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

Cancers
Jikui GuanB Hallberg

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 ...Continue Reading

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Citations

Jun 17, 2018·Cold Spring Harbor Molecular Case Studies·Jikui GuanBengt Hallberg
Mar 7, 2021·Proceedings of the National Academy of Sciences of the United States of America·Keshav PatilRavi Radhakrishnan

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Methods Mentioned

BETA
transfection

Software Mentioned

GraphPad Prism
COSMIC
GenScript
Image Studio Lite

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