerful genetic approaches available in Drosophila through mutant studies and transgenic manipulations of spatial and temporal gene expression provide a system that allows rapid progress in identifying the underlying cellular and molecular mechanisms for complex behaviors. The use of Drosophila as an investigative tool has permitted substantive advances in understanding alcohol neurobiology that can be rapidly translated to mammals [14][15][16] . In order to facilitate understanding of the molecular mechanisms through which the circadian clock modulates alcohol sensitivity and to uniformly measure behavioral responses across circadian time points, an alcohol administration protocol suitable for use in dim red light conditions is required.…”

Section: Introductionmentioning

confidence: 99%

The FlyBar: Administering Alcohol to Flies

Linde

Fumagalli

Roman

et al. 2014

JoVE

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Fruit flies (Drosophila melanogaster) are an established model for both alcohol research and circadian biology. Recently, we showed that the circadian clock modulates alcohol sensitivity, but not the formation of tolerance. Here, we describe our protocol in detail. Alcohol is administered to the flies using the FlyBar. In this setup, saturated alcohol vapor is mixed with humidified air in set proportions, and administered to the flies in four tubes simultaneously. Flies are reared under standardized conditions in order to minimize variation between the replicates. Three-day old flies of different genotypes or treatments are used for the experiments, preferably by matching flies of two different time points (e.g., CT 5 and CT 17) making direct comparisons possible. During the experiment, flies are exposed for 1 hr to the pre-determined percentage of alcohol vapor and the number of flies that exhibit the Loss of Righting reflex (LoRR) or sedation are counted every 5 min. The data can be analyzed using three different statistical approaches. The first is to determine the time at which 50% of the flies have lost their righting reflex and use an Analysis of the Variance (ANOVA) to determine whether significant differences exist between time points. The second is to determine the percentage flies that show LoRR after a specified number of minutes, followed by an ANOVA analysis. The last method is to analyze the whole times series using multivariate statistics. The protocol can also be used for non-circadian experiments or comparisons between genotypes. Video LinkThe video component of this article can be found at

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An Evolutionary Conserved Role for Anaplastic Lymphoma Kinase in Behavioral Responses to Ethanol

Cited by 98 publications

References 55 publications

ALKoma: A Cancer Subtype with a Shared Target

ALKoma: A Cancer Subtype with a Shared Target

Ovary ecdysteroidogenic hormone requires a receptor tyrosine kinase to activate egg formation in the mosquito Aedes aegypti

The FlyBar: Administering Alcohol to Flies

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