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Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent.

Journal article
Authors Jikui Guan
Georg Wolfstetter
Joachim T. Siaw
Damini Chand
Fredrik Hugosson
Ruth H. Palmer
Bengt Hallberg
Published in Oncotarget
Volume 2017
Issue 8
Pages 11566-11578
ISSN 1949-2553
Publication year 2017
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 11566-11578
Language en
Links dx.doi.org/10.18632/oncotarget.1414...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Cell and Molecular Biology

Abstract

Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALK-G1201E mutations were originally identified in anaplastic thyroid cancer (ATC) and characterized as constitutively activating mutations. In this study, we employed in vitro cell culture assays together with biochemical and in vivo Drosophila analyses to characterize their sensitivity to either activation by the FAM150A (AUG-β) and FAM150B (AUG-α) ALK ligands or inhibition by ALK inhibitors. Here we report that neither ALK-L1198F nor ALK-G1201E mutations result in ligand independent gain-of-function (GOF) activity in either in vitro biochemical analysis or the various model systems employed. ALK-L1198F is activated by the FAM150 (AUG) ligands and its ligand-dependant activity is similar to the wild type full length ALK receptor. ALK-G1201E is only very weakly activated by the FAM150 (AUG) ligands, most likely due to impaired protein stability. We conclude that neither ALK-L1198F nor ALK-G1201E displays ligand independent kinase activity, with ALK-L1198F belonging to the class of ligand dependent ALK mutations which are not constitutively active but that responds to ligand activation, while the ALK-G1201E mutation generates an unstable receptor with very low levels of kinase activity.

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