| The Phosphatase of Regenerating Liver (PRL) family, consisting of PRL-1, PRL-2, and PRL-3, is a group of prenylated phosphatases that are candidate cancer biomarkers and therapeutic targets. Individual PRLs are over-expressed in a variety of cancer cell lines and tissues, and elevated PRL expression has been associated with tumorigenesis and metastasis. Although several studies have documented that altered expression of PRL-1 or PRL-3 can influence cell proliferation, migration and invasion, there is an absence of knowledge about the biological functions of PRL-2. Thus, the current study was designed to evaluate the role of PRL-2 in cell migration and invasion in human cancer cells. I found that four lung cancer cells, including A549, over-expressed PRL-2 when compared with normal lung cells. PRL-2 suppression by siRNA or shRNA markedly inhibited cell migration and invasion. PRL-2 suppression by siRNA decreased p130Cas and vinculin expression, increased phosphorylation of Ezrin on tyrosine 146, and decreased ERK phosphorylation upon serum stimulation. There were no significant changes in total p53, Akt and c-Src expression levels or their phosphorylation status, suggesting PRL-2 suppression could inhibit tumor cell migration and invasion through a Src-independent p130Cas signaling pathway. Ectopic expression of wild type PRL-2, a catalytic inactive C101S mutant, and a C-terminal CAAX deletion revealed a requirement for both the PRL-2 catalytic functionality and prenylation site. Expression of wild type but not the mutant forms of PRL-2 caused ERK phosphorylation and nuclear translocation, and promoted tumor cell migration and invasion. These results support a model in which PRL-2 promotes cell migration and invasion through an ERK-dependent signaling pathway. In addition, thienopyridone, a previously reported PRL inhibitor, showed antiproliferative activity in a concentration-dependent manner, and decreased cell migration and invasion. In summary, these studies demonstrate for the first time that PRL-2 regulates cell migration and invasion in non-small cell lung cancer, and I propose that PRL-2 stimulates cell migration and invasion through an ERK signaling pathway. |
