Low density lipoprotein receptor-related protein (LRP) is a multifunctional receptor which delivers its ligands to lysosomes and then rapidly recycles back to the cell surface. Although numerous LRP ligands have been identified, the function of this receptor remains unclear. Neutralization of LRP, in human and murine fibroblasts, promotes cellular adhesion, spreading, and motility selectively on vitronectin-coated surfaces. LRP neutralization also allows greatly increased accumulation of two related LRP ligands, urokinase-type plasminogen activator (u-PA) and the u-PA receptor (u-PAR), which have been strongly implicated in the regulation of adhesion and motility. The investigator hypothesizes that LRP neutralization alters the catabolism of u-PA and u-PAR so that the activity of the u-PA/u-PAR system is greatly increased and that this process is directly responsible for the observed changes in cellular adhesion and migration.
In Specific Aim 1, three subaims are proposed with the common goal of testing the major hypothesis. Human and murine fibroblast cell lines, in which LRP is neutralized, either at the level of expression or activity, will be studied in experiments designed to evaluate the u-PA/u-PAR system and cellular adhesion, spreading, and motility. Using these novel cell lines, the investigator will directly test whether the increase in activity of the u-PA/u-PAR system, which results from LRP neutralization, is responsible for the observed changes in cellular adhesion and migration. He will then elucidate the mechanism whereby LRP neutralization increases cell-surface expression of u-PAR and accumulation of u-PA in the medium.
Specific Aim 2 includes three subaims with the common goal of characterizing the potentially complex pathway through which LRP neutralization leads to the observed alterations in fibroblast adhesion and motility. The three subaims focus on the role of u-PAR-initiated signal transduction, the activities of vitronectin-binding integrins, and the contributions of plasminogen activator inhibitors. The studies proposed in this grant application will elucidate a defined activity of LRP, on a cell biological level, and contribute to our understanding of multiprotein systems involved in the regulation of cellular motility. The studies are relevant to diverse physiologic and pathophysiologic processes that require cellular adhesion and motility, including tumor invasion, the inflammatory response, angiogenesis, and atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060551-02
Application #
6184513
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1999-08-01
Project End
2003-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$248,788
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Campana, Wendy M; Mantuano, Elisabetta; Azmoon, Pardis et al. (2017) Ionotropic glutamate receptors activate cell signaling in response to glutamate in Schwann cells. FASEB J 31:1744-1755
Fl├╝tsch, Andreas; Henry, Kenneth; Mantuano, Elisabetta et al. (2016) Evidence that LDL receptor-related protein 1 acts as an early injury detection receptor and activates c-Jun in Schwann cells. Neuroreport 27:1305-1311
Mantuano, Elisabetta; Brifault, Coralie; Lam, Michael S et al. (2016) LDL receptor-related protein-1 regulates NF?B and microRNA-155 in macrophages to control the inflammatory response. Proc Natl Acad Sci U S A 113:1369-74
Laudati, Emilia; Gilder, Andrew S; Lam, Michael S et al. (2016) The activities of LDL Receptor-related Protein-1 (LRP1) compartmentalize into distinct plasma membrane microdomains. Mol Cell Neurosci 76:42-51
Mantuano, Elisabetta; Lam, Michael S; Shibayama, Masataka et al. (2015) The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration. J Cell Sci 128:3478-88
Gonias, Steven L; Campana, W Marie (2014) LDL receptor-related protein-1: a regulator of inflammation in atherosclerosis, cancer, and injury to the nervous system. Am J Pathol 184:18-27
Stiles, Travis L; Dickendesher, Travis L; Gaultier, Alban et al. (2013) LDL receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by MAG and CNS myelin. J Cell Sci 126:209-20
Fernandez-Castaneda, Anthony; Arandjelovic, Sanja; Stiles, Travis L et al. (2013) Identification of the low density lipoprotein (LDL) receptor-related protein-1 interactome in central nervous system myelin suggests a role in the clearance of necrotic cell debris. J Biol Chem 288:4538-48
Orita, Sumihisa; Henry, Kenneth; Mantuano, Elisabetta et al. (2013) Schwann cell LRP1 regulates remak bundle ultrastructure and axonal interactions to prevent neuropathic pain. J Neurosci 33:5590-602
Bristow, Jeanne M; Reno, Theresa A; Jo, Minji et al. (2013) Dynamic phosphorylation of tyrosine 665 in pseudopodium-enriched atypical kinase 1 (PEAK1) is essential for the regulation of cell migration and focal adhesion turnover. J Biol Chem 288:123-31

Showing the most recent 10 out of 36 publications