Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase.
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.
Shetty
Praveenkumar
P
Texas Lung Injury Institute, Department of Specialty Care Services, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Lab C-6, Tyler, TX 75708, USA.
Velusamy
Thirunavukkarasu
T
Bhandary
Yashodhar P
YP
Liu
Ming C
MC
Shetty
Sreerama
S
D001665:Binding Sites; D006801:Humans; D010735:Phosphoglycerate Kinase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D014443:Tyrosine; D010735:Phosphoglycerate Kinase