Phosphorylation of Ewing's sarcoma protein (EWS) and EWS-Fli1 in response to DNA damage.
In Ewing's sarcomas, chromosomal translocations 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 p38alpha/p38beta MAPKs. MMS induced a much stronger phosphorylation of EWS-Fli1 than EWS in heterodimers comprising both proteins.
Klevernic
Iva V
IV
MRC Protein Phosphorylation Unit, The Sir James Black Centre, University of Dundee, Dundee, Scotland, U.K.
Morton
Simon
S
Davis
Roger J
RJ
Cohen
Philip
P
D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008741:Methyl Methanesulfonate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009281:Naphthalenes; D015514:Oncogene Proteins, Fusion; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D051789:Proto-Oncogene Protein c-fli-1; D011720:Pyrazoles; D034802:RNA-Binding Protein EWS; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C106031:EWS-FLI fusion protein; C576324:ATM protein, human; C576597:ATR protein, human; C452139:doramapimod; D010671:Phenylurea Compounds