Identification of the Wallenda JNKKK as an Alk suppressor reveals increased competitiveness of Alk-expressing cells.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
11 09 2020
11 09 2020
Historique:
received:
16
12
2019
accepted:
05
08
2020
entrez:
12
9
2020
pubmed:
13
9
2020
medline:
15
12
2020
Statut:
epublish
Résumé
Anaplastic lymphoma kinase (Alk) is a receptor tyrosine kinase of the insulin receptor super-family that functions as oncogenic driver in a range of human cancers such as neuroblastoma. In order to investigate mechanisms underlying Alk oncogenic signaling, we conducted a genetic suppressor screen in Drosophila melanogaster. Our screen identified multiple loci important for Alk signaling, including members of Ras/Raf/ERK-, Pi3K-, and STAT-pathways as well as tailless (tll) and foxo whose orthologues NR2E1/TLX and FOXO3 are transcription factors implicated in human neuroblastoma. Many of the identified suppressors were also able to modulate signaling output from activated oncogenic variants of human ALK, suggesting that our screen identified targets likely relevant in a wide range of contexts. Interestingly, two misexpression alleles of wallenda (wnd, encoding a leucine zipper bearing kinase similar to human DLK and LZK) were among the strongest suppressors. We show that Alk expression leads to a growth advantage and induces cell death in surrounding cells. Our results suggest that Alk activity conveys a competitive advantage to cells, which can be reversed by over-expression of the JNK kinase kinase Wnd.
Identifiants
pubmed: 32917927
doi: 10.1038/s41598-020-70890-6
pii: 10.1038/s41598-020-70890-6
pmc: PMC7486895
doi:
Substances chimiques
Drosophila Proteins
0
Anaplastic Lymphoma Kinase
EC 2.7.10.1
MAP Kinase Kinase Kinases
EC 2.7.11.25
wnd protein, Drosophila
EC 2.7.11.25
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14954Références
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