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J. Biol. Chem., Vol. 279, Issue 37, 38881-38888, September 10, 2004

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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^*

Andrew Wilcox, Kostas D. Katsanakis, Farheen Bheda, and T. S. Pillay

From the Institute of Cell Signaling & School of Biomedical Sciences, University of Nottingham Medical School, Nottingham NG7 2UH, United Kingdom

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.

Received for publication, June 2, 2004 , and in revised form, June 22, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY665653 (for the Asb6 sequence).

^* This work was supported by project grants from Diabetes UK and Novo Nordisk. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

Recipient of a Biotechnology and Biological Scienes Research Council Special Committee studentship award. Present address: University of California at San Francisco, Dept. of Radiation Oncology, 1855 Folsom St., MCB 200/Box 0806, San Francisco, CA 94103.

Recipient of a Wellcome Senior Fellow in Clinical Science award. To whom correspondence should be addressed: Inst. of Cell Signaling, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. Tel.: 44-115-970-9488; Fax: 44-115-919-4493; E-mail: tpillay{at}nottingham.ac.uk.

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