Abstract
The extracellular matrix (ECM) is a biological substrate composed of collagens, proteoglycans and glycoproteins that ensures proper cell migration and adhesion and keeps the cell architecture intact. The regulation of the ECM composition is a vital process strictly controlled by, among others, proteases, growth factors and adhesion receptors. As it appears, ECM remodeling is also essential for proper neuronal and glial development and the establishment of adequate synaptic signaling. Hence, disturbances in ECM functioning are often present in neurodegenerative diseases like Alzheimer’s disease. Moreover, mutations in ECM molecules are found in some forms of epilepsy and malfunctioning of ECM-related genes and pathways can be seen in, for example, cancer or ischemic injury. Low density lipoprotein receptor-related protein 1 (Lrp1) is a member of the low density lipoprotein receptor family. Lrp1 is involved not only in ligand uptake, receptor mediated endocytosis and lipoprotein transport—functions shared by low density lipoprotein receptor family members—but also regulates cell surface protease activity, controls cellular entry and binding of toxins and viruses, protects against atherosclerosis and acts on many cell signaling pathways. Given the plethora of functions, it is not surprising that Lrp1 also impacts the ECM and is involved in its remodeling. This review focuses on the role of Lrp1 and some of its major ligands on ECM function. Specifically, interactions with two Lrp1 ligands, integrins and tissue plasminogen activator are described in more detail.
Highlights
Lrp1: A Hidden MultitaskerLow density lipoprotein receptor-related protein-1 (Lrp1), known as CD91 or α-2-macroglobulin (α-2-M) receptor, is a member of the low density lipoprotein receptor family and is expressed in various tissues including liver, adipose tissue, lungs and brain
Pregnancy zone protein (PZP) is a member of the α-2 globulin family; protease inhibitor and extracellular chaperone; role in immune regulation during pregnancy Serine protease, urokinase-type plasminogen activator single-chain zymogen with little intrinsic enzymatic activity Toxin from Pseudomonas aeruginosa Endoplasmic reticulum resident chaperone glycoprotein, inhibits binding of ligands to low density lipoprotein receptor family members Ribosome-inactivating protein found in the seeds of Ricinus communis; potent toxin Ribosome-inactivating protein found in the seeds of Saponaria officinalis; potent toxin Glycoprotein precursor of saposins involved in glycosphingolipid catabolism Adaptor protein that becomes phosphorylated on tyrosine residues in response to extracellular stimuli Main carriers of triglycerides in the blood; involved in lipoprotein metabolism and transport Protease inhibitors of matrix metalloproteinases
With this and a follow-up study we showed that Lrp1 plays a role in the differentiation of neural stem precursor cells (NSPCs) (Hennen et al, 2013; Safina et al, 2016)
Summary
Low density lipoprotein receptor-related protein-1 (Lrp1), known as CD91 or α-2-macroglobulin (α-2-M) receptor, is a member of the low density lipoprotein receptor family and is expressed in various tissues including liver, adipose tissue, lungs and brain. As suggested by Huang et al (1999), each ligand-binding domain of Lrp presents very different charge densities and hydrophobic patches These differences in turn lead to varying receptor-ligand interactions and are responsible for a distinct ligand specificity of each cluster, despite similar backbone folds. With their studies, May et al (2004); Liu et al (2010) and Nakajima et al (2013), highlight and support earlier findings showing that Lrp regulates postsynaptic signaling via interactions with PSD-95 and N-methyl-D-aspartate receptor (NMDAR) and is crucial for synaptic transmission (Bacskai et al, 2000; Qiu et al, 2002). Knock-in mutations in the NPxY2 region lead to a reduced Lrp internalization rate (Roebroek et al, 2006; Reekmans et al, 2010; Gordts et al, 2012) and interfere with NMDAR recycling and NMDAR-mediated activation of the ERK1/2
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