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THE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR (UPAR) PROMOTES EFFEROCYTOSIS OF APOPTOTIC CELLS

by
Veera Dmello
Biochemistry & Molecular Biology

M.S. 2000, Mumbai University
B.S. 1998, Mumbai University


Thesis Advisor: Raymond B. Birge, Ph.D.

Associate Professor

Department: Biochemistry and Molecular Biology

MSB E-609B

Tuesday, May 26, 2009
11:00 am


Abstract

Apoptotic cell clearance, also known as efferocytosis, is of paramount importance to the general health of an individual as it maintains cellular turnover and tissue homeostasis, an anti-inflammatory tissue environment and contributes to healing and regenerative processes by influencing angiogenesis. Apoptotic cell surface markers are specifically recognized by phagocytic receptors and mediate clearance of apoptotic corpses. In this thesis, we have identified a novel function for urokinase plasminogen activator receptor (uPAR) in the efferocytosis of apoptotic cells. uPAR is a glycosylphosphatidylinositol (GPI) anchored protein with a large extracellular region that interacts with integrins including v3 and v5 integrin phagocytic receptors and growth factor receptors. uPAR mediated efferocytosis was found to be independent of v3 and v5 integrins and was completely abrogated by the cleavage of the GPI anchor of cell surface uPAR. Imaging of uPAR dependent efferocytosis revealed that uPAR promoted uptake of both apoptotic blebs and bodies similar to known phagocytic receptors. uPAR as well as the v5 integrin are often overexpressed in metastatic cancer cells. Therefore we also investigated if acquired overexpression of uPAR in cancer cells conferred higher efferocytic capacity to these cells. uPAR expression correlated with invasive potential of metastatic breast cancer cells and was found to positively correlate with efferocytosis. Further, cleavage of uPAR from the surface of highly metastatic breast cancer cells resulted in significant reduction in efferocytosis. These observations contribute to a general debate regarding the role of upregulation of phagocytic receptors and increased efferocytosis during tumor progression. We hypothesize that efferocytosis of apoptotic cells in the tumor microenvironment might present a novel pathway that induces anti-inflammatory and growth promoting effects leading to tumor growth, neo-angiogenesis and metastasis.


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