The low density lipoprotein receptor-related protein (LRP-1) is a member of the LDL receptor gene family; however, LRP-1 expresses diverse activities that are unrelated to lipid homeostasis. First, LRP-1 binds over forty documented ligands and facilitates cellular internalization of these ligands. LRP-1 also functions as a co-receptor for many signaling proteins, altering the magnitude and kinetics of the signaling response and as a result, the impact on cell physiology. Finally, there is substantial evidence that LRP-1 regulates levels of multiple plasma membrane proteins and thereby models the plasma membrane. This process may involve extracellular ligands that bridge LRP-1 to other membrane proteins, bifunctional intracellular adaptor proteins, and direct interactions, all of which allow LRP-1 to facilitate endocytosis of the other membrane protein or alter its localization in the plasma membrane. Much of our understanding regarding the function of LRP-1 in membrane modeling emerged from our studies of LRP-1 and the urokinase receptor, during the last cycle of this grant; however, we now hypothesize that this activity extends to multiple proteins including amyloid precursor protein, tissue factor, PDGF beta-receptor, uPAR-associated protein, and possibly integrins. LRP-1 also regulates assembly of the extracellular matrix in association with the cell surface. The major goal of this grant application is to characterize the function of LRP-1 in plasma membrane modeling and cell signaling.
In Specific Aim 1, cell culture model systems and proteomics methods, which have been developed specifically for this research project, will be used to determine how LRP-1 affects the composition of the plasma membrane.
In Specific Aim 2, we will determine the mechanisms by which LRP-1 regulates levels of plasma membrane proteins.
In Specific Aim 3, we will characterize how plasma membrane modeling, by LRP-1, affects cell signaling, growth, and cell migration. Our preliminary proteomics data have already identified a number of receptor systems for analysis in Aims 2 and 3; however, we are prepared to characterize novel targets, as they are identified in Aim 1. Overall, our goal is to generate an integrated model for the function of LRP-1, at the level of the cell. This information is critical to understand the function of LRP-1 in diverse processes, such as development, hemostasis, atherogenesis, and angiogenesis.
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