Subsequent studies have corroborated PRL3’s association with colon cancer metastases and extended the correlation between PRL-3 expression and metastasis of several other cancers. In contrast, a few studies failed to support a positive relationship between PRLs and cancer; one study found that PRL-3 levels did not affect outcomes of ovarian cancer and another study demonstrated that a 10-fold reduction in levels of PRL-3 correlated to lung cancer metastasis. Failure to demonstrate the ability of PRL-3 to serve as an independent prognostic factor led Hatate et al. to speculate that PRL-3 expression may not represent a direct causative mechanism of liver metastasis. Surprisingly, PRL-3 was isolated as a p53 target that contributed to the cell cycle arrest of damaged cells. Additional studies also demonstrated PRL-3 to halt cell cycle progression when exogenously introduced into non-damaged cells. Paclitaxel However, the ability of PRL-3 to inhibit cell cycle progression was not universal, occurring in three of five cell lines tested. The authors hypothesized that the discrete responses likely reflect existing mutations in the various tumor cell lines that alter downstream effectors of PRL-3. Because their initial findings were from primary mouse embryo fibroblasts, the ability for PRL-3 to suppress cell growth may be its “normal” function. In vivo expression surveys support the notion that PRLs can contribute to growth arrest. For example, PRL-1 is highly expressed in differentiated intestinal cells relative to undifferentiated counterparts. In addition, Kong et al. showed that PRL-1 expression correlates with terminal differentiation of other epithelial tissues, such as the kidney and lung. PRL-2 and -3 can also associate with differentiated tissues, with both preferentially expressed in muscle tissue. All three PRL family members contain a consensus tyrosine phosphatase domain and a C-terminal prenylation, CAAX motif,. Only two proteins have been shown to be directly dephosphorylated by PRL: Ezrin and a poorly characterized basic leucine zipper RWJ 64809 protein called ATF-7. However, in all cases examined, a catalytically active phosphatase domain was required for phenotypes resulting from PRL-3 overexpression, including increases in proliferation, migration,, and metastases formation in animal models. Another important regulator of PRL function is farnesylation of the CAAX motif. Either mutating the motif or adding a farnesyltransferase inhibitor leads to subcellular redistribution of PRLs, 
from membrane to nucleus,. This relocalization results in a block to cellular responses to ectopic PRL expression, such as enhanced proliferation, migration,, and metastasis. However, another group determined that cytoplasmic localization is positively related to metastasis of cervical cancer, confounding a direct relationship between PRL subcellular localization and cellular outcome. Two signal transduction pathways that have been implicated as oncogenic effectors of PRLs are Src and PI3K signaling. PRL-3 activates Src signaling,, by reducing the synthesis of protein, Csk, an inhibitor of the pathway, and upregulation of PRL1 activates the Src kinase through increased Tyr416 phosphorylation and cell migration. Similar to its effect on Src signaling, PRL-3 promotes PI3K signaling by reducing levels of a protein that normally antagonizes.