An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines.
The human myeloid cell line HL60 secretes urokinase-type plasminogen activator (uPA) and expresses its receptor. When stimulated with phorbol myristate acetate (PMA), both secretion of uPA and the expression of its receptor are up-regulated, and these cells differentiate to an adherent phenotype. This adhesive response is markedly reduced in the presence of uPA antibodies. The PMA response is restored by the addition of native uPA, an amino-terminal fragment of uPA (residues 1-143) devoid of proteolytic activity, or a synthetic peptide (residues 12-32) from the uPA growth factor domain known to mediate receptor binding. In contrast, the addition of catalytically active low molecular weight uPA, which is missing the growth factor domain, or a peptide from the catalytic domain (residues 247-266) is ineffective. The influence of uPA antibodies on a second marker of macrophage differentiation, cysteine proteinase activity, was also examined. Cysteine proteinase activity of HL60 cells is increased in PMA-treated cells after 24 h but it fails to increase in the presence of anti-uPA. This increase in cathepsin B-like activity is also restored by exogenous uPA. These experiments indicate that an autocrine interaction of the growth factor domain of uPA with its receptor mediates an essential step in PMA-mediated myeloid cell differentiation.
Nusrat
A R
AR
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Chapman
H A
HA
D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006410:Hematopoiesis; D006801:Humans; D007158:Immunologic Techniques; D066298:In Vitro Techniques; D007951:Leukemia, Myeloid / Q000473:pathology; D008264:Macrophages / Q000166:cytology*; D010446:Peptide Fragments / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology; D011956:Receptors, Cell Surface / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*
C524898:PLAUR protein, human; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D003546:Cysteine Endopeptidases; D013755:Tetradecanoylphorbol Acetate