Platelet-derived growth factor receptor-beta mediates the tyrosine phosphorylation of the low-density lipoprotein receptor-related protein throughout the endocytic process.

摘要

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a large transmembrane receptor belonging to the LDL receptor (LDLR) superfamily. LRP plays important roles in both physiological and pathological cellular events, including normal development and Alzheimer's disease, respectively. Knockout mice are embryonic lethal, although the exact role of LRP in development is unknown. LRP functions in endocytosis and cargo transport, binding and internalizing over 30 different ligands. Recent data suggest that in addition to its roles in development, endocytosis, and cargo transport, LRP also functions in signaling.; The platelet-derived growth factor receptor-beta (PDGFR-beta) is an important signaling protein with roles in many cellular processes, including development, proliferation, migration, differentiation, and survival, and implications in several clinical situations including wound healing, pulmonary fibrosis, and atherosclerosis. When smooth muscle cells and fibroblasts are treated with the BB homodimer isoform of platelet-derived growth factor (PDGF-BB), the preferential ligand of PDGFR-beta, LRP is phosphorylated on the tyrosine residue in its second cytoplasmic NPXY motif, thereby forming a binding site for numerous cytoplasmic adaptor proteins. Furthermore, vascular smooth muscle cell-specific inactivation of LRP in LDLR -/- mice results in increased signaling by PDGFR-beta, leading to the development of an athero-phenotype that can be rescued by an inhibitor of PDGFR signaling.; The aim of this research was to identify the mechanism of PDGF-mediated tyrosine phosphorylation of LRP and to determine where in the cell this phosphorylation mechanism takes place. Our data suggest that the tyrosine phosphorylation of LRP likely occurs through direct interaction with PDGFR-beta and that the PDGFR-beta-mediated tyrosine phosphorylation of LRP occurs throughout the endocytic process, on the surface of cells, within the cells following receptor internalization, and during retrograde transport.; The findings presented in this dissertation establish a close, physical relationship between LRP and PDGFR-beta. The idea that LRP is a simple scavenger protein is dead. This multifunctional endocytic receptor utilizes intricate cross-talking mechanisms to remain highly involved in numerous signaling pathways. While these mechanisms have not been entirely uncovered yet, it seems clear that the co-receptor function of LRP and PDGFR-beta is critical in determining the signaling and downstream effects of both receptors.