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PMID:19249087

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Citation

Padmanabhan, S, Mukhopadhyay, A, Narasimhan, SD, Tesz, G, Czech, MP and Tissenbaum, HA (2009) A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 136:939-51

Abstract

The C. elegans insulin/IGF-1 signaling (IIS) cascade plays a central role in regulating life span, dauer, metabolism, and stress. The major regulatory control of IIS is through phosphorylation of its components by serine/threonine-specific protein kinases. An RNAi screen for serine/threonine protein phosphatases that counterbalance the effect of the kinases in the IIS pathway identified pptr-1, a B56 regulatory subunit of the PP2A holoenzyme. Modulation of pptr-1 affects IIS pathway-associated phenotypes including life span, dauer, stress resistance, and fat storage. We show that PPTR-1 functions by regulating worm AKT-1 phosphorylation at Thr 350. With striking conservation, mammalian B56beta regulates Akt phosphorylation at Thr 308 in 3T3-L1 adipocytes. In C. elegans, this ultimately leads to changes in subcellular localization and transcriptional activity of the forkhead transcription factor DAF-16. This study reveals a conserved role for the B56 regulatory subunit in regulating insulin signaling through AKT dephosphorylation, thereby having widespread implications in cancer and diabetes research.

Links

PubMed PMC2707143 Online version:10.1016/j.cell.2009.01.025

Keywords

Animals; Caenorhabditis elegans/growth & development; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/metabolism; Insulin/metabolism; Insulin-Like Growth Factor I/metabolism; Longevity; Phosphoric Monoester Hydrolases/analysis; Phosphorylation; Proto-Oncogene Proteins c-akt/metabolism; Receptors, Cell Surface/metabolism; Signal Transduction

Significance

Annotations

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

CAEEL:2A51

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q17941

F

Seeded From UniProt

complete

CAEEL:2A51

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

WB:WBGene00000102

F

Seeded From UniProt

complete

CAEEL:2A51

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:2A51

involved_in

GO:0008340: determination of adult lifespan

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:2A51

involved_in

GO:0010883: regulation of lipid storage

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:2A51

involved_in

GO:0009408: response to heat

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:2A51

involved_in

GO:0006470: protein dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:2A51

contributes_to

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(WB:WBGene00000102)

Seeded From UniProt

complete

CAEEL:2A51

part_of

GO:0000159: protein phosphatase type 2A complex

ECO:0000305: curator inference used in manual assertion

GO:0006470

C

Seeded From UniProt

complete

CAEEL:2A51

enables

GO:0072542: protein phosphatase activator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:2A51

involved_in

GO:0046627: negative regulation of insulin receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000102
WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:2A51

involved_in

GO:0040024: dauer larval development

ECO:0000316: genetic interaction evidence used in manual assertion

WB:WBGene00000898

P

Seeded From UniProt

complete

CAEEL:AKT1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O18178

F

Seeded From UniProt

complete


See also

References

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