Insulin-Like Growth Factor-II/Cation-Independent Mannose 6-Phosphate Receptor in Neurodegenerative Diseases

Abstract

The insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6P) receptor is a multifunctional single-transmembrane glycoprotein. Recent studies have advanced our understanding of the structure, ligand binding properties and trafficking of the IGF-II/M6P receptor. This receptor has been implicated in a variety of important cellular processes including growth and development, clearance of IGF-II, proteolytic activation of enzymes and growth factor precursors, in addition to its well-known role in the delivery of lysosomal enzymes. The IGF-II/M6P receptor, distributed widely in the central nervous system, has additional roles in mediating neurotransmitter release and memory enhancement/consolidation, possibly through activating IGF-II-related intracellular signaling pathways. Recent studies suggest that overexpression of the IGF-II/M6P receptor may have an important role in regulating the levels of transcripts and proteins involved in the development of Alzheimer’s disease (AD) – the prevalent cause of dementia affecting the elderly population in our society. It is reported that IGF-II/M6P receptor overexpression can increase the levels/processing of amyloid precursor protein leading to the generation of β-amyloid peptide, which is associated with degeneration of neurons and subsequent development of AD pathology. Given the significance of the receptor in mediating the transport and functioning of the lysosomal enzymes, it is being considered for therapeutic delivery of enzymes to the lysosomes to treat lysosomal storage disorders. Notwithstanding these results, additional studies are required to validate and fully characterize the function of the IGF-II/M6P receptor in the normal brain and its involvement in various neurodegenerative disorders including AD. It is also critical to understand the interaction between the IGF-II/M6P receptor and lysosomal enzymes in neurodegenerative processes, which may shed some light on developing approaches to detect and prevent neurodegeneration through the dysfunction of the receptor and the endosomal-lysosomal system.

Rapid Clathrin-Mediated Uptake of Recombinant α-Gal-A to Lysosome Activates Autophagy

“…IGF2R/M6P receptor is localized mostly in the Golgi and endosomal compartments with less than 10% on the plasma membrane. The receptor always shuttles between intracellular compartments and cytoplasmic membrane during endocytosis (Figure 9) [14,16]. The IGF2R/M6P mediated endocytosis has been very well characterized; however, the mechanisms of IGF2R/M6P shuttle between membrane-Golgi-lysosome during rapid delivery of rh-α-Gal A to lysosomes, is unknown.…”

“…It is shown that, in most ERT, the IGF2R/M6P-mediated endocytosis is crucial for efficient enzyme delivery [12][13][14]. IGF2R/M6P is a bifunctional receptor that mediates binding and endocytosis of proteins via the clathrin-associated pathway [15,16]. IGF2R/M6P is essential for several cell signaling processes, including lysosomal enzyme trafficking from trans-Golgi apparatus, clearance, activation of growth factors, endocytosis-mediated delivery of macromolecules to the lysosomes [16].…”

“…IGF2R/M6P is a bifunctional receptor that mediates binding and endocytosis of proteins via the clathrin-associated pathway [15,16]. IGF2R/M6P is essential for several cell signaling processes, including lysosomal enzyme trafficking from trans-Golgi apparatus, clearance, activation of growth factors, endocytosis-mediated delivery of macromolecules to the lysosomes [16]. IGF2R/M6P is expressed in most tissues, with relatively higher expression in kidneys and lungs, which makes this receptor attractive for the development of intracellular drug delivery.…”

Genome-wide RNA sequencing analysis reveals that IGF-2 attenuates memory decline, oxidative stress and amyloid plaques in an Alzheimer’s disease mouse model (AD) by activating the PI3K/AKT/CREB signaling pathway

“…Insulin-like growth factor II (IGF-2) is a type of pleiotropic polypeptide widely distributed in various tissues/organs, including the central nervous system (CNS) (Wang et al, 2017). The IGF system is heavily involved in cell genesis and growth during development.…”

General Linker Diversification Approach to Bivalent Ligand Assembly: Generation of an Array of Ligands for the Cation-Independent Mannose 6-Phosphate Receptor

“…3 Evidence suggests that over-expression of the receptor may be associated with prostate cancer 4 and neurodegenerative disease. 5 The CI-MPR regulates intracellular trafficking of lysosomal glycoproteins through multiple interactions with M6P-terminated N-glycans, including uPAR, granzyme B, proliferin, and TGF-beta precursor (Figure 1). 6 This receptor also binds and internalizes the growth factor IGF2.…”