Heterotrimeric G proteins and the single-transmembrane domain IGF-II/M6P receptor: Functional interaction and relevance to cell signaling

C. Hawkes, A. Amritraj, R. G. MacDonald, J. H. Jhamandas, S. Kar

Research output: Contribution to journalReview articlepeer-review

18 Scopus citations


The G protein-coupled receptor (GPCR) family represents the largest and most versatile group of cell surface receptors. Classical GPCR signaling constitutes ligand binding to a seven-transmembrane domain receptor, receptor interaction with a heterotrimeric G protein, and the subsequent activation or inhibition of downstream intracellular effectors to mediate a cellular response. However, recent reports on direct, receptor-independent G protein activation, G protein-independent signaling by GPCRs, and signaling of nonheptahelical receptors via trimeric G proteins have highlighted the intrinsic complexities of G protein signaling mechanisms. The insulin-like growth factor-II/mannose-6 phosphate (IGF-II/M6P) receptor is a single-transmembrane glycoprotein whose principal function is the intracellular transport of lysosomal enzymes. In addition, the receptor also mediates some biological effects in response to IGF-II binding in both neuronal and nonneuronal systems. Multidisciplinary efforts to elucidate the intracellular signaling pathways that underlie these effects have generated data to suggest that the IGF-II/M6P receptor might mediate transmembrane signaling via a G protein-coupled mechanism. The purpose of this review is to outline the characteristics of traditional and nontraditional GPCRs, to relate the IGF-II/M6P receptor's structure with its role in G protein-coupled signaling and to summarize evidence gathered over the years regarding the putative signaling of the IGF-II/M6P receptor mediated by a G protein.

Original languageEnglish (US)
Pages (from-to)329-345
Number of pages17
JournalMolecular Neurobiology
Issue number3
StatePublished - Jun 2007


  • G protein-coupled receptor
  • Heterotrimeric G protein

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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