Urokinase-type plasminogen activator up-regulates its own expression by endothelial cells and monocytes via the u-PAR pathway.
Signal transduction by urokinase-type plasminogen activator (u-PA) bound to its cell receptor has been well established. In the present study, we found, for the first time to our knowledge, that u-PA promotes its own synthesis by endothelial cells and monocytes. This phenomenon was characterized and shown to involve the u-PA receptor (u-PAR) pathway. The finding may be of general importance, since most cells that express u-PAR also produce u-PA. Human umbilical vein endothelial cells (HUVECs), U937 monocytes, and human peripheral blood monocytes (PFMCs) were incubated with diisopropylfluorophosphate (DFP)-pretreated u-PA, the amino-terminal fragment (ATF) of u-PA, or the kringle domain. A threefold up-regulation of u-PA secretion and synthesis by u-PA or ATF was found. The predominant effect was expressed in HUVECs, in which u-PA mRNA was also up-regulated. The u-PA kringle domain had no effect on u-PA synthesis, leading to the conclusion that the EGF domain was responsible. This was also consistent with the additional finding that the u-PAR, to which the EGF domain binds, was necessary for the up-regulation. The results indicate that u-PA up-regulates itself via its EGF domain and u-PAR. The possibilities that the results were related to displacement of receptor-bound u-PA or the blocking of u-PA incorporation into the cells were excluded. A modest up-regulation of u-PAR was also associated with this phenomenon.
Li
C
C
Institute of Molecular Medicine, Nanjing University, Nanjing 10008, China.
Zhang
J
J
Jiang
Y
Y
Gurewich
V
V
Chen
Y
Y
Liu
J N
JN
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D025461:Feedback, Physiological; D006801:Humans; D007700:Kinetics; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins / Q000502:physiology*; D009000:Monocytes / Q000201:enzymology*; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology
C404106:MRC2 protein, human; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D014568:Urokinase-Type Plasminogen Activator