Members of the LDL receptor family play a major role in cargo transport by binding extracellular ligands and facilitating their delivery to lysosomes for degradation. In addition to their important cargo function, recent studies indicate that these two LDL receptors also modulate signaling pathways. While the details of this are not yet fully established, this is accomplished by cooperation with cell surface molecules that associate directly or indirectly with LDL receptor family members and cellular adaptor molecules that associate with their cytoplasmic tail. We recently obtained evidence that LRP may modulate the trafficking and therefore the signaling properties of certain receptor tyrosine kinases. Specifically, we found that activation of platelet derived growth factor (PDGF)beta receptor initiates a transient phosphorylation of the cytoplasmic domain of LRP. The phosphorylation occurs at the second NpXY motif within LRP's cytoplasmic domain, and provides a docking site for Shc, an adaptor protein that is thought to play a crucial role during cellular transformation by v-Src. This process requires c-Src family kinase and PI-3 kinase activity. In resting fibroblasts and smooth muscle cells, LRP co-localizes with PDGFbeta in caveolae, but following PDGF-stimulation, LRP and the PDGFbeta receptor are co-localized within endosomal compartments. The central hypothesis of this application is that LRP regulates signaling pathways mediated by the certain tyrosine-kinase receptors such as the PDGF receptor thereby modulating the function of this signaling pathway. The specific hypotheses to be tested are: 1) That LRP co-localizes with the PDGF receptor in caveolae and interacts via extracellular and/or cytoplasmic domain interactions; 2) that this association modulates the cellular trafficking of the PDGF receptor; and 3) that expression of the LRP gene modulates the response of the cells to PDGF. These hypotheses will be tested in the following specific aims: 1) Identify the molecular basis for the selective phosphorylation of LRP by the PDGF receptor; 2) Identify the cellular compartment where tyrosine-phosphorylation of LRP occurs, and determine if LRP modulates the trafficking of the PDGF receptor; and 3) Define the mechanism by which LRP modulates signaling pathways mediated by PDGF.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Link, Rebecca P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
American National Red Cross
United States
Zip Code
Strickland, Dudley K; Muratoglu, Selen C (2016) LRP in Endothelial Cells: A Little Goes a Long Way. Arterioscler Thromb Vasc Biol 36:213-6
Wahler, Anke; Beyer, Anja-Silke; Keller, Ilona E et al. (2013) Engulfment adaptor phosphotyrosine-binding-domain-containing 1 (GULP1) is a nucleocytoplasmic shuttling protein and is transactivationally active together with low-density lipoprotein receptor-related protein 1 (LRP1). Biochem J 450:333-43
Craig, Julie; Mikhailenko, Irina; Noyes, Nathaniel et al. (2013) The LDL receptor-related protein 1 (LRP1) regulates the PDGF signaling pathway by binding the protein phosphatase SHP-2 and modulating SHP-2- mediated PDGF signaling events. PLoS One 8:e70432
Muratoglu, Selen C; Belgrave, Shani; Hampton, Brian et al. (2013) LRP1 protects the vasculature by regulating levels of connective tissue growth factor and HtrA1. Arterioscler Thromb Vasc Biol 33:2137-46
Yakovlev, Sergiy; Mikhailenko, Irina; Cao, Chunzhang et al. (2012) Identification of VLDLR as a novel endothelial cell receptor for fibrin that modulates fibrin-dependent transendothelial migration of leukocytes. Blood 119:637-44
Strickland, Dudley K; Muratoglu, Selen Catania; Antalis, Toni M (2011) Serpin-Enzyme Receptors LDL Receptor-Related Protein 1. Methods Enzymol 499:17-31
Muratoglu, Selen Catania; Belgrave, Shani; Lillis, Anna P et al. (2011) Macrophage LRP1 suppresses neo-intima formation during vascular remodeling by modulating the TGF-? signaling pathway. PLoS One 6:e28846
Ranganathan, Sripriya; Cao, Chunzhang; Catania, Jason et al. (2011) Molecular basis for the interaction of low density lipoprotein receptor-related protein 1 (LRP1) with integrin alphaMbeta2: identification of binding sites within alphaMbeta2 for LRP1. J Biol Chem 286:30535-41
Ranganathan, Sripriya; Noyes, Nathaniel C; Migliorini, Mary et al. (2011) LRAD3, a novel low-density lipoprotein receptor family member that modulates amyloid precursor protein trafficking. J Neurosci 31:10836-46
Meng, He; Zhang, Xiaojie; Lee, Soo Jung et al. (2010) Low density lipoprotein receptor-related protein-1 (LRP1) regulates thrombospondin-2 (TSP2) enhancement of Notch3 signaling. J Biol Chem 285:23047-55

Showing the most recent 10 out of 64 publications