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      Asb6, an adipocyte-specific ankyrin and SOCS box protein, interacts with APS to enable recruitment of elongins B and C to the insulin receptor signaling complex.

      The Journal of Biological Chemistry

      Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, chemistry, metabolism, Adipocytes, Amino Acid Sequence, Animals, Ankyrins, physiology, Base Sequence, Biological Transport, CHO Cells, Cricetinae, DNA, Complementary, Epitopes, Gene Library, Glucose, Glutathione Transferase, Insulin, Mice, Microscopy, Confocal, Microscopy, Fluorescence, Models, Biological, Molecular Sequence Data, Phosphorylation, Plasmids, Proline, Protein Binding, Protein Structure, Tertiary, Rabbits, Receptor, Insulin, Recombinant Fusion Proteins, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Transcription Factors, Transfection, Two-Hybrid System Techniques, Tyrosine, 3T3-L1 Cells

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          Abstract

          The APS adapter protein plays a pivotal role in coupling the insulin receptor to CAP and c-Cbl in the phosphatidylinositol 3-kinase-independent pathway of insulin-stimulated glucose transport. Yeast two-hybrid screening of a 3T3-L1 adipocyte library using APS as a bait identified a 418-amino acid ankyrin and SOCS (suppressor of cytokine signaling) box protein Asb6 as an interactor. Asb6 is an orphan member of a larger family of Asb proteins that are ubiquitously expressed. However, Asb6 expression appears to be restricted to adipose tissue. Asb6 was specifically expressed in 3T3-L1 adipocytes as a 50-kDa protein but not in fibroblasts. In Chinese hamster ovary-insulin receptor (CHO-IR) cells Myc epitope-tagged APS interacted constitutively with FLAG-tagged Asb6 in the presence or absence of insulin stimulation and insulin stimulation did not alter the interaction. In 3T3-L1 adipocytes, insulin receptor activation was accompanied by the APS-dependent recruitment of Asb6. Asb6 did not appear to undergo tyrosine phosphorylation. Immunofluorescence and confocal microscopy studies revealed that Asb6 colocalized with APS in CHO cells and in 3T3-L1 adipocytes. In immunoprecipitation studies in CHO cells or 3T3-L1 adipocytes, the Elongin BC complex was found to be bound to Asb6, and activation of the insulin receptor was required to facilitate Asb6 recruitment along with Elongins B/C. Prolonged insulin stimulation resulted in the degradation of APS when Asb6 was co-expressed but not in the absence of Asb6. We conclude that Asb6 functions to regulate components of the insulin signaling pathway in adipocytes by facilitating degradation by the APS-dependent recruitment of Asb6 and Elongins BC.

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          Journal
          15231829
          10.1074/jbc.M406101200

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