Urokinase receptor mRNA stability involves tyrosine phosphorylation in lung epithelial cells.
Interaction between urokinase-type plasminogen activator (uPA) and its receptor (uPAR) localizes cellular proteolysis and promotes cellular proliferation and migration, effects that may contribute to the pathogenesis of lung inflammation and neoplasia. Enhanced uPAR expression as well as stabilization of uPAR mRNA by transforming growth factor-beta and phorbol myristate acetate (PMA) shares a common mechanism involving phosphorylation and dephosphorylation of a uPAR mRNA-binding protein (uPAR mRNABp). PMA-induced tyrosine phosphorylation of the uPAR mRNABp inhibited the uPAR mRNA-uPAR mRNABp interaction, stabilized uPAR mRNA and enhanced uPAR protein expression. Downregulation of the uPAR mRNA and uPAR mRNABp interaction by PMA and transforming growth factor-beta can be reversed by pretreatment of cells with herbimycin which in turn inhibits expression of uPAR protein via a decrease in uPAR mRNA stability. Our experiments indicate that post-transcriptional regulation of uPAR expression requires activation of tyrosine kinases. Cytokines can regulate uPAR expression of lung-derived epithelial cells at the post-transcriptional level by tyrosine phosphorylation of the uPAR mRNA binding protein and may thereby influence tissue remodeling in lung injury or neoplasia.
Shetty
Sreerama
S
Associate Professor of Medicine, University of Texas Health Center at Tyler, Tyler, TX, 75708, USA. sreerama.shetty@uthct.edu
Idell
Steven
S
D016227:Benzoquinones; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D011809:Quinones / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D017828:Rifabutin / Q000031:analogs & derivatives; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism*
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C524898:PLAUR protein, human; D011809:Quinones; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D016212:Transforming Growth Factor beta; D017828:Rifabutin; D014443:Tyrosine; C020754:herbimycin; D013755:Tetradecanoylphorbol Acetate