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Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation

Numerous mutations have been observed in the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) in both germline and sporadic neuroblastoma. Here, we have investigated the Y1278S mutation, observed in four patient cases, and its potential importance in the activation of the full length...

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Autores principales: Guan, Jikui, Yamazaki, Yasuo, Chand, Damini, van Dijk, Jesper R., Ruuth, Kristina, Palmer, Ruth H., Hallberg, Bengt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704167/
https://www.ncbi.nlm.nih.gov/pubmed/29084134
http://dx.doi.org/10.3390/cancers9110149
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author Guan, Jikui
Yamazaki, Yasuo
Chand, Damini
van Dijk, Jesper R.
Ruuth, Kristina
Palmer, Ruth H.
Hallberg, Bengt
author_facet Guan, Jikui
Yamazaki, Yasuo
Chand, Damini
van Dijk, Jesper R.
Ruuth, Kristina
Palmer, Ruth H.
Hallberg, Bengt
author_sort Guan, Jikui
collection PubMed
description Numerous mutations have been observed in the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) in both germline and sporadic neuroblastoma. Here, we have investigated the Y1278S mutation, observed in four patient cases, and its potential importance in the activation of the full length ALK receptor. Y1278S is located in the 1278-YRASYY-1283 motif of the ALK activation loop, which has previously been reported to be important in the activation of the ALK kinase domain. In this study, we have characterized activation loop mutations within the context of the full length ALK employing cell culture and Drosophila melanogaster model systems. Our results show that the Y1278S mutant observed in patients with neuroblastoma harbors gain-of-function activity. Secondly, we show that the suggested interaction between Y1278 and other amino acids might be of less importance in the activation process of the ALK kinase than previously proposed. Thirdly, of the three individual tyrosines in the 1278-YRASYY-1283 activation loop, we find that Y1283 is the critical tyrosine in the activation process. Taken together, our observations employing different model systems reveal new mechanistic insights on how the full length ALK receptor is activated and highlight differences with earlier described activation mechanisms observed in the NPM-ALK fusion protein, supporting a mechanism of activation more in line with those observed for the Insulin Receptor (InR).
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spelling pubmed-57041672017-11-30 Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation Guan, Jikui Yamazaki, Yasuo Chand, Damini van Dijk, Jesper R. Ruuth, Kristina Palmer, Ruth H. Hallberg, Bengt Cancers (Basel) Article Numerous mutations have been observed in the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) in both germline and sporadic neuroblastoma. Here, we have investigated the Y1278S mutation, observed in four patient cases, and its potential importance in the activation of the full length ALK receptor. Y1278S is located in the 1278-YRASYY-1283 motif of the ALK activation loop, which has previously been reported to be important in the activation of the ALK kinase domain. In this study, we have characterized activation loop mutations within the context of the full length ALK employing cell culture and Drosophila melanogaster model systems. Our results show that the Y1278S mutant observed in patients with neuroblastoma harbors gain-of-function activity. Secondly, we show that the suggested interaction between Y1278 and other amino acids might be of less importance in the activation process of the ALK kinase than previously proposed. Thirdly, of the three individual tyrosines in the 1278-YRASYY-1283 activation loop, we find that Y1283 is the critical tyrosine in the activation process. Taken together, our observations employing different model systems reveal new mechanistic insights on how the full length ALK receptor is activated and highlight differences with earlier described activation mechanisms observed in the NPM-ALK fusion protein, supporting a mechanism of activation more in line with those observed for the Insulin Receptor (InR). MDPI 2017-10-30 /pmc/articles/PMC5704167/ /pubmed/29084134 http://dx.doi.org/10.3390/cancers9110149 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guan, Jikui
Yamazaki, Yasuo
Chand, Damini
van Dijk, Jesper R.
Ruuth, Kristina
Palmer, Ruth H.
Hallberg, Bengt
Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation
title Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation
title_full Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation
title_fullStr Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation
title_full_unstemmed Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation
title_short Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation
title_sort novel mechanisms of alk activation revealed by analysis of the y1278s neuroblastoma mutation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704167/
https://www.ncbi.nlm.nih.gov/pubmed/29084134
http://dx.doi.org/10.3390/cancers9110149
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