The urokinase plasminogen activator receptor promotes efferocytosis of apopotic cells

Veera D'mello, Sukhwinder Singh, Yi Wu, Raymond B. Birge

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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 β5 integrin, nor was αvβ5 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.

Original languageEnglish (US)
Pages (from-to)17030-17038
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number25
DOIs
StatePublished - Jun 19 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'The urokinase plasminogen activator receptor promotes efferocytosis of apopotic cells'. Together they form a unique fingerprint.

Cite this