Ankyrin repeat and SOCS box containing protein 4 (Asb-4) colocalizes with insulin receptor substrate 4 (IRS4) in the hypothalamic neurons and mediates IRS4 degradation

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  • Li, Ji-Yao
    • Other Affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109 USA
  • Chai, Biaoxin
    • Other Affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109 USA
  • Zhang, Weizhen
    • Other Affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109 USA
  • Wu, Xiaobin
    • Other Affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109 USA
  • Zhang, Chao
    • Other Affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109 USA
  • Fritze, Danielle
    • Other Affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109 USA
  • Xia, Zefeng
    • Other Affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109 USA
  • Patterson, Cam
    • Other Affiliation: Carolina Cardiovascular Biology Center
  • Mulholland, Michael W
    • Other Affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109 USA
Abstract
  • Abstract Background The arcuate nucleus of the hypothalamus regulates food intake. Ankyrin repeat and SOCS box containing protein 4 (Asb-4) is expressed in neuropeptide Y and proopiomelanocortin (POMC) neurons in the arcuate nucleus, target neurons in the regulation of food intake and metabolism by insulin and leptin. However, the target protein(s) of Asb-4 in these neurons remains unknown. Insulin receptor substrate 4 (IRS4) is an adaptor molecule involved in the signal transduction by both insulin and leptin. In the present study we examined the colocalization and interaction of Asb-4 with IRS4 and the involvement of Asb-4 in insulin signaling. Results In situ hybridization showed that the expression pattern of Asb-4 was consistent with that of IRS4 in the rat brain. Double in situ hybridization showed that IRS4 colocalized with Asb-4, and both Asb-4 and IRS4 mRNA were expressed in proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons within the arcuate nucleus of the hypothalamus. In HEK293 cells co-transfected with Myc-tagged Asb-4 and Flag-tagged IRS4, Asb-4 co-immunoprecipitated with IRS4; In these cells endogenous IRS4 also co-immunoprecipitated with transfected Myc-Asb-4; Furthermore, Asb-4 co-immunoprecipitated with IRS4 in rat hypothalamic extracts. In HEK293 cells over expression of Asb-4 decreased IRS4 protein levels and deletion of the SOCS box abolished this effect. Asb-4 increased the ubiquitination of IRS4; Deletion of SOCS box abolished this effect. Expression of Asb-4 decreased both basal and insulin-stimulated phosphorylation of AKT at Thr308. Conclusions These data demonstrated that Asb-4 co-localizes and interacts with IRS4 in hypothalamic neurons. The interaction of Asb-4 with IRS4 in cell lines mediates the degradation of IRS4 and decreases insulin signaling.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • Ji-Yao Li et al.; licensee BioMed Central Ltd.
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Journal title
  • BMC Neuroscience
Journal volume
  • 12
Journal issue
  • 1
Page start
  • 95
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1471-2202
Bibliographic citation
  • BMC Neuroscience. 2011 Sep 28;12(1):95
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • August 23, 2012

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