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 is 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 orthovanidate 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 prime untranslated sequence with 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 prime 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.