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PMID:12944463

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Citation

Chiang, CW, Kanies, C, Kim, KW, Fang, WB, Parkhurst, C, Xie, M, Henry, T and Yang, E (2003) Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis. Mol. Cell. Biol. 23:6350-62

Abstract

BAD, a proapoptotic molecule of the BCL2 family, is regulated by reversible phosphorylation. During survival, BAD is sequestered by 14-3-3 through serine 136 phosphorylation and is dissociated from BCL-X(L) through serine 155 phosphorylation. We report that phosphoserine 112 (pSer112) dephosphorylation functions as a gatekeeper for BAD-mediated apoptosis. During apoptosis, dephosphorylation of pSer112 preceded pSer136 dephosphorylation. Dephosphorylation of pSer112 accelerated dephosphorylation of pSer136, and inhibition of pSer112 dephosphorylation prevented pSer136 dephosphorylation, indicating that dephosphorylation of pSer112 is required for dephosphorylation of pSer136. Protein phosphatase 2A (PP2A) is the major pSer112 phosphatase. PP2A competed with 14-3-3 for BAD binding, and survival factor withdrawal enhanced PP2A association with BAD. Dephosphorylation of the critical residue, pSer136, could only be blocked by inhibition of all known subfamilies of serine/threonine phosphatases, suggesting that multiple phosphatases are involved in pSer136 dephosphorylation. Inhibition of PP2A rescued FL5.12 cells from apoptosis, demonstrating a physiologic role for PP2A-mediated pSer112 dephosphorylation. Thus, PP2A dephosphorylation of pSer112 is the key initiating event regulating the activation of BAD during interleukin-3 withdrawal-induced apoptosis.

Links

PubMed PMC193703

Keywords

14-3-3 Proteins; 3T3 Cells; Animals; Apoptosis/physiology; Binding Sites; Binding, Competitive; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cells, Cultured; Enzyme Inhibitors/pharmacology; Humans; Mice; Mutation; Oxazoles/pharmacology; Phosphoprotein Phosphatases/antagonists & inhibitors; Phosphoprotein Phosphatases/genetics; Phosphoprotein Phosphatases/metabolism; Phosphorylation; Phosphoserine/metabolism; Protein Phosphatase 2; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; Tyrosine 3-Monooxygenase/metabolism; bcl-Associated Death Protein; bcl-X Protein

Significance

Annotations

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

MOUSE:IL3

involved_in

GO:0097192: extrinsic apoptotic signaling pathway in absence of ligand

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IL3

involved_in

GO:0035304: regulation of protein dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:1433Z

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q61337

F

Seeded From UniProt

complete

MOUSE:1433T

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q61337

F

Seeded From UniProt

complete

MOUSE:BAD

involved_in

GO:0097192: extrinsic apoptotic signaling pathway in absence of ligand

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAD

enables

GO:0019903: protein phosphatase binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q76MZ3

F

Seeded From UniProt

complete

MOUSE:BAD

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P68254

F

Seeded From UniProt

complete

MOUSE:BAD

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P63104

F

Seeded From UniProt

complete

MOUSE:2AAA

involved_in

GO:0070262: peptidyl-serine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:2AAA

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:2AAA

involved_in

GO:2001241: positive regulation of extrinsic apoptotic signaling pathway in absence of ligand

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:2AAA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q61337

F

Seeded From UniProt

complete

MOUSE:BAD

enables

GO:0019903: protein phosphatase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q76MZ3

F

Seeded From UniProt

complete

MOUSE:BAD

acts_upstream_of_or_within

GO:0097192: extrinsic apoptotic signaling pathway in absence of ligand

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IL3

acts_upstream_of_or_within

GO:0035304: regulation of protein dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

regulates_o_has_input:(MGI:MGI:1096330)

Seeded From UniProt

complete

MOUSE:IL3

acts_upstream_of_or_within

GO:0097192: extrinsic apoptotic signaling pathway in absence of ligand

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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