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PMID:12813029

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Citation

Zhang, R, He, X, Liu, W, Lu, M, Hsieh, JT and Min, W (2003) AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. J. Clin. Invest. 111:1933-43

Abstract

TNF-alpha activates ASK1 in part by dissociating 14-3-3 from apoptosis signal-regulating kinase 1 (ASK1). In the present study, we identified a novel Ras GTPase-activating protein (Ras-GAP) as an ASK1-interacting protein (AIP1). AIP1 binds to the C-terminal domain of ASK1 via a lysine-rich cluster within the N-terminal C2 domain. AIP1 exists in a closed form through an intramolecular interaction between the N-terminus and the C-terminus, and TNF-alpha induces unfolding of AIP1 leading to association of AIP1 with ASK1. Thus, the N-terminus of AIP1 containing the C2 and GAP domains constitutively binds to ASK1 and facilitates the release of 14-3-3 from ASK1. In contrast to 14-3-3, AIP1 binds preferentially to dephosphorylated ASK1. Recruited AIP1 enhances ASK1-induced JNK activation, and the ASK1 binding and the GAP activity of AIP1 are critical for AIP1-enhanced ASK1 activation. Furthermore, TNF-induced ASK1/JNK activation is significantly blunted in cells where AIP1 is knocked down by RNA interference. These data suggest that AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating dissociation of inhibitor 14-3-3 from ASK1, a novel mechanism by which TNF-alpha activates ASK1.

Links

PubMed PMC161425 Online version:10.1172/JCI17790

Keywords

14-3-3 Proteins; Amino Acid Sequence; Animals; Apoptosis/physiology; Base Sequence; Cattle; Cells, Cultured; DNA, Complementary/genetics; Endothelium, Vascular/metabolism; Enzyme Activation; Enzyme Inhibitors/metabolism; HeLa Cells; Humans; MAP Kinase Kinase Kinase 5; MAP Kinase Kinase Kinases/antagonists & inhibitors; MAP Kinase Kinase Kinases/genetics; MAP Kinase Kinase Kinases/physiology; MAP Kinase Signaling System; Molecular Sequence Data; Recombinant Proteins/antagonists & inhibitors; Recombinant Proteins/genetics; Tumor Necrosis Factor-alpha/physiology; Two-Hybrid System Techniques; Tyrosine 3-Monooxygenase/metabolism; ras GTPase-Activating Proteins/chemistry; ras GTPase-Activating Proteins/genetics; ras GTPase-Activating Proteins/physiology

Significance

Annotations

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

HUMAN:TNFA

involved_in

GO:0031334: positive regulation of protein-containing complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0043243: positive regulation of protein-containing complex disassembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAB2P

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q5VWQ8

F

Seeded From UniProt

complete

HUMAN:DAB2P

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99683

F

Seeded From UniProt

complete

HUMAN:DAB2P

involved_in

GO:0007257: activation of JUN kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAB2P

enables

GO:0031435: mitogen-activated protein kinase kinase kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99683

F

Seeded From UniProt

complete

HUMAN:DAB2P

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q5VWQ8

F

Seeded From UniProt

complete

HUMAN:DAB2P

involved_in

GO:0071356: cellular response to tumor necrosis factor

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DAB2P

involved_in

GO:0043407: negative regulation of MAP kinase activity

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:Q5VWQ8

F

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0043406: positive regulation of MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0043243: positive regulation of protein complex disassembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0031334: positive regulation of protein complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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