Regulation of urokinase receptor expression by protein tyrosine phosphatases.
Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play a major role in several physiological processes such as cell migration, proliferation, morphogenesis, and regulation of gene expression. Many of the biological activities of uPA depend on its association with uPAR. uPAR expression and its induction by uPA are regulated at the posttranscriptional level. Inhibition of protein tyrosine phosphatase-mediated dephosphorylation by sodium orthovanadate induces uPAR expression and, with uPA, additively induces cell surface uPAR expression. Sodium orthovanadate induces uPAR by increasing uPAR mRNA in a time- and concentration-dependent manner. Both sodium orthovanadate and uPA induce uPAR mRNA stability, indicating that dephosphorylation could contribute to uPA-induced posttranscriptional regulation of uPAR expression. Induction of the tyrosine phosphatase SHP2 in Beas2B and H157 cells inhibits basal cell surface uPAR expression and uPA-induced uPAR expression. Sodium orthovanadate also increases uPAR expression by decreasing the interaction of a uPAR mRNA coding region sequence with phosphoglycerate kinase (PGK) as well as by enhancing the interaction between a uPAR mRNA 3' untranslated sequence with heterogeneous nuclear ribonucleoprotein C (hnRNPC). On the contrary, overexpression of SHP2 in Beas2B cells increased interaction of PGK with the uPAR mRNA coding region and inhibited hnRNPC binding to the 3' untranslated sequence. These findings confirm a novel mechanism by which uPAR expression of lung airway epithelial cells is regulated at the level of mRNA stability by inhibition of protein tyrosine phosphatase-mediated dephosphorylation of uPAR mRNA binding proteins and demonstrate that the process involves SHP2.
Shetty
Sreerama
S
The Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, TX 75708, USA. sreerama.shetty@uthct.edu
Velusamy
Thirunavukkarasu
T
Idell
Steven
S
Tang
Hua
H
Shetty
Praveen Kumar
PK
D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C524898:PLAUR protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014638:Vanadates; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D014568:Urokinase-Type Plasminogen Activator