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PMID:20801214

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Citation

Voss, M, Paterson, J, Kelsall, IR, Martín-Granados, C, Hastie, CJ, Peggie, MW and Cohen, PT (2011) Ppm1E is an in cellulo AMP-activated protein kinase phosphatase. Cell. Signal. 23:114-24

Abstract

Activation of 5'-AMP-activated protein kinase (AMPK) is believed to be the mechanism by which the pharmaceuticals, metformin and phenformin, exert their beneficial effects for treatment of type 2 diabetes. These biguanide drugs elevate 5'-AMP, which allosterically activates AMPK and promotes phosphorylation on Thr172 of AMPK catalytic α subunits. Although kinases phosphorylating this site have been identified, phosphatases that dephosphorylate it are unknown. The aim of this study is to identify protein phosphatase(s) that dephosphorylate AMPKα-Thr172 within cells. Our initial data indicated that members of the protein phosphatase Mg/Mn(2+)-dependent [corrected] (PPM) family and not those of the PPP family of protein serine/threonine phosphatases may be directly or indirectly inhibited by phenformin. Using antibodies raised to individual Ppm phosphatases that facilitated the assessment of their activities, phenformin stimulation of cells was found to decrease the Mg(2+)/Mn(2+)-dependent [corrected] protein serine/threonine phosphatase activity of Ppm1E and Ppm1F, but not that attributable to other PPM family members, including Ppm1A/PP2Cα. Depletion of Ppm1E, but not Ppm1A, using lentiviral-mediated stable gene silencing, increased AMPKα-Thr172 phosphorylation approximately three fold in HEK293 cells. In addition, incubation of cells with low concentrations of phenformin and depletion of Ppm1E increased AMPK phosphorylation synergistically. Ppm1E and the closely related Ppm1F interact weakly with AMPK and assays with lysates of cells stably depleted of Ppm1F suggest [corrected] that this phosphatase contributes to dephosphorylation of AMPK. The data indicate that Ppm1E and probably PpM1F are in cellulo AMPK phosphatases and that Ppm1E is a potential anti-diabetic drug target.

Links

PubMed Online version:10.1016/j.cellsig.2010.08.010

Keywords

AMP-Activated Protein Kinases/metabolism; Gene Silencing; HEK293 Cells; Humans; Phenformin/pharmacology; Phosphoprotein Phosphatases/genetics; Phosphoprotein Phosphatases/metabolism; Phosphorylation; RNA Interference

Significance

Annotations

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

HUMAN:PPM1D

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPM1D

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q13131)

Seeded From UniProt

complete

HUMAN:PPM1G

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPM1G

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q13131)

Seeded From UniProt

complete

HUMAN:PPM1B

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPM1B

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q13131)

Seeded From UniProt

complete

RAT:PDP2

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RAT:PDP2

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q13131)

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:Q13131)

Seeded From UniProt

complete

HUMAN:PPM1F

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P54646

F

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:0071466: cellular response to xenobiotic stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(CHEBI:6801)

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:Q13131)

Seeded From UniProt

complete

HUMAN:AAPK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49593

F

Seeded From UniProt

complete

HUMAN:AAPK2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8WY54

F

Seeded From UniProt

complete

HUMAN:PPM1E

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P54646

F

Seeded From UniProt

complete

HUMAN:PPM1E

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PPM1E

involved_in

GO:0071466: cellular response to xenobiotic stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(CHEBI:6801)

Seeded From UniProt

complete

HUMAN:PPM1E

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q13131)

Seeded From UniProt

complete

HUMAN:PDP1

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PDP1

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q13131)

Seeded From UniProt

complete

RAT:PPM1E

enables

GO:0004722: protein serine/threonine phosphatase activity

ECO:0000266: sequence orthology evidence used in manual assertion

RGD:1350294

F

Seeded From UniProt


RAT:PPM1E

involved_in

GO:0035690: cellular response to drug

ECO:0000266: sequence orthology evidence used in manual assertion

RGD:1350294

P

Seeded From UniProt


RAT:PPM1E

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000266: sequence orthology evidence used in manual assertion

RGD:1350294

P

Seeded From UniProt


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

involved_in

GO:0035970: peptidyl-threonine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

has_direct_input:(UniProtKB:Q13131)

Seeded From UniProt

complete

See also

References

See Help:References for how to manage references in GONUTS.