Phosphorylation of Ewing's sarcoma protein (EWS) and EWS-Fli1 in response to DNA damage

Iva V. Klevernic, Simon Morton, Roger J. Davis, Philip Cohen

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    19 Citations (Scopus)

    Abstract

    In Ewing's sarcomas, chromosomal trans locations cause the N-terminal domain of the EWS (Ewing's sarcoma protein) to fuse with the DNA-binding domains of the Ets (E26 transformation-specific) family of transcription factors. Here we show that EWS and EWS-Fli1 (Friend leukaemia virus integration 1), the fusion most frequently found in Ewing's sarcomas, become phosphorylated at Thr(79) in response to either mitogens or DNA-damaging agents. The much weaker mitogen-induced phosphorylation of EWS is catalysed by the MAPKs (mitogen-activated protein kinases) ERK1 (extracellular signal-regulated kinase 1) and ERK2, whereas the much stronger phosphorylation of EWS induced by the DNA alkylating agent MMS (methyl methanesulphonate) can be catalysed by JNK (c-Jun N-terminal kinase) and at least one other protein kinase distinct from ERK1/ERK2. In contrast, the phosphorylation of EWS-Fli1 induced by MMS was largely mediated by p38 alpha/p38 beta MAPKs. MMS induced a much stronger phosphorylation of EWS-Fli1 than EWS in heterodimers comprising both proteins.

    Original languageEnglish
    Pages (from-to)625-634
    Number of pages10
    JournalBiochemical Journal
    Volume418
    DOIs
    Publication statusPublished - 15 Mar 2009

    Keywords

    • c-Jun N-terminal kinase (JNK)
    • DNA damage
    • Ewing's sarcoma
    • Ewing's sarcoma protein (EWS)
    • EWS-Fli1
    • p38 MAPK (mitogen-activated protein kinase)
    • EWS/FLI-1 FUSION GENE
    • RNA-BINDING PROTEIN
    • TRANSCRIPTIONAL ACTIVATOR
    • CHROMOSOME-TRANSLOCATION
    • MALIGNANT-MELANOMA
    • MEDIATE ACTIVATION
    • TYROSINE KINASE
    • POLYMERASE-II
    • SOFT PARTS
    • IQ DOMAIN

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