Shetty Sreerama, Velusamy Thirunavukkarasu, Idell Steven, Tang Hua, Shetty Praveen Kumar
The Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, TX 75708, USA.
Am J Physiol Lung Cell Mol Physiol. 2007 Feb;292(2):L414-21. doi: 10.1152/ajplung.00121.2006. Epub 2006 Oct 6.
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.
尿激酶型纤溶酶原激活剂（uPA）及其受体（uPAR）在细胞迁移、增殖、形态发生和基因表达调控等多种生理过程中发挥着重要作用。uPA的许多生物学活性取决于其与uPAR的结合。uPAR的表达及其由uPA诱导的过程在转录后水平受到调控。原钒酸钠抑制蛋白酪氨酸磷酸酶介导的去磷酸化可诱导uPAR表达，并与uPA协同诱导细胞表面uPAR表达。原钒酸钠以时间和浓度依赖的方式通过增加uPAR mRNA来诱导uPAR。原钒酸钠和uPA均诱导uPAR mRNA稳定性，表明去磷酸化可能有助于uPA诱导的uPAR表达的转录后调控。在Beas2B和H157细胞中诱导酪氨酸磷酸酶SHP2可抑制基础细胞表面uPAR表达和uPA诱导的uPAR表达。原钒酸钠还通过减少uPAR mRNA编码区序列与磷酸甘油酸激酶（PGK）的相互作用以及增强uPAR mRNA 3'非翻译序列与异质性核核糖核蛋白C（hnRNPC）之间的相互作用来增加uPAR表达。相反，在Beas2B细胞中过表达SHP2增加了PGK与uPAR mRNA编码区的相互作用，并抑制了hnRNPC与3'非翻译序列的结合。这些发现证实了一种新机制，即通过抑制蛋白酪氨酸磷酸酶介导的uPAR mRNA结合蛋白的去磷酸化，在mRNA稳定性水平上调节肺气道上皮细胞的uPAR表达，并证明该过程涉及SHP2。
