Clusterin Is a Ligand for Apolipoprotein E Receptor 2 (ApoER2) and Very Low Density Lipoprotein Receptor (VLDLR) and Signals via the Reelin-signaling Pathway

• Published in: The Journal of biological chemistry Vol. 289; no. 7; pp. 4161 - 4172
• Main Authors: Leeb, Christian, Eresheim, Christine, Nimpf, Johannes
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.02.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; apoE Receptor 2; Apolipoproteins; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Cell Biology; Cell Proliferation; Cell Signaling; Cells, Cultured; Clusterin; Clusterin - genetics; Clusterin - metabolism; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; HEK293 Cells; Humans; LDL-Receptor Related Proteins - genetics; LDL-Receptor Related Proteins - metabolism; Lipoprotein Receptor; Mice; Midline Thalamic Nuclei - cytology; Midline Thalamic Nuclei - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurogenesis; Neurogenesis - physiology; NIH 3T3 Cells; Receptors, LDL - genetics; Receptors, LDL - metabolism; Reelin; Reelin Protein; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Signal Transduction - physiology; Very Low Density Lipoprotein Receptor; apoE Receptor 2; Cell Proliferation; Reelin; Lipoprotein Receptor; Cell Signaling; Apolipoproteins; Neurogenesis; Very Low Density Lipoprotein Receptor; Clusterin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.529271

Clusterin, also known as apolipoprotein J, is a multifunctional glycoprotein with the capacity to interact with a wide range of molecules. Although clusterin has been implicated in a broad spectrum of physiological and pathological processes, such as Alzheimer disease or cancer, its precise functions remain elusive. Here we report, that clusterin binds to apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) and is internalized by cells expressing either one of these receptors. Binding of clusterin to these receptors triggers a Reelin-like signal in cells expressing disabled-1 (Dab1). It induces phosphorylation of Dab1, which leads to activation of PI3K/Akt and n-cofilin. Cell proliferation and neuroblast chain formation in subventricular zone (SVZ) explants are compromised when clusterin, which is present in the subventricular zone, is blocked in vitro. These data suggest that in the subventricular zone where Reelin is not present but ApoER2, VLDLR, and Dab1, clusterin might be involved in maintaining neurogenesis in vivo. Clusterin is a highly conserved glycoprotein with broad tissue distribution but enigmatic biological functions. Clusterin signals via the lipoprotein receptors ApoER2 and VLDLR and stimulates cell proliferation in subventricular zone explants enabling neuronal outgrowth. Clusterin-mediated signaling is essential for neuronal chain formation in vitro. Discovery of a novel function of clusterin in neurogenesis.