Research Interests:
Our laboratory is interested in identifying and characterizing novel pathways by which proteases and their cell-surface receptors regulate cell physiology. We are particularly interested in the function of proteases in cancer but also have active projects related to Alzheimers disease and Cardiovascular Biology.
Urokinase-type plasminogen activator (uPA) is a serine protease and plasminogen activator. uPA binds with high affinity to a glycosylphosphatidylinositol (GPI)-anchored receptor called uPAR. This event activates multiple cell-signaling pathways of interest to this laboratory, including the Ras-ERK/MAP kinase pathway, which controls cell migration, growth, and apoptosis. uPAR also regulates cell-signaling independently of uPA, through activation of factors such as the small GTPase, Rac1. Our goal is to determine how uPAR-initiated cell signaling responses are integrated to regulate cell physiology.
When uPA reacts with the protease inhibitor, plasminogen activator inhibitor-1, the complex is recognized by a receptor in the LDL receptor family, called LRP-1. LRP-1 is also the receptor for other ligands, including activated alpha2-macroglobulin (alpha2M). Recent studies suggest that LRP-1 controls various cell physiologic processes, including cell migration, and may have direct cell-signaling activities. A unique property of LRP-1 is the ability to regulate levels of other plasma membrane proteins, including uPAR. Using proteomics approaches, we are actively investigating the ability of LRP-1 to model or shape the composition of the plasma membrane.
Our third area of focus concerns the plasma protease inhibitor, alpha2M. Our laboratory has demonstrated that this protein functions as a conformation-dependent carrier of growth factors. A growth factor binding-sequence has been identified near the center of the alpha2M subunit. In addition, we have identified a completely distinct binding site, which has the potential to interact with alpha-amyloid peptide. A major goal for our laboratory is to explore the function of the two protein-interaction sites in alpha2M, especially in cancer and Alzheimers disease.
Track(s):
Molecular Pathology
BMS Focus Areas:
Cancer Biology
Neurobiology
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