The Phosphatase PRL-3 Is Involved in Key Steps of Cancer Metastasis

Duciel, Laura; Gómez, Luis Cristóbal Monraz; Kondratova, Maria; Kuperstein, Inna; Saule, Simon

doi:10.1016/j.jmb.2019.06.008

Cited by 26 publications

(23 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, additional focus should also be paid to PTPs for their therapeutic potential in HCC. In the present study, we showed that a well-known PTP, PRL-3, which has been well studied in many malignant tumours, is involved in promoting HCC 36 . In fact, some studies have shown that PRL-3 is upregulated in HCC tissues and contributes to HCC progression through the PI3K/AKT pathway 5 , 37 .…”

Section: Discussionsupporting

confidence: 54%

PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK

Zhou

Liu

et al. 2020

Theranostics

View full text Add to dashboard Cite

Background: In addition to protein tyrosine kinases, accumulating evidence has shown that protein tyrosine phosphatases (PTPs) are suitable therapeutic targets in cancer. PRL-3 is a PTP member that has been well studied in many malignant tumours. The goal of the present study was to elucidate the role of PRL-3 in hepatocellular carcinoma (HCC), which remains largely unknown. Methods: Bioinformatic and immunohistochemical analyses were performed to analyse PRL-3 expression in HCC tissue samples and determine its clinical relevance. PRL-3 gene copy number variations were evaluated by bioinformatic analysis and quantitative-genomic polymerase chain reaction. The biological functions of PRL-3 were investigated in vivo and vitro. Gene microarray assays, RT-qPCR, western blotting and luciferase experiments were performed to identify the downstream effectors of PRL-3 that mediate its functions in HCC. Results: PRL-3 expression was upregulated in HCC samples from public databases and in cohort samples from our centre. High PRL-3 expression was associated with poor prognosis. Copy number gains and amplification of chromosome 8q24.3 in HCC were determined to be positively correlated with the PRL-3 overexpression. PRL-3 overexpression promoted HCC cell proliferation, migration and adhesion, while its loss had the opposite effects. Further study showed that focal adhesion kinase (FAK) was co-amplified and co-expressed with PRL-3 in HCC. Interestingly, PRL-3 also promoted the phosphorylation of FAK, which subsequently mediated the oncogenic functions of PRL-3 in HCC cells. Moreover, TGFB1 was identified as a downstream molecule of PRL-3. TGF-β signalling was shown to mediate the PRL-3-induced activation of FAK. Furthermore, the p38 and PI3K/AKT pathways were observed to mediate the PRL-3-induced expression of TGFB1 and the subsequent activation of FAK, while the activation of FAK in turn stimulated activation of the p38 and PI3K/AKT pathways, forming a PRL-3-triggered AKT/p38/TGFB1/FAK positive feedback loop. Conclusion: Collectively, our findings indicate that the PTP PRL-3 plays a crucial role in the progression of HCC and provides an example of how co-amplified genes work together in HCC.

show abstract

Section: Discussionsupporting

confidence: 54%

PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK

Zhou

Liu

et al. 2020

Theranostics

View full text Add to dashboard Cite

show abstract

“…Phosphatase of regenerating liver-3 (PRL-3) also known as protein tyrosine phosphatase 4A3 (PTP4A3) promotes key steps of cancer metastasis [39]. PRL-3 is expressed in 43% of AML samples, absent in normal haematopoietic cells [40] and implicated in LSC formation [41].…”

Section: Wnt Signalling In the Pathogenesis Of Acute Myeloid Leukamentioning

confidence: 99%

Wnt Signalling in Acute Myeloid Leukaemia

Gruszka-Westwood

Valli

Alcalay

2019

Cells

View full text Add to dashboard Cite

Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor cells, which upregulate Wnt signalling through a variety of mechanisms. Other mechanisms of Wnt activation in AML have been described such as Wnt antagonist inactivation through promoter methylation. Wnt signalling is necessary for the maintenance of leukaemic stem cells. Several molecules involved in or modulating Wnt signalling have a prognostic value in AML. These include: β-catenin, LEF-1, phosphorylated-GSK3β, PSMD2, PPARD, XPNPEP, sFRP2, RUNX1, AXIN2, PCDH17, CXXC5, LLGL1 and PTK7. Targeting Wnt signalling for tumour eradication is an approach that is being explored in haematological and solid tumours. A number of preclinical studies confirms its feasibility, albeit, so far no reliable clinical trial data are available to prove its utility and efficacy.

show abstract

“…The mechanism of PRL oncogenicity remains an enigma. A number of different signaling pathways have been implicated but without a clear consensus (17)(18)(19). As an alternative, PRLs were shown to directly bind and inhibit a class of Mg 21 transport-associated proteins, CBS domain divalent metal cation transport mediators (CNNMs) (4,20).…”

mentioning

confidence: 99%

PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth

Kozlov

Funato

Chen

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Phosphatases of regenerating liver (PRLs) are markers of cancer and promote tumor growth. They have been implicated in a variety of biochemical pathways but the physiologically relevant target of phosphatase activity has eluded 20 years of investigation. Here, we show that PRL3 catalytic activity is not required in a mouse model of metastasis. PRL3 binds and inhibits CNNM4, a membrane protein associated with magnesium transport. Analysis of PRL3 mutants specifically defective in either CNNM-binding or phosphatase activity demonstrate that CNNM-binding is necessary and sufficient to promote tumor metastasis. As PRLs do have phosphatase activity, they are in fact pseudo-pseudophosphatases. Phosphatase activity leads to formation of phosphocysteine, which blocks CNNM-binding and may play a regulatory role. We show levels of PRL cysteine phosphorylation vary in response to culture conditions and in different tissues. Examination of related protein phosphatases shows the stability of phosphocysteine is a unique and evolutionarily conserved property of PRLs. The demonstration that PRL3 functions as a pseudophosphatase has important ramifications for the design of PRL inhibitors for cancer.

show abstract

The Phosphatase PRL-3 Is Involved in Key Steps of Cancer Metastasis

Cited by 26 publications

References 87 publications

PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK

PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK

Wnt Signalling in Acute Myeloid Leukaemia

PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth

Contact Info

Product

Resources

About