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Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligandindependent

Guan, Jikui ; Wolfstetter, Georg ; Siaw, Joachim LU orcid ; Chand, Damini ; Hugosson, Fredrik ; Palmer, Ruth H. and Hallberg, Bengt (2017) In Oncotarget 8(7). p.11566-11578
Abstract

Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALKG1201E 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 gainof- function (GOF) activity in either in vitro biochemical analysis or the various model systems... (More)

Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALKG1201E 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 gainof- 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. ALKG1201E 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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author
; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
ATC, Brigatinib, Ceritinib, Crizotinib, Neuroblastom
in
Oncotarget
volume
8
issue
7
pages
11566 - 11578
publisher
Impact Journals
external identifiers
  • scopus:85012935408
  • pmid:28030793
ISSN
1949-2553
DOI
10.18632/oncotarget.14141
language
English
LU publication?
no
id
30122969-d2dd-48ed-a825-c6f5b4d105a5
date added to LUP
2025-03-19 11:49:00
date last changed
2025-06-25 20:09:03
@article{30122969-d2dd-48ed-a825-c6f5b4d105a5,
  abstract     = {{<p>Activating mutations in full length anaplastic lymphoma kinase (ALK) have been reported in neuroblastoma and in anaplastic thyroid cancer. ALK-L1198F and ALKG1201E 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 gainof- 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. ALKG1201E 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.</p>}},
  author       = {{Guan, Jikui and Wolfstetter, Georg and Siaw, Joachim and Chand, Damini and Hugosson, Fredrik and Palmer, Ruth H. and Hallberg, Bengt}},
  issn         = {{1949-2553}},
  keywords     = {{ATC; Brigatinib; Ceritinib; Crizotinib; Neuroblastom}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{11566--11578}},
  publisher    = {{Impact Journals}},
  series       = {{Oncotarget}},
  title        = {{Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligandindependent}},
  url          = {{http://dx.doi.org/10.18632/oncotarget.14141}},
  doi          = {{10.18632/oncotarget.14141}},
  volume       = {{8}},
  year         = {{2017}},
}