The Urokinase Plasminogen Activator Receptor Promotes Efferocytosis of Apoptotic Cells

J Biol Chem. 2009 Jun 19;284(25):17030-8. doi: 10.1074/jbc.M109.010066. Epub 2009 Apr 21.

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 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.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Base Sequence
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Breast Neoplasms / physiopathology
  • Cell Line
  • Cell Line, Tumor
  • Cricetinae
  • DNA Primers / genetics
  • Female
  • Humans
  • Integrin alphaVbeta3 / genetics
  • Integrin alphaVbeta3 / metabolism
  • Jurkat Cells
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / physiopathology
  • Mutation
  • Phagocytes / physiology
  • Phagocytosis / physiology*
  • Receptors, Urokinase Plasminogen Activator / genetics
  • Receptors, Urokinase Plasminogen Activator / physiology*
  • Receptors, Vitronectin / genetics
  • Receptors, Vitronectin / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • T-Lymphocytes / physiology
  • Transfection

Substances

  • DNA Primers
  • Integrin alphaVbeta3
  • Receptors, Urokinase Plasminogen Activator
  • Receptors, Vitronectin
  • Recombinant Proteins
  • integrin alphaVbeta5