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PMID:21771788

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Citation

Seong, HA, Jung, H, Manoharan, R and Ha, H (2011) Positive regulation of apoptosis signal-regulating kinase 1 signaling by ZPR9 protein, a zinc finger protein. J. Biol. Chem. 286:31123-35

Abstract

A zinc finger protein, ZPR9, has been identified as a physiological substrate of murine protein serine/threonine kinase 38 (MPK38), which is involved in various cellular responses, including the cell cycle, apoptosis, embryonic development, and oncogenesis. Here, ZPR9 was found to physically interact with apoptosis signal-regulating kinase 1 (ASK1) through a disulfide linkage involving Cys(1351) and Cys(1360) of ASK1 and Cys(305) and Cys(308) of ZPR9. ASK1 directly phosphorylated ZPR9 at Ser(314) and Thr(318), suggesting that ZPR9 can act as an ASK1 substrate. Ectopic expression of wild-type ZPR9, but not an S314A/T318A mutant, stimulated ASK1 kinase activity and positively regulated ASK1-mediated signaling to both JNK and p38 kinases by destabilizing complex formation between ASK1 and its negative regulators, Trx and 14-3-3, or by increasing complex formation between ASK1 and its substrate MKK3. ZPR9 functionally stimulated ASK1-induced AP-1 transcriptional activity as well as H(2)O(2)-mediated apoptosis in a phosphorylation-dependent manner. ASK1-mediated phosphorylation of ZPR9 at Ser(314) and Thr(318) was also responsible for ZPR9-induced apoptosis. Moreover, ZPR9 inhibited PDK1-mediated signaling through ASK1 activation. These results suggest that ZPR9 functions as a novel positive regulator of ASK1.

Links

PubMed PMC3173094 Online version:10.1074/jbc.M111.248674

Keywords

Animals; Apoptosis; Cell Line; Disulfides; Humans; Intracellular Signaling Peptides and Proteins/metabolism; MAP Kinase Kinase 3; MAP Kinase Kinase Kinase 5/metabolism; Mice; Nuclear Proteins/metabolism; Phosphoproteins/metabolism; Phosphorylation; Protein Binding; Signal Transduction; Transcription, Genetic; Zinc Fingers

Significance

Annotations

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

HUMAN:THIO

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99683

F

Seeded From UniProt

complete

HUMAN:1433B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99683

F

Seeded From UniProt

complete

HUMAN:MP2K3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99683

F

Seeded From UniProt

complete

HUMAN:ZN622

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99683

F

Seeded From UniProt

complete

HUMAN:ZN622

involved_in

GO:0033674: positive regulation of kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ZN622

involved_in

GO:0008631: intrinsic apoptotic signaling pathway in response to oxidative stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ZN622

involved_in

GO:0046330: positive regulation of JNK cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ZN622

involved_in

GO:0043410: positive regulation of MAPK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ZN622

involved_in

GO:0043065: positive regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:M3K5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P10599

F

Seeded From UniProt

complete

HUMAN:M3K5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31946

F

Seeded From UniProt

complete

HUMAN:M3K5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46734

F

Seeded From UniProt

complete

HUMAN:M3K5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q969S3

F

Seeded From UniProt

complete

HUMAN:M3K5

involved_in

GO:0043065: positive regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:M3K5

involved_in

GO:0008631: intrinsic apoptotic signaling pathway in response to oxidative stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:M3K5

involved_in

GO:0007254: JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:M3K5

enables

GO:0004672: protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:M3K5

involved_in

GO:0000165: MAPK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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