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PMID:11559703

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Citation

Tan, KM, Chan, SL, Tan, KO and Yu, VC (2001) The Caenorhabditis elegans sex-determining protein FEM-2 and its human homologue, hFEM-2, are Ca2+/calmodulin-dependent protein kinase phosphatases that promote apoptosis. J. Biol. Chem. 276:44193-202

Abstract

In Caenorhabditis elegans, fem-1, fem-2, and fem-3 play pivotal roles in sex determination. Recently, a mammalian homologue of the C. elegans sex-determining protein FEM-1, F1Aalpha, has been described. Although there is little evidence to link F1Aalpha to sex determination, F1Aalpha and FEM-1 both promote apoptosis in mammalian cells. Here we report the identification and characterization of a human homologue of the C. elegans sex-determining protein FEM-2, hFEM-2. Similar to FEM-2, hFEM-2 exhibited PP2C phosphatase activity and associated with FEM-3. hFEM-2 shows striking similarity (79% amino acid identity) to rat Ca(2+)/calmodulin (CaM)-dependent protein kinase phosphatase (rCaMKPase). hFEM-2 and FEM-2, but not PP2Calpha, were demonstrated to dephosphorylate CaM kinase II efficiently in vitro, suggesting that hFEM-2 and FEM-2 are specific phosphatases for CaM kinase. Furthermore, hFEM-2 and FEM-2 associated with F1Aalpha and FEM-1 respectively. Overexpression of hFEM-2, FEM-2, or rCaMKPase all mediated apoptosis in mammalian cells. The catalytically active, but not the inactive, forms of hFEM-2 induced caspase-dependent apoptosis, which was blocked by Bcl-XL or a dominant negative mutant of caspase-9. Taken together, our data suggest that hFEM-2 and rCaMKPase are mammalian homologues of FEM-2 and they are evolutionarily conserved CaM kinase phosphatases that may have a role in apoptosis signaling.

Links

PubMed Online version:10.1074/jbc.M105880200

Keywords

Amino Acid Sequence; Animals; Apoptosis; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Cell Line; Helminth Proteins/chemistry; Helminth Proteins/metabolism; Humans; Mice; Molecular Sequence Data; Phosphoprotein Phosphatases; Phosphorylation; Sequence Homology, Amino Acid

Significance

Annotations

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

CAEEL:FEM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49593

F

Seeded From UniProt

complete

CAEEL:FEM3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49593

F

Seeded From UniProt

complete

HUMAN:PPM1A

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q8N5S9)

Seeded From UniProt

complete

HUMAN:PPM1F

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UK73

F

Seeded From UniProt

complete

HUMAN:PPM1F

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P34691

F

Seeded From UniProt

complete

HUMAN:PPM1F

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P17221

F

Seeded From UniProt

complete

HUMAN:PPM1F

enables

GO:0033192: calmodulin-dependent protein phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPM1F

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PPM1F

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPM1F

involved_in

GO:0043280: positive regulation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PPM1F

involved_in

GO:0097193: intrinsic apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PPM1F

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q8N5S9)

Seeded From UniProt

complete

CAEEL:FEM2

involved_in

GO:0006470: protein dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:FEM2

enables

GO:0004721: phosphoprotein phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:FEM2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49594

F

Seeded From UniProt

complete

CAEEL:FEM2

enables

GO:0033192: calmodulin-dependent protein phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:FEM2

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:FEM2

involved_in

GO:0043280: positive regulation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:FEM2

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q8N5S9)

Seeded From UniProt

complete

HUMAN:FEM1B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49593

F

Seeded From UniProt

complete

RAT:PPM1F

involved_in

GO:0043280: positive regulation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PPM1A

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPM1A

enables

GO:0033192: calmodulin-dependent protein phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPM1A

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

has_direct_input:(UniProtKB:Q8N5S9)

Seeded From UniProt

complete


See also

References

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