title: Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage.
abstract: Cells undergo apoptosis upon exposure to severe DNA damage stress. Under this condition, p73 is phosphorylated and activated by c-Abl. The transcription coactivator Yap1 binds p73 to generate a complex that escapes p73 proteasomal degradation and recruits p300 to support transcription of proapoptotic genes. However, the mechanism of selective activation of proapoptotic genes by Yap1 remained unclear. In this study, we show that c-Abl directly phosphorylates Yap1 at position Y357 in response to DNA damage. Tyrosine-phosphorylated Yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes. Furthermore, we show that Yap1 switches between p73-mediated proapoptotic and growth arrest target genes based on its phosphorylation state. Thus, our data demonstrate that modification of a transcription coactivator, namely the DNA damage-induced phosphorylation of Yap1 by c-Abl, influences the specificity of target gene activation.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Levy
authors.forename: Yaarit
authors.initials: Y
authors.lastname: Adamovich
authors.forename: Nina
authors.initials: N
authors.lastname: Reuven
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shaul
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics*; D001549:Benzamides; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays; D045325:HCT116 Cells; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D010879:Piperazines; D010957:Plasmids; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D010879:Piperazines; D011500:Protein Synthesis Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D014443:Tyrosine; D000068877:Imatinib Mesylate; D003513:Cycloheximide; D016315:Proto-Oncogene Proteins c-abl; D002945:Cisplatin