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.
Mol Cell Biochem. 2010 Feb;335(1-2):235-47. doi: 10.1007/s11010-009-0273-4. Epub 2009 Sep 26.
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.
尿激酶型纤溶酶原激活物（uPA）与其受体 uPAR 的相互作用在包括癌症在内的几种病理生理过程中起着核心作用。uPA 通过稳定 uPAR mRNA 来诱导其自身细胞表面受体表达。该机制涉及与磷酸甘油激酶（PGK）结合的 51nt uPAR mRNA 编码序列，以下调细胞表面 uPAR 表达。uPA 处理介导的 PGK 酪氨酸磷酸化增强了 uPAR mRNA 的稳定性。相比之下，抑制酪氨酸磷酸化增强了 PGK 与 uPAR mRNA 的结合，并减弱了 uPA 诱导的 uPAR 表达。PGK 的特定肽区的作图表明，其四分之一（氨基酸 1-100）与 uPAR mRNA 相互作用。为了确定 uPA 是否通过激活 PGK 的酪氨酸残基来调节 uPAR 的表达，我们突变了特定的酪氨酸残基，并测试了突变的 PGK 对 uPAR 表达的干扰能力。通过突变 Y76 残基抑制酪氨酸磷酸化，消除了 uPA 处理诱导的 uPAR 表达。这些发现共同表明，PGK 分子的四分之一中存在的 Y76 残基参与了肺上皮细胞表面 uPAR 的表达。该区域可以有效地模拟整个 PGK 分子在抑制肿瘤细胞生长中的功能。
