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PMID:21707536

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Citation

Wu, CL, Buszard, B, Teng, CH, Chen, WL, Warr, CG, Tiganis, T and Meng, TC (2011) Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling. Biochem. J. 439:151-9

Abstract

PTP1B (protein tyrosine phosphatase 1B) is a negative regulator of IR (insulin receptor) activation and glucose homoeostasis, but the precise molecular mechanisms governing PTP1B substrate selectivity and the regulation of insulin signalling remain unclear. In the present study we have taken advantage of Drosophila as a model organism to establish the role of the SH3 (Src homology 3)/SH2 adaptor protein Dock (Dreadlocks) and its mammalian counterpart Nck in IR regulation by PTPs. We demonstrate that the PTP1B orthologue PTP61F dephosphorylates the Drosophila IR in S2 cells in vitro and attenuates IR-induced eye overgrowth in vivo. Our studies indicate that Dock forms a stable complex with PTP61F and that Dock/PTP61F associate with the IR in response to insulin. We report that Dock is required for effective IR dephosphorylation and inactivation by PTP61F in vitro and in vivo. Furthermore, we demonstrate that Nck interacts with PTP1B and that the Nck/PTP1B complex inducibly associates with the IR for the attenuation of IR activation in mammalian cells. Our studies reveal for the first time that the adaptor protein Dock/Nck attenuates insulin signalling by recruiting PTP61F/PTP1B to its substrate, the IR.

Links

PubMed Online version:10.1042/BJ20110799

Keywords

Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Cell Line; Drosophila; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Humans; Insulin/pharmacology; Microscopy, Electron, Scanning; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Oncogene Proteins/genetics; Oncogene Proteins/metabolism; Phosphorylation/drug effects; Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism; Protein Tyrosine Phosphatases, Non-Receptor/genetics; Protein Tyrosine Phosphatases, Non-Receptor/metabolism; Receptor, Insulin/metabolism; Signal Transduction/drug effects

Significance

Annotations

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

DROME:INSR

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NCK1

enables

GO:0030674: protein-macromolecule adaptor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NCK1

involved_in

GO:0046627: negative regulation of insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTN1

enables

GO:0004725: protein tyrosine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P06213)

Seeded From UniProt

complete

DROME:Q9VPU1

enables

GO:0030674: protein-macromolecule adaptor activity

ECO:0000353: physical interaction evidence used in manual assertion

FB:FBgn0267487,FB:FBgn0283499

F

Seeded From UniProt

complete

DROME:Q9VPU1

involved_in

GO:0046627: negative regulation of insulin receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0267487,FB:FBgn0283499

P

Seeded From UniProt

complete

DROME:PTP61

enables

GO:0004725: protein tyrosine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PTN1

enables

GO:0004725: protein tyrosine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

has_direct_input:(UniProtKB:P06213)

Seeded From UniProt

complete

DROME:PTP61

involved_in

GO:0046627: negative regulation of insulin receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

FB:FBgn0283499

P

Seeded From UniProt

complete

DROME:PTP61

enables

GO:0004725: protein tyrosine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_direct_input:(FB:FBgn0283499)
  • part_of:(GO:0046627)

Seeded From UniProt

complete

DROME:PTP61

involved_in

GO:0035335: peptidyl-tyrosine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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