Single transmembrane domain IGF-II/M6P receptor: potential interaction with G protein and its association with cholesterol rich membrane domains

Amritraj, A., Posse de Chaves, E.I., Hawkes, C.A., MacDonald, R.G. and Kar, S. (2012) Single transmembrane domain IGF-II/M6P receptor: potential interaction with G protein and its association with cholesterol rich membrane domains. Endocrinology, 153 (10), 4784-4798. (doi:10.1210/en.2012-1139). (PMID:22903618)

Abstract

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 ?-arrestin remains unclear. Here we report that [(125)I]IGF-II receptor binding in the rat hippocampal formation is sensitive to guanosine-5'-[?-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 [(125)I]IGF-II receptor binding. The IGF-II/M6P receptor, as observed for several GPCRs, was found to be associated with ?-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 ?-arrestin 2. Collectively these results suggest that the IGF-II/M6P receptor may interact either directly or indirectly with G protein as well as ?-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.

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