The urokinase plasminogen activator receptor promotes efferocytosis of apoptotic cells.
The urokinase receptor (uPAR), expressed on the surface of many cell types, coordinates plasmin-mediated cell surface proteolysis for matrix remodeling and promotes cell adhesion by acting as a binding protein for vitronectin. There is great clinical interest in uPAR in the cancer field as numerous reports have demonstrated that up-regulation of the uPA system is correlated with malignancy of various carcinomas. Using both stable cell lines overexpressing uPAR and transient gene transfer, here we provide evidence for a non-reported role of uPAR in the phagocytosis of apoptotic cells, a process that has recently been termed efferocytosis. When uPAR was expressed in human embryonic kidney cells, hamster melanoma cells, or breast cancer cells (BCCs), there was a robust enhancement in the efferocytosis of apoptotic cells. uPAR-expressing cells failed to stimulate engulfment of viable cells, suggesting that uPAR enhances recognition of one or more determinant on the surface of the apoptotic cell. uPAR-mediated engulfment was not inhibited by expression of mutant beta5 integrin, nor was alphavbeta5 integrin-mediated engulfment modulated by cleavage of uPAR by phosphatidylinositol-specific phospholipase C. Further, we found that the more aggressive BCCs had a higher phagocytic capacity that correlated with uPAR expression and cleavage of membrane-associated uPAR in MDA-MB231 BCCs significantly impaired phagocytic activity. Because efferocytosis is critical for the resolution of inflammation and production of anti-inflammatory cytokines, overexpression of uPAR in tumor cells may promote a tolerogenic microenvironment that favors tumor progression.
D'mello
Veera
V
From the Departments of Biochemistry and Molecular Biology, Newark, New Jersey 07103.
Singh
Sukhwinder
S
From the Departments of Biochemistry and Molecular Biology, Newark, New Jersey 07103; Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103.
Wu
Yi
Y
From the Departments of Biochemistry and Molecular Biology, Newark, New Jersey 07103.
Birge
Raymond B
RB
From the Departments of Biochemistry and Molecular Biology, Newark, New Jersey 07103. Electronic address: birgera@umdnj.edu.
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D010586:Phagocytes / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000502:physiology*; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D014162:Transfection
D017931:DNA Primers; D039302:Integrin alphaVbeta3; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin; D011994:Recombinant Proteins; C064660:integrin alphaVbeta5