Identification of the Wallenda JNKKK as an Alk suppressor reveals increased competitiveness of Alk-expressing cells
| Autor: | Kathrin Pfeifer, Ruth H. Palmer, Georg Wolfstetter, Sa Chen, Anne Uv, Patricia Mendoza-Garcia, Tafheem A Masudi, Mattias Backman, Ezgi Uçkun, SK Sukumar, Gaurav K. Varshney, Hannah Sonnenberg |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer microenvironment
MAPK/ERK pathway Cell- och molekylärbiologi lcsh:Medicine Genetic mapping Article Receptor tyrosine kinase hemic and lymphatic diseases Animals Drosophila Proteins Humans Anaplastic lymphoma kinase Anaplastic Lymphoma Kinase Cancer models lcsh:Science Transcription factor PI3K/AKT/mTOR pathway Multidisciplinary Cell Death biology Kinase Genetic interaction lcsh:R Transgenic organisms Oncogenes MAP Kinase Kinase Kinases Insulin receptor Drosophila melanogaster Differentiation Mutation biology.protein FOXO3 Cancer research Drosophila lcsh:Q Non-small-cell lung cancer Cell and Molecular Biology Cell signalling Signal Transduction |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-17 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-70890-6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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