Identification of the Wallenda JNKKK as an Alk suppressor reveals increased competitiveness of Alk-expressing cells

Author:

Wolfstetter GeorgORCID,Pfeifer KathrinORCID,Backman Mattias,Masudi Tafheem A.,Mendoza-García PatriciaORCID,Chen Sa,Sonnenberg Hannah,Sukumar Sanjay K.,Uçkun Ezgi,Varshney Gaurav K.ORCID,Uv Anne,Palmer Ruth H.ORCID

Abstract

AbstractAnaplastic 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.

Funder

Carl Tryggers Stiftelse för Vetenskaplig Forskning

Cancerfonden

Barncancerfonden

Vetenskapsrådet

Stiftelsen för Strategisk Forskning

Knut och Alice Wallenbergs Stiftelse

Göran Gustafssons Stiftelse för Naturvetenskaplig och Medicinsk Forskning

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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