Posttranscriptional Regulation of Urokinase Receptor Expression by Heterogeneous Nuclear Ribonuclear Protein C †

Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Center at Tyler, 11937 U.S. Highway 271, Tyler, Texas 75708, USA.
Biochemistry (Impact Factor: 3.02). 07/2008; 47(24):6508-17. DOI: 10.1021/bi702338y
Source: PubMed


Interaction of urokinase-type plasminogen activator (uPA) with its receptor, uPAR, is a key regulatory step in uPA-mediated cell proliferation and migration. Our previous studies demonstrated that posttranscriptional stabilization of uPAR mRNA by uPA contributes to the induction of cell surface uPAR expression, and heterogeneous nuclear ribonuclear protein C1 (hnRNPC) binds to a 110 nt sequence of uPAR mRNA 3'-UTR, thereby preventing its degradation. These observations indicate that hnRNPC could be involved in the induction of uPAR expression by uPA. In the present study, we investigated this possibility and confirmed that uPA increased the binding of hnRNPC to the 3'-UTR of uPAR mRNA. Furthermore, uPA induced tyrosine phosphorylation of hnRNPC and uPAR expression through mRNA stabilization. Inhibition of hnRNPC tyrosine phosphorylation abolished its interaction with uPAR mRNA and suppressed mRNA stabilization and cell surface uPAR expression. Deletion experiments revealed that hnRNPC binds to uPAR mRNA through its RNA binding domain (RBD). Site-directed mutagenesis studies further indicated that phosphorylation of tyrosine residue 57 (Y57) present in RBD of hnRNPC by uPA is essential for uPAR 3'-UTR mRNA binding and uPAR expression. Increased hnRNPC interaction with the uPAR mRNA 3'-UTR through phosphorylation of Y57 represents a novel mechanism by which uPA regulates posttranscriptional uPAR mRNA turnover and cell surface uPAR expression.

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    • "The difference between the two isoforms is that C2 has an additional 13 amino acid insert after Ser107(4). hnRNPC plays multiple roles in post-transcriptional regulation, including alternative splicing (5), nuclear retention and export (6), stability (7,8) and translation (3,9,10). Several studies have shown that hnRNPC is overexpressed in tumors, including hepatocellular carcinoma and breast cancer (2,11). "
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    • "Heterogeneous nuclear ribonuclear protein C1 (hnRNP C1) and HuR bind to the uPA 3'-UTR, which leads to uPA mRNA stabilization (4). Similarly, hnRNP C1 binds to a 110-nucleotide sequence of the uPAR mRNA 3'-UTR, thereby preventing its degradation (5). Conversely, p53 decreased both uPA and uPAR mRNA stability by binding to a 35-nucleotide sequence in the uPA 3'-UTR and a 37-nucleotide sequence in the uPAR 3'-UTR, resulting in decreased cellular expression. "
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