Low Density Lipoprotein Receptor Related Proteins as Regulators of Neural Stem and Progenitor Cell Function

Abstract

The central nervous system (CNS) is a highly organised structure. Many signalling systems work in concert to ensure that neural stem cells are appropriately directed to generate progenitor cells, which in turn mature into functional cell types including projection neurons, interneurons, astrocytes, and oligodendrocytes. Herein we explore the role of the low density lipoprotein (LDL) receptor family, in particular family members LRP1 and LRP2, in regulating the behaviour of neural stem and progenitor cells during development and adulthood. The ability of LRP1 and LRP2 to bind a diverse and extensive range of ligands, regulate ligand endocytosis, recruit nonreceptor tyrosine kinases for direct signal transduction and signal in conjunction with other receptors, enables them to modulate many crucial neural cell functions.

Figure 1

LRP1 maturation and structure. This schematic depicts the LRP1 precursor protein, which is synthesized in the endoplasmic reticulum and is bound to the chaperone protein, receptor associated protein (RAP). The LRP1 precursor is transported to the trans-Golgi network where the low pH causes RAP to dissociate. The protease Furin cleaves the LRP1 precursor at the RX(K/R)R consensus sequence to generate a large α-chain (515 kDa) and a smaller β-chain (85 kDa) which are noncovalently linked and shuttled to the cell membrane, where they are embedded as one functional unit. The α-chain contains four ligand-binding domains (red) that interact with a large number of ligands. The β-chain contains a small extracellular region, a transmembrane region which anchors the LRP1 protein within the plasma membrane, as well as two dileucine (LL, green) motifs and two asparagine-proline-x-tyrosine (NPXY, blue) motifs, where the distal motif is contiguous with a tyrosine-x-x-leucine (YXXL, pink) motif which interact with intracellular adaptor proteins and the endocytotic machinery.

Figure 2

Signalling mechanisms employed by LRP1. (a) The extracellular domain of LRP1 can be shed following cleavage by beta-site APP cleaving enzyme 1 (BACE1) and metalloproteinases (MP) producing a soluble form of LRP1 (sLRP1). The intracellular domain can be cleaved by γ-secretase and is thought to translocate to the nucleus to influence gene transcription. (b) Ligand binding to LRP1 can result in receptor and ligand internalisation. Once internalised, the ligand/receptor complex can be processed in a multitude of ways, including degradation by lysosomes or resecretion via transcytotic and recycling vesicles. Note that while they are depicted together, ligand and receptor/s are trafficked independently. (c) Specific regions on the intracellular region of LRP1 interact with adaptor proteins such as Disabled-1 (Dab1), which interacts with the NPXY motifs and can recruit nonreceptor tyrosine kinases such as Src and Abl allowing signal transduction. (d) Activation of LRP1 by specific ligands can transactivate other receptors such as tropomyosin receptor kinase A (TrkA), which can then activate downstream signalling pathways to regulate cell function.