title: Dock/Nck facilitates PTP61F/PTP1B regulation of insulin signalling.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, 115 Taiwan.
authors.forename: Chia-Lun
authors.initials: CL
authors.lastname: Wu
authors.forename: Bree
authors.initials: B
authors.lastname: Buszard
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Teng
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Chen
authors.forename: Coral G
authors.initials: CG
authors.lastname: Warr
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Meng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D007328:Insulin; C078332:Nck protein; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; C099753:dock protein, Drosophila; D011972:Receptor, Insulin; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C107962:Ptp61F protein, Drosophila