Guo K, Li J, Tang J, Koh V, Gan B, Zeng QCatalytic domain of PRL-3 plays an essential role in tumor metastasis: Formation of PRL-3 Tumors inside the blood vessels. Cancer Biol Ther 3: 945-951

Institute of Molecular and Cell Biology, Singapore.
Cancer biology & therapy (Impact Factor: 3.07). 11/2004; 3(10):945-51. DOI: 10.4161/cbt.3.10.1111
Source: PubMed


PRL-3, a protein tyrosine phosphatase, has attracted much attention as its transcript is consistently upregulated in the process of colorectal cancer metastases to secondary organs. We studied mice injected via the tail vein with CHO cells stably expressing EGFP-tagged PRL-3 or catalytically inactive mutant PRL-3 (C104S). Our data showed that the EGFP-PRL-3-expressing cells rapidly induce metastatic tumor formation in lung, while EGFP-PRL-3 (C104S)-expressing cells lose this metastastic activity. Furthermore, detailed microscopic examinations revealed that some EGF-PRL-3-, but not EGFP-PRL-3 (C104S)-, expressing cells form micro- and macro-metastatic solid tumors that sprout into blood vessels. Our studies provide clear evidence for a causative role of PRL-3 phosphatase activity in cancer metastasis and tumor-related angiogenesis events. The catalytic domain of PRL-3 could serve as an ideal therapeutic target for drug development to block the spread of colorectal cancer.

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    • "However, both the mutants have greatly abolished this phenomenon, especially for the mutant PRL-3(ΔCAAX) had its ability decreased to a more significant degree. The defeat of PRL-3(C104S) mutant could be explained by its loss of phosphatase activity or a potential to form an inter- molecular disulfide bond to act on its downstream targets, which is also observed in colon cancer in Guo’s study [29]. It is therefore hypothesized that both the phosphatase catalytic activity and its cytomembrane location is indispensable for its function in gastric cancer metastasis. "
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    ABSTRACT: PRL-3 is a member of phosphatases of regenerating liver family, characterized by phosphatase active domain and C-terminal prenylation motif. Overexpression of PRL-3 has been implicated in multiple cancers. Here we examined the clinical significance of PRL-3 in gastric cancer together with its metastatic biological functions utilizing different structural mutants. PRL-3 expression was analyzed immunohistochemically in 196 gastric cancer patients and 21 cases of liver metastasis. A series of wild type PRL-3 or its mutant plasmids were expressed in BGC823 cells to investigate the relationship between its catalytic activity, cellular localization and metastatic potential in vitro. Positive staining of PRL-3 was observed in 19.4% (38/196) gastric cancer tissues compared with 76.2% (16/21) in liver metastasis. Statistical analysis revealed that PRL-3 expression correlated with lymph node metastasis and vascular invasion (P < 0.05). Patients with high PRL-3 expression showed poorer 5-year overall survival (P = 0.011). Wild type PRL-3 expressing cells resulted in enhanced migration and invasion ability, which were greatly crippled in form of PRL-3(C104S) or PRL-3(DeltaCAAX) mutants accompanied with its alteration in subcellular localization. Metastasis associated protein PRL-3 may serve as a potential prognostic biomarker in human gastric cancer. Both the phosphatase catalytic activity and cellular localization are critical for its function.
    Full-text · Article · Dec 2013 · Journal of Translational Medicine
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    • "The Drosophila genome encodes a single PRL protein (dPRL-1), which is highly similar (74–76%) to all three human PRLs and contains the three domains shown to be required for PRL function in mammals: a Dual Specific Phosphatase (DSP) active site (HCxxGxxR) [9],[12],[13],[15],[48], an aspartate (Asp77) that has been demonstrated to facilitate phosphate transfer [58], and a C-terminal, membrane-targeting CAAX motif adjacent to a polybasic region [48]–[51]. Transgenic animals containing full-length dPRL-1 under the control of Upstream Activating Sequences (UAS) were crossed to numerous lines of animals that expressed the transcriptional activator GAL4 in a tissue-specific manner. "
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    ABSTRACT: Phosphatase of Regenerating Liver (PRL) family members have emerged as molecular markers that significantly correlate to the ability of many cancers to metastasize. However, contradictory cellular responses to PRL expression have been reported, including the inhibition of cell cycle progression. An obvious culprit for the discrepancy is the use of dozens of different cell lines, including many isolated from tumors or cultured cells selected for immortalization which may have missing or mutated modulators of PRL function. We created transgenic Drosophila to study the effects of PRL overexpression in a genetically controlled, organismal model. Our data support the paradigm that the normal cellular response to high levels of PRL is growth suppression and furthermore, that PRL can counter oncogenic activity of Src. The ability of PRL to inhibit growth under normal conditions is dependent on a CAAX motif that is required to localize PRL to the apical edge of the lateral membrane. However, PRL lacking the CAAX motif can still associate indiscriminately with the plasma membrane and retains its ability to inhibit Src function. We propose that PRL binds to other membrane-localized proteins that are effectors of Src or to Src itself. This first examination of PRL in a model organism demonstrates that PRL performs as a tumor suppressor and underscores the necessity of identifying the conditions that enable it to transform into an oncogene in cancer.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "PRL-3 is frequently overexpressed in a variety of cancer tissues, which correlates with disease progression and patients' survival [5] [6] [7] [8]. Mutation at PRL-3's catalytic domain could reduce cancer cell motility, suggesting PRL-3's PTP activity is essential for cancer cell migration [9] [10]. Mechanistic investigations show that PRL-3 stimulates invasion and motility of cancer cells by activating the Rho family of small GTPases and the matrix metalloproteinase-2 (MMP-2) [11] [12]. "
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    ABSTRACT: Phosphatase of regenerating liver (PRL-3) promotes cancer metastasis through enhanced cell motility and invasiveness, however its role in tumorigenesis remains unclear. Herein, we reported that PRL-3 interacts with telomere-related protein RAP1. PRL-3 promotes the cytosolic localization of RAP1, which is counteracted by silencing of PRL-3. Immunohistochemical staining of colon cancer tissue array (n=170) revealed that high level of PRL-3 associates with cytosolic localization of RAP1 (p=0.01). Microarray analysis showed that PRL-3 regulates expression of diverse genes and enhances phosphorylation of p65 subunit of NF-κB in a RAP1-dependent manner. Furthermore, PRL-3 transcriptionally activates RAP1 expression, which is counteracted by ablating p65. Therefore, our results demonstrate PRL-3 as a novel regulator of NF-κB signaling pathway through RAP1.
    Preview · Article · Nov 2012 · Biochemical and Biophysical Research Communications
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