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Cancers 2017, 9(11), 149; https://doi.org/10.3390/cancers9110149

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

1
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy, University of Gothenburg, SE-40530 Göteborg, Sweden
2
Department of Molecular Biology, Umeå universtiy, SE-901-87 Umeå, Sweden
*
Author to whom correspondence should be addressed.
Academic Editor: Samuel C. Mok
Received: 14 August 2017 / Revised: 9 October 2017 / Accepted: 23 October 2017 / Published: 30 October 2017
(This article belongs to the Special Issue Targeting ALK in Cancer)
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Abstract

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). View Full-Text
Keywords: ALK; kinase activation; activation loop; gain-of-function; mutation analyses; Insulin receptor; NPM-ALK; oncogene; neuroblastoma ALK; kinase activation; activation loop; gain-of-function; mutation analyses; Insulin receptor; NPM-ALK; oncogene; neuroblastoma
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Guan, J.; Yamazaki, Y.; Chand, D.; van Dijk, J.R.; Ruuth, K.; Palmer, R.H.; Hallberg, B. Novel Mechanisms of ALK Activation Revealed by Analysis of the Y1278S Neuroblastoma Mutation. Cancers 2017, 9, 149.

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