Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase

Abstract

The interaction of urokinase-type plasminogen activator (uPA) with its receptor, uPAR, plays a central role in several pathophysiological processes, including cancer. uPA induces its own cell surface receptor expression through stabilization of uPAR mRNA. The mechanism involves binding of a 51 nt uPAR mRNA coding sequence with phosphoglycerate kinase (PGK) to down regulate cell surface uPAR expression. Tyrosine phosphorylation of PGK mediated by uPA treatment enhances uPAR mRNA stabilization. In contrast, inhibition of tyrosine phosphorylation augments PGK binding to uPAR mRNA and attenuates uPA-induced uPAR expression. Mapping the specific peptide region of PGK indicated that its first quarter (amino acids 1-100) interacts with uPAR mRNA. To determine if uPAR expression by uPA is regulated through activation of tyrosine residues of PGK, we mutated the specific tyrosine residue and tested mutant PGK for its ability to interfere with uPAR expression. Inhibition of tyrosine phosphorylation by mutating Y76 residue abolished uPAR expression induced by uPA treatment. These findings collectively demonstrate that Y76 residue present in the first quarter of the PGK molecule is involved in lung epithelial cell surface uPAR expression. This region can effectively mimic the function of a whole PGK molecule in inhibiting tumor cell growth.

The impact of COX-2 on invasion of osteosarcoma cell and its mechanism of regulation

“…The degradation of the extracellular matrix requires the involvement of a variety of extracellular proteolytic enzymes, with which the urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play important roles [13]. uPA interacts with uPAR at the tumor cell surface, with uPA concentrated on the cell surface.…”

Role of tyrosine phosphorylation in modulating cancer cell metabolism

“…Moreover, they also demonstrated that tyrosine phosphorylation of PGK enhances uPAR mRNA stabilization, thereby stimulating receptor synthesis [40]. To date, no evidence is available about the effect of Y76 phosphorylation on the enzyme activity but mutational studies revealed that inhibition of tyrosine phosphorylation increases PGK binding to uPAR mRNA and attenuates uPA-induced uPAR expression [40]. Interestingly, it has been shown that, upon overexpression, uPAR assembles with and activates α5β1-integrin and EGFR, thereby favouring the activation of PI3K/ pAKT/mTOR/HIF-1α signaling pathway [41].…”

“…Shetty and co-authors reported that the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) promotes phosphorylation of the Y76 residue of PGK. Moreover, they also demonstrated that tyrosine phosphorylation of PGK enhances uPAR mRNA stabilization, thereby stimulating receptor synthesis [40]. To date, no evidence is available about the effect of Y76 phosphorylation on the enzyme activity but mutational studies revealed that inhibition of tyrosine phosphorylation increases PGK binding to uPAR mRNA and attenuates uPA-induced uPAR expression [40].…”

Understanding protein multifunctionality: from short linear motifs to cellular functions

“…In the case of the human phosphoglycerate kinase 1 (PGK1), a glycolytic enzyme that moonlights during tumour angiogenesis [35], early studies showed that it can bind the mRNA of the urokinase plasminogen activator surface receptor (PLAUR) and regulate its expression. This is mediated by the phosphorylation of a PGK1 tyrosine residue (Y76), that reduces the binding affinity of PGK1 to PLAUR mRNA, resulting in its stabilization and expression induction [36].…”