Antibody Array Revealed PRL-3 Affects Protein Phosphorylation and Cytokine Secretion

Yang, Yongyong; Lian, Shenyi; Meng, Lin; Qu, Like; Shou, Chengchao

doi:10.1371/journal.pone.0169665

Cited by 17 publications

(28 citation statements)

References 57 publications

(85 reference statements)

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“…Studies using transient PTP4A3 overexpression systems implicate a number of signaling molecules and cellular pathways; however, we do not have a solid understanding of the mechanism by which PTP4A3 influences these signaling mechanisms and subsequent cellular responses. It appears that, within these transient expression systems, PTP4A3 has a central role in regulating the phosphorylation status of important intracellular signaling proteins, yet, paradoxically, hyper-rather than hypophosphorylation of tyrosines, serines, and threonines has been observed in cells with elevated levels of PTP4A3 (47). Such results imply that the observed changes in the phosphorylation status of the signaling proteins are an indirect effect of PTP4A3 activity (28).…”

Section: Discussionmentioning

confidence: 99%

A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion

et al. 2018

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Dysregulation of the tightly controlled protein phosphorylation networks that govern cellular behavior causes cancer. The membrane-associated, intracellular protein tyrosine phosphatase PTP4A3 is overexpressed in human colorectal cancer and contributes to cell migration and invasion. To interrogate further the role of PTP4A3 in colorectal cancer cell migration and invasion, we deleted the Ptp4a3 gene from murine colorectal tumor cells. The resulting PTP4A3 cells exhibited impaired colony formation, spheroid formation, migration, and adherence compared with the paired PTP4A3 cells. We replicated these phenotypic changes using the new small-molecule, allosteric PTP4A3 inhibitor JMS-053. A related structure, JMS-038, which lacked phosphatase inhibition, displayed no cellular activity. Reduction in cell viability and colony formation by JMS-053 occurred in both mouse and human colorectal cell lines and required PTP4A3 expression. Ptp4a3 deletion increased the expression of extracellular matrix (ECM) and adhesion genes, including the tumor suppressor Emilin 1. JMS-053 also increased Emilin 1 gene expression. Moreover, The Cancer Genome Atlas genomic database revealed human colorectal tumors with high Ptp4a3 expression had low Emilin 1 expression. These chemical and biologic reagents reveal a previously unknown communication between the intracellular PTP4A3 phosphatase and the ECM and support efforts to pharmacologically target PTP4A3.-McQueeney, K. E., Salamoun, J. M., Ahn J. G., Pekic, P., Blanco, I. K., Struckman, H. L., Sharlow, E. R., Wipf, P., Lazo, J. S. A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion.

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Section: Discussionmentioning

confidence: 99%

A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion

et al. 2018

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“…High-throughput proteomic approaches to identify de novo PRL-3 targets revealed widespread global phosphorylation, suggesting that a number of signaling pathways converge on PRL-3 (9,10). Furthermore, PRL-3 is highly involved in cytokine and growth factor signaling (15,16). In multiple myeloma, PRL-3 was identified as an IL6-responsive gene with a role in myeloma cell migration (16,17).…”

Section: Introductionmentioning

confidence: 99%

IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma

et al. 2019

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Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity, and tumorigenesis, and detailed mechanistic studies revealed "deactivation" of effector proteins such as Akt, Erk1/2, Src, STAT1, and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-Myc and Mcl-1, and antiapoptotic genes Bcl2 and Bcl-xL. PRL-3 also played a role in the acquired resistance of myeloma cells to bortezomib, which could be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression was positively correlated in five independent cohorts, and the STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PRL-3 could be used as a biomarker to identify highrisk patients with multiple myeloma that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (proteasome inhibitors and immunomodulatory imide drugs). Conclusively, our results support a feedforward mechanism between STAT3 and PRL-3 that prolongs prosurvival signaling in multiple myeloma, and suggest targeting PRL-3 as a valid therapeutic opportunity in multiple myeloma. Significance: IL6 promotes STAT3-dependent transcriptional upregulation of PRL-3, which in turn rephosphorylates STAT3 and aberrantly activates STAT3 target genes, leading to bortezomib resistance in multiple myeloma.

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“… 4 , 7 – 9 Besides, several proteomic analyses revealed that PRL-3 could widely increase intracellular protein phosphorylation. 10 , 11 The previous study showed that maintenance of basal PRL-3 levels is important for proper cell cycle progression in normal cells. 12 Our recent study showed that overexpression of PRL-3 could promote telomere deprotection through interaction with telomeric binding protein, repressor activator protein 1 (RAP1).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of PRL-3 increases mitochondrial superoxide anion production through transcriptional regulation of RAP1

Yang

Lian

Meng

et al. 2018

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BackgroundPhosphatase of regenerating liver-3 (PRL-3) has been shown to be highly expressed in various types of cancers and is related to poor prognosis. Our previous study showed that silencing of PRL-3 leads to increased reactive oxygen species (ROS). However, the mechanism of PRL-3 regulating ROS is not clear.Materials and methodsPRL-3 or Repressor activator protein 1 (RAP1) was knockdown in human colorectal cancer cell lines HCT116 and SW480. The mRNA level was measured by quantitative real-time (qRT)-PCR and the protein level was measured by western blot. ROS was detected by specific oxidationsensitive fluorescent probes. Cell cycle was analyzed through flow cytometry. Luciferase assay and chromatin immunoprecipitation (ChIP) were performed to investigate the regulation of RAP1 by PRL-3. Gene expression correlation was analyzed through an interactive web server. Statistical analysis was performed with SPSS software.ResultsKnockdown of PRL-3 significantly increases mitochondrial superoxide anion, mitochondria membrane potential, and induces cell cycle arrest. Decreased PRL-3-induced mitochondrial superoxide anion accumulation is related to the downregulation of RAP1, which could also affect the level of mitochondria superoxide anion. PRL-3 regulates the expression of RAP1 through binding to the promoter of rap1 gene. PRL-3 could regulate the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) through the mediation of RAP1. Both PRL-3 and RAP1 could regulate the expression of manganese superoxide dismutase 2 (SOD2) and the uncoupling protein 2 (UCP2), which may be related to PRL-3 suppression induced mitochondria superoxide anion.ConclusionOur study presents the first evidence that PRL-3 is involved in the regulation of mitochondria superoxide anion as a transcriptional factor.

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Antibody Array Revealed PRL-3 Affects Protein Phosphorylation and Cytokine Secretion

Cited by 17 publications

References 57 publications

A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion

A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion

IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma

Knockdown of PRL-3 increases mitochondrial superoxide anion production through transcriptional regulation of RAP1

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