The Mouse Insulin-like Growth Factor II/Cation-Independent Mannose 6-Phosphate (IGF-II/MPR) Receptor Gene: Molecular Cloning and Genomic Organization

The mammalian insulin-like growth factor II/cation-independent mannose 6-phosphate receptor (IGF-II/MPR) is a multifunctional protein that binds both IGF-II and ligands containing a mannose 6-phosphate recognition marker through distinct high-affinity sites. This receptor plays an integral part in lysosomal enzyme transport, has a potential role in growth factor maturation and clearance, and may mediate IGF-II-activated signal transduction through a G-protein-coupled mechanism. Recent studies have shown that production of IGF-II/MPR mRNA and protein begins in the mouse embryo soon after fertilization and have demonstrated that the receptor gene is on mouse chromosome 17 and is maternally imprinted. In this paper, we report the cloning and characterization of the mouse IGF-II/MPR gene. The gene is 93 kb long, is composed of 48 exons, and codes for a predicted protein of 2482 amino acids. The extracellular part of the receptor is encoded by exons 1-46, with each of 15 related repeating motifs being determined by parts of 3-5 exons. A single fibronectin type II-like element is found in exon 39. The transmembrane portion of the receptor also is encoded by exon 46, and the cytoplasmic region by exons 46-48. The positions of exon-intron splice junctions are conserved between several of the repeats in the IGF-II/MPR and the homologous extracellular region of the gene for the other known lysosomal sorting receptor, the cation-dependent mannose 6-phosphate receptor. The gene duplications that gave rise to the modern IGF-II/MPR probably occurred before the divergence of mammals, since there is more extensive protein sequence conservation between receptors from different species than between any pair of repeating motifs within a single receptor.