Aminopeptidase N (APN)/CD13-dependent CXCR4 downregulation is associated with diminished cell migration, proliferation and invasion.
Aminopeptidase N (APN/CD13) is a 150 kDa membrane-bound ubiquitously expressed protease with a broad functional repertoire. It hydrolyzes small peptide mediators, modulates cell motility and adhesion to extracellular matrix and also acts as a viral receptor. In order to dissect the function of enzymatically active and inactive APN/CD13, substitutions of different enzymatic active amino acid residues were generated by site-directed mutagenesis and stably transfected into human embryonic kidney cells. All APN variants analyzed exhibited a complete loss of enzymatic activity, whereas wild type APN transfectants exerted a strong aminopeptidase-specific activity. Furthermore, wild type APN expression was associated with a significant decrease in proliferation, migration and also reduced anchorage-independent growth when compared to enzymatically inactive APN variants and controls. This appeared to be due to a downregulated mRNA and protein expression of the chemokine receptor CXCR4 and an inhibition of the stromal cell-derived factor (SDF)-1alpha/CXCL12-mediated migration. Thus, high APN enzyme activity may antagonize the cellular properties regulated by the CXCR4/SDF-1alpha system in embryonic kidney cells.
D018826:CD13 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D020298:U937 Cells
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D018826:CD13 Antigens