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PMID:18280240

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Citation

Levy, D, Adamovich, Y, Reuven, N and Shaul, Y (2008) Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol. Cell 29:350-61

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.

Links

PubMed Online version:10.1016/j.molcel.2007.12.022

Keywords

Adaptor Proteins, Signal Transducing/analysis; Adaptor Proteins, Signal Transducing/chemistry; Adaptor Proteins, Signal Transducing/metabolism; Apoptosis/genetics; Cell Line; Cell Line, Tumor; Cisplatin/pharmacology; Cycloheximide/pharmacology; DNA Damage; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Gamma Rays; HCT116 Cells; Half-Life; HeLa Cells; Humans; Kidney/cytology; Kinetics; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Phosphoproteins/analysis; Phosphoproteins/chemistry; Phosphoproteins/metabolism; Phosphorylation; Piperazines; Plasmids; Protein Structure, Tertiary; Protein Synthesis Inhibitors/pharmacology; Proto-Oncogene Proteins c-abl/physiology; Pyrimidines/pharmacology; RNA, Messenger/analysis; RNA, Messenger/metabolism; Transfection; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Tyrosine/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:P73

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46937

F

Seeded From UniProt

complete

HUMAN:YAP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q01196

F

Seeded From UniProt

complete

HUMAN:YAP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15350

F

Seeded From UniProt

complete

HUMAN:YAP1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:YAP1

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RUNX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46937

F

Seeded From UniProt

complete

HUMAN:ABL1

involved_in

GO:0006975: DNA damage induced protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:YAP1

enables

GO:0003713: transcription coactivator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:YAP1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:YAP1

involved_in

GO:0006974: cellular response to DNA damage stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:YAP1

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:YAP1

involved_in

GO:0071480: cellular response to gamma radiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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