期刊
ENDOCRINOLOGY
卷 153, 期 10, 页码 4784-4798出版社
OXFORD UNIV PRESS INC
DOI: 10.1210/en.2012-1139
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-
资金
- Natural Sciences and Engineering Research Council of Canada
The IGF-II/mannose 6-phosphate (M6P) receptor is a single-transmembrane domain glycoprotein that plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of IGF-II. The receptor may also mediate certain biological effects in response to IGF-II binding by interacting with G proteins. However, the nature of the IGF-II/M6P receptor's interaction with the G protein or with G protein-coupled receptor (GPCR) interacting proteins such as beta-arrestin remains unclear. Here we report that [I-125]IGF-II receptor binding in the rat hippocampal formation is sensitive to guanosine-5'-[gamma-thio]triphosphate, mastoparan, and Mas-7, which are known to interfere with the coupling of the classical GPCR with G protein. Monovalent and divalent cations also influenced [I-125]IGF-II receptor binding. The IGF-II/M6P receptor, as observed for several GPCRs, was found to be associated with beta-arrestin 2, which exhibits sustained ubiquitination after stimulation with Leu(27)IGF-II, an IGF-II analog that binds rather selectively to the IGF-II/M6P receptor. Activation of the receptor by Leu(27)IGF-II induced stimulation of extracellular signal-related kinase 1/2 via a pertussis toxin-dependent pathway. Additionally, we have shown that IGF-II/M6P receptors under normal conditions are associated mostly with detergent-resistant membrane domains, but after stimulation with Leu(27)IGF-II, are translocated to the detergent-soluble fraction along with a portion of beta-arrestin 2. Collectively these results suggest that the IGF-II/M6P receptor may interact either directly or indirectly with G protein as well as beta-arrestin 2, and activation of the receptor by an agonist can lead to alteration in its subcellular distribution along with stimulation of an intracellular signaling cascade. (Endocrinology 153: 4784-4798, 2012)
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