Affinage

PTP4A3

Protein tyrosine phosphatase type IVA 3 · UniProt O75365

Length
173 aa
Mass
19.5 kDa
Annotated
2026-06-10
100 papers in source corpus 47 papers cited in narrative 47 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTP4A3 (PRL-3) is a prenylated, membrane-associated dual-specificity phosphatase whose catalytic activity at Cys104 drives pro-metastatic cellular behaviors including migration, invasion, EMT, and metastatic colonization in vivo (PMID:12782572, PMID:15326366, PMID:17409395). Structurally it adopts a dual-specificity phosphatase fold with an unusually hydrophobic active site whose loops are conformationally flexible until stabilized by substrate or vanadate binding, and its C-terminal CAAX motif both directs prenylation-dependent plasma membrane anchoring required for migration and modulates catalytic efficiency (PMID:14704153, PMID:15135076, PMID:28284838, PMID:19040419). PRL-3 dephosphorylates a range of direct substrates that converge on cytoskeletal and adhesion remodeling — Ezrin-Thr567, keratin 8, integrin β1, CRMP2-T514, and the phosphoinositide PI(4,5)P2 — linking its activity to lamellipodial dynamics, focal-adhesion turnover, and directed cell movement (PMID:18078820, PMID:19115206, PMID:21806020, PMID:28284838, PMID:30816227). A central output is activation of PI3K/Akt signaling, achieved in part by down-regulating PTEN and NHERF1-dependent PTEN compartmentalization, feeding EMT, survival, and mTORC1 activation (PMID:17409395, PMID:25897829, PMID:26597054); PRL-3 additionally suppresses PTP1B to hyperactivate EGFR, engages integrin β1–ERK1/2 and VEGF–Src axes, and activates NF-κB through RAP1 (PMID:23867504, PMID:19930715, PMID:24403062, PMID:23178297). Beyond the cytoplasm, nuclear PRL-3 promotes genomic instability by dephosphorylating FZR1 to drive APC/C-mediated AURKA degradation and by displacing the shelterin proteins RAP1/TRF2 from telomeres, and it dephosphorylates the PAF-complex subunit Leo1 to activate β-catenin/TCF transcription in leukemia (PMID:30498084, PMID:28482095, PMID:30305722). PRL-3 dephosphorylates p38 MAPK to confer stress and apoptosis resistance and supports tumor-initiating cell self-renewal in vivo (PMID:34662712, PMID:24950307). Its expression is tightly controlled — transcriptionally by p53, TGFβ/Smad, VEGF/MEF2C, and NSD2-SMARCA2 chromatin remodeling, translationally by PCBP1, and post-translationally by FKBP38 and USP4 governing proteasomal stability (PMID:18471976, PMID:21084277, PMID:22073279, PMID:33602783, PMID:20609352, PMID:21320469, PMID:26669864).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 Medium

    Establishing that PRL-3 is a bona fide enzyme answered whether the protein had intrinsic catalytic activity and tied that activity to a cellular signaling output.

    Evidence Recombinant phosphatase activity assay inhibited by vanadate, plus C104S mutant in HEK293 calcium/p130cas assays

    PMID:11355880

    Open questions at the time
    • No physiological substrate identified at this stage
    • Cellular readouts were indirect
  2. 2004 High

    Solution structures defined PRL-3 as a dual-specificity phosphatase and revealed an unusual hydrophobic, conformationally dynamic active site with a potential redox-regulatory disulfide, framing the enzymatic basis of its activity.

    Evidence NMR solution structures of apo and phosphate/vanadate-bound states with kinetic mutant analysis

    PMID:14704153 PMID:15135076

    Open questions at the time
    • Structure alone did not define endogenous substrates
    • Redox regulation not demonstrated in cells
  3. 2004 High

    Linking catalytic activity to metastasis answered whether PRL-3's phosphatase function is causally required for malignant dissemination, not merely correlated.

    Evidence WT vs C104S PRL-3 stable CHO lines in transwell assays and tail-vein mouse metastasis models

    PMID:12782572 PMID:15326366

    Open questions at the time
    • Substrates mediating the phenotype unknown at this point
    • Mechanism of membrane association not defined
  4. 2009 High

    Identification of direct substrates (Ezrin-Thr567, keratin 8, integrin β1) connected catalytic activity to specific cytoskeletal and adhesion targets driving motility.

    Evidence Phosphoproteomics, in vitro dephosphorylation, Co-IP, colocalization, and siRNA epistasis with catalytic mutant controls

    PMID:16472776 PMID:18078820 PMID:19115206 PMID:19930715

    Open questions at the time
    • Relative contribution of each substrate to metastasis not ranked
    • Substrate selectivity determinants not defined
  5. 2011 High

    Demonstrating phosphatase activity toward PI(4,5)P2 expanded PRL-3's substrate repertoire to lipids and correlated lipid activity with migration across mutants.

    Evidence Two complementary in vitro phosphoinositide assays, docking, and migration assays with multiple mutants

    PMID:21806020

    Open questions at the time
    • In vivo phosphoinositide dephosphorylation not shown
    • Tension with protein-substrate findings unresolved
  6. 2013 High

    Mapping PRL-3 onto PI3K/Akt, EGFR, and PTEN axes explained how phosphatase activity is amplified into broad oncogenic signaling and EMT.

    Evidence PTP1B knockdown/rescue across cancer lines, PI3K inhibitor epistasis, EMT marker profiling

    PMID:17409395 PMID:23867504

    Open questions at the time
    • Direct substrate linking PRL-3 to PTP1B transcription not identified
    • Quantitative pathway hierarchy unclear
  7. 2014 High

    Genetic knockout models established PTP4A3 as physiologically required for tumor formation, tumor-initiating cell self-renewal, and VEGF-driven angiogenesis.

    Evidence Ptp4a3-null mice in AOM/DSS colon cancer, CD133+ clonogenicity/transplantation, and VEGF-Src endothelial signaling assays

    PMID:23555575 PMID:24403062 PMID:24950307

    Open questions at the time
    • Substrates mediating self-renewal not fully defined
    • Endothelial Src substrate not identified
  8. 2018 High

    Nuclear and chromatin-linked functions answered how PRL-3 promotes genomic instability and stemness, via FZR1/APC/C-AURKA, telomeric RAP1/TRF2 displacement, and Leo1/β-catenin signaling.

    Evidence Co-IP, ubiquitination and APC/C activity assays, telomeric ChIP and in vitro dissociation, SILAC proteomics with rescue and xenograft models

    PMID:24686170 PMID:28482095 PMID:30305722 PMID:30498084

    Open questions at the time
    • How a prenylated membrane phosphatase accesses telomeric/nuclear substrates not mechanistically resolved
    • Coordination between nuclear and cytoplasmic pools unclear
  9. 2021 High

    Layered regulation of PTP4A3 expression — chromatin (NSD2-SMARCA2), transcription factors, translation (PCBP1), and protein stability (FKBP38, USP4) — explained how its oncogenic dosage is set.

    Evidence SILAC/Co-IP, promoter ChIP and reporter assays, polyribosome fractionation, deubiquitination and degradation assays across cancer models

    PMID:20609352 PMID:21320469 PMID:26669864 PMID:33602783

    Open questions at the time
    • Integration of multiple regulatory inputs in a single context not modeled
    • Upstream cues selecting each mode unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PRL-3 selects among its diverse protein and lipid substrates in different subcellular compartments, and which substrate set dominates clinically relevant metastasis, remains unresolved.
  • No unifying model reconciling lipid-phosphatase and protein-phosphatase activities
  • Compartment-specific substrate prioritization unknown
  • No human Mendelian disease link established in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3 GO:0008289 lipid binding 1
Localization
GO:0005634 nucleus 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 1
Partners
ARF1AURKAFKBP38FZR1HDAC4ITGB1RAP1USP4

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 NMR solution structure of PRL-3 (residues 1-162) reveals it belongs to the dual-specificity phosphatase class with closest structural homology to VHR phosphatase. The active site is unusually hydrophobic and lacks the catalytically important serine/threonine found in most other phosphatases. Cys49 forms an intramolecular disulfide bond with the catalytic Cys104 under mildly reducing conditions, suggesting a potential redox-regulatory mechanism. NMR solution structure determination combined with kinetic studies of site-directed mutants The Journal of biological chemistry High 14704153
2004 NMR structure of human PRL-3 phosphatase domain shows conformational flexibility of active-site loops; addition of phosphate or vanadate stabilizes active-site residues, indicating the apo form has a disordered active site that is stabilized by substrate/inhibitor binding. NMR spectroscopy of apo and phosphate/vanadate-bound states FEBS letters High 15135076
2003 PRL-3 catalytic activity is required for its pro-migratory and pro-invasive function; a catalytically inactive C104S mutant has significantly reduced migration-promoting activity. PRL-3 is associated with diverse membrane structures involved in cell movement. Stable expression of PRL-3 in CHO cells induces metastatic tumor formation in mice. Stable cell line expression, catalytically inactive mutant (C104S), transwell migration/invasion assays, mouse metastasis model Cancer research High 12782572
2004 The catalytic domain of PRL-3 is essential for metastasis in vivo; CHO cells expressing catalytically inactive PRL-3 (C104S) lose metastatic activity in a tail-vein mouse model, while wild-type PRL-3-expressing cells form metastatic tumors in the lung and can sprout into blood vessels. Tail-vein injection of EGFP-PRL-3 vs EGFP-PRL-3(C104S) CHO cells in mice, microscopic examination Cancer biology & therapy High 15326366
2007 PRL-3 promotes epithelial-mesenchymal transition (EMT) by activating PI3K/Akt, inactivating GSK-3β, up-regulating mesenchymal markers (fibronectin, Snail) and down-regulating epithelial markers (E-cadherin, γ-catenin, integrin β3). PRL-3 down-regulates PTEN expression. These effects require phosphatase activity (C104S mutant abrogates them) and are blocked by PI3K inhibitor LY294002. Stable and transient transfection, phospho-specific antibodies, PI3K inhibitor, catalytic mutant Cancer research High 17409395
2007 Ezrin is a direct cellular substrate of PRL-3. PRL-3 overexpression dephosphorylates Ezrin-Thr567 (and tyrosine residues) in HCT116 cells, with Thr567 identified as the primary target. In vitro dephosphorylation assays confirm Ezrin-Thr567 as a direct substrate and establish PRL-3 as a dual-specificity phosphatase. Phosphoproteomic profiling, RNA interference, in vitro dephosphorylation assay, catalytic mutant comparison Biochimica et biophysica acta High 18078820
2006 Integrin α1 is a PRL-3-interacting protein identified by yeast two-hybrid screen and verified by pull-down and co-immunoprecipitation. PRL-3 down-regulates tyrosine phosphorylation of integrin β1 and increases ERK1/2 phosphorylation. Yeast two-hybrid screen, pull-down assay, co-immunoprecipitation, Western blot Biochemical and biophysical research communications Medium 16472776
2009 PRL-3 associates with integrin β1 (co-immunoprecipitation) and its expression positively correlates with ERK1/2 phosphorylation. siRNA depletion of integrin β1 abrogates PRL-3-induced ERK1/2 activation and blocks PRL-3-induced motility and invasion. PRL-3 promotes MMP2 gelatinolytic activity and reduces TIMP2 expression, mediating invasion downstream of integrin β1-ERK1/2 signaling. Co-immunoprecipitation, siRNA knockdown, transwell assay, gelatin zymography, ERK inhibitor (U0126), nude mouse lung metastasis model Molecular cancer High 19930715
2009 PRL-3 interacts with and dephosphorylates keratin 8 (KRT8) at S73 and S431. PRL-3 and KRT8 co-localize at cellular lamellipodia and ruffles in vivo. This interaction requires PRL-3 phosphatase activity (C104S mutant and PRL-3 inhibitor block KRT8 dephosphorylation). Reduction in KRT8 phosphorylation is observed at invasive front and liver metastases in colorectal cancer tissue. Phosphoprotein expression profiling, co-immunoprecipitation, colocalization, PRL-3 inhibitor, catalytic mutant (C104S) International journal of cancer Medium 19115206
2001 PRL-3 possesses enzymatic phosphatase activity (demonstrated by cleavage of 6,8-difluoro-4-methylumbelliferyl phosphate substrate), which is inhibited by vanadate. Catalytically inactive C104S mutant fails to inhibit angiotensin II-induced calcium mobilization, while wild-type PRL-3 inhibits it. Wild-type PRL-3 promotes dephosphorylation of p130cas in response to AngII. Purified recombinant enzyme activity assay, HEK293 transfection, FLIPR calcium assay, Western blot with phospho-specific antibodies Biochemical and biophysical research communications Medium 11355880
2010 PCBP1 suppresses PRL-3 protein expression post-transcriptionally by binding to triple GCCCAG motifs in the 5' UTR of PRL-3 mRNA and retarding its incorporation into polyribosomes. PCBP1 overexpression inhibits PRL-3 expression and inactivates AKT; PCBP1 knockdown causes PRL-3 upregulation and AKT activation. 5' UTR mutational analysis, polyribosome fractionation, RNA-protein binding assay, PCBP1 overexpression/knockdown Cancer cell High 20609352
2011 PRL-3 shows phosphatase activity toward the phosphoinositide PI(4,5)P2 in vitro (demonstrated by two complementary biochemical assays), suggesting it is a phosphatidylinositol 5-phosphatase. Wild-type PRL-3 does not dephosphorylate tested phosphopeptides. The C104S mutant is structurally destabilized and cannot promote cell migration; the hyperactive A111S mutant is inactive against PIPs and also cannot promote migration. Correlation between PI(4,5)P2 dephosphorylation activity and cell migration phenotype across mutants supports PI(4,5)P2 as a functionally relevant substrate. In vitro phosphoinositide dephosphorylation assays (two complementary biochemical methods), molecular docking, stable HEK293 cell lines, migration assay Biochemistry High 21806020
2008 Prl-3 is a p53 transcriptional target gene. Prl-3 overexpression induces G1 cell-cycle arrest downstream of p53 via PI3K-Akt-activated negative feedback. Loss of Prl-3 expression also induces cell-cycle arrest, indicating that basal Prl-3 is required for normal cell-cycle progression. Reporter assays for p53 transcriptional activation, PI3K inhibitor epistasis, cell-cycle analysis by FACS, gain/loss-of-function Molecular cell High 18471976
2013 PRL-3 induces hyperactivation of EGFR and its downstream cascades by transcriptionally downregulating PTP1B (an inhibitory phosphatase for EGFR), thereby creating cellular addiction to EGFR signaling. Loss of PTP1B mediates PRL-3's EGFR activation effect. Multiple human cancer cell lines, PTP1B knockdown/rescue, phospho-EGFR Western blot, gene expression analysis The Journal of clinical investigation High 23867504
2015 USP4 (ubiquitin-specific protease 4) physically interacts with PRL-3 and stabilizes it via deubiquitination. USP4 knockdown reduces PRL-3 protein levels; USP4 overexpression increases PRL-3 stability. This stabilization leads to AKT activation and E-cadherin reduction. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Western blot Cancer research Medium 26669864
2010 PRL-3 interacts with stathmin (co-immunoprecipitation in cell lines and tissues), and both contribute to microtubule destabilization in colorectal cancer cells. Proteomic screen, co-immunoprecipitation in cell lines and CRC tissue, microtubule stability assay Journal of proteome research Medium 20806969
2010 TGFβ suppresses PRL-3 transcription through Smad-dependent inhibition at the PRL-3 promoter. PRL-3 activates PI3K/AKT signaling to promote cell survival against stress-induced apoptosis, mediating metastatic colonization independently of primary tumor growth. Promoter-luciferase reporter assays, Smad knockdown, PI3K inhibitor, orthotopic mouse metastasis model, siRNA knockdown Cancer research High 21084277
2011 PRL-3 is a downstream target of FLT3-STAT5 signaling in AML; FLT3 inhibition (ABT-869) reduces PRL-3 expression. PRL-3 interacts with HDAC4 (co-immunoprecipitation). SAHA (HDAC inhibitor) downregulates PRL-3 via a proteasome-dependent pathway. Ectopic PRL-3 expression confers therapeutic resistance through upregulation of STAT pathway activity and anti-apoptotic Mcl-1. Co-immunoprecipitation (PRL-3-HDAC4), siRNA knockdown, FLT3 inhibitor treatment, proteasome inhibitor, STAT pathway Western blot PloS one Medium 21589872
2006 PRL-3-expressing tumor cells reduce IL-4 expression, attenuating IL-4's inhibitory effects on HUVEC vasculature, and directly recruit endothelial cells and initiate angiogenesis in vivo. Both CHO and DLD-1 cells expressing PRL-3 redirect HUVEC migration and enhance vascular formation. In vitro co-culture system with HUVECs, in vivo tumor implantation in nude mice with host endothelial cell recruitment, IL-4 assay Cancer research Medium 17018620
2014 PTP4A3-null endothelial cells exhibit severely reduced VEGF-stimulated migration. VEGF-induced Src phosphorylation is completely ablated in Ptp4a3-null endothelial cells, placing PTP4A3 as a required mediator in VEGF-Src signaling in endothelial cells. Ptp4a3-null mice show reduced tumor microvessel density and attenuated VEGF-mediated vascular permeability. Ptp4a3 knockout mouse model, primary endothelial cell isolation, VEGF stimulation, phospho-Src Western blot, wound healing assay, in vivo vascular permeability assay The Journal of biological chemistry High 24403062
2014 PTP4A3 deletion from murine colorectal tumor cells impairs colony formation, spheroid formation, migration, adherence, and increases expression of the extracellular matrix tumor suppressor Emilin1. These phenotypes are recapitulated by the allosteric small-molecule PTP4A3 inhibitor JMS-053 in a PTP4A3-expression-dependent manner. CRISPR/gene-targeted Ptp4a3 knockout in murine tumor cells, JMS-053 inhibitor, gene expression analysis, colony/spheroid/migration assays FASEB journal High 29746167
2011 VEGF induces PRL-3 transcription in HUVECs through the transcription factor MEF2C acting on two functional MEF2 binding sites in the PRL-3-iso2 promoter. MEF2C knockdown abolishes VEGF-induced PRL-3 upregulation. PRL-3 blocking suppresses tube formation by HUVECs. 5'UTR mapping, promoter-luciferase reporter with MEF2 site mutations, MEF2C siRNA, MEF2C overexpression, tube formation assay PloS one Medium 22073279
2012 PRL-3 interacts with ADP-ribosylation factor 1 (Arf1), co-localizes with Arf1 in an endosomal compartment, and regulates Arf1 activation. PRL-3-mediated cell migration depends on Arf1 expression and activation and is sensitive to Brefeldin A. PRL-3 modulates recycling of α5 integrins, requiring phosphatase activity and Arf1 co-compartmentalization. Co-immunoprecipitation, colocalization, Arf1 knockdown, Brefeldin A treatment, integrin recycling assay, catalytic mutant Journal of cell science Medium 22595524
2012 PRL-3 activates NF-κB signaling by interacting with the telomere-associated protein RAP1. PRL-3 promotes cytosolic localization of RAP1, enhances phosphorylation of the p65 NF-κB subunit in a RAP1-dependent manner, and transcriptionally activates RAP1 in a p65-dependent manner, forming a positive feedback loop. Co-immunoprecipitation, siRNA knockdown of RAP1, microarray analysis, p65 phosphorylation Western blot, colon cancer tissue array Biochemical and biophysical research communications Medium 23178297
2009 PRL-3 interacts with CDH22 (a cadherin family member), identified by yeast two-hybrid and confirmed by GST pull-down, Co-IP, and colocalization. PRL-3 inactivates GSK-3β (by phosphorylation), increases Snail expression, and promotes vimentin upregulation/E-cadherin downregulation consistent with EMT. Yeast two-hybrid, GST pull-down, Co-IP, colocalization, phospho-specific antibodies, GSK-3β inhibitor lithium chloride Cancer biology & therapy Medium 19440036
2012 Nuclear PRL-3 is observed in colorectal cancer cells and regulates histone H3K9 methylation by affecting the activities of the histone demethylases JMJD1B and JMJD2B, which are enriched among PRL-3-associated proteins. Subcellular fractionation/immunofluorescence (nuclear PRL-3), siRNA knockdown of JMJD1B/JMJD2B, histone methylation Western blot, proteomic association analysis Gut Medium 22345654
2011 FKBP38 directly binds PRL-3 (yeast two-hybrid and confirmed in vivo by Co-IP; N-terminal region of FKBP38 required for binding). FKBP38 overexpression reduces endogenous PRL-3 via proteasome-dependent degradation; FKBP38 depletion increases PRL-3 protein. FKBP38 suppresses PRL-3-mediated p53 activity and cell proliferation. Yeast two-hybrid, Co-IP, FKBP38 overexpression/siRNA, proteasome inhibitor, proliferation assay Biochemical and biophysical research communications Medium 21320469
2013 Targeted genetic deletion of Ptp4a3 in mice reduces colon tumor formation by ~50% in the azoxymethane/dextran sodium sulfate colitis-associated cancer model. Ptp4a3-null tumors show elevated IGF1Rβ and c-MYC levels compared to wildtype tumors. Gene-targeted Ptp4a3 knockout mouse, AOM/DSS colon cancer model, qPCR, Western blot PloS one High 23555575
2014 PRL-3 accumulates in autophagosomes upon inhibition of autophagic degradation and enhances PIK3C3-BECN1-dependent autophagosome formation in an ATG5-dependent manner. PRL-3's promotion of autophagy requires both catalytic activity and prenylation-dependent membrane association. PRL-3 itself becomes an autophagic substrate, establishing a negative feedback loop. Autophagy pathway is used by PRL-3 to promote cell growth with concomitant AKT activation. Autophagosome isolation/co-localization, LC3-I/II conversion assay, ATG5 knockdown, catalytic and prenylation mutants, SQSTM1 degradation assay Autophagy Medium 25136802
2015 PRL-3 dephosphorylates NHERF1 at a serine site, triggering NHERF1 cytoplasmic translocation. This co-translocates PTEN from nucleus to cytoplasm, reducing nuclear PTEN and elevating AKT phosphorylation, promoting melanoma malignant progression. Phosphorylation analysis, subcellular fractionation, co-localization imaging, siRNA knockdown, in vivo tumor model The Journal of investigative dermatology Medium 25897829
2015 PRL-3 increases mTOR translocation to lysosomes via increased mTOR binding affinity to Rag GTPases in an Akt-independent manner, and also activates mTORC1 via PI3K/Akt-mediated TSC2 suppression/Rheb-GTP activation, leading to downstream p70S6K and 4E-BP1 phosphorylation and increased MMP-2 secretion and invasiveness. mTOR lysosomal localization by immunofluorescence, Rag GTPase co-immunoprecipitation, Akt inhibitor, rapamycin treatment, invasion assay, multiple cancer models Scientific reports Medium 26597054
2015 PRL-3 mediates protein maturation of the NKG2D ligand ULBP2 by regulating tyrosine phosphorylation of HSP60, which constitutively associates with ULBP2. PRL-3 inhibition/knockdown blocks posttranslational maturation of ULBP2, causing intracellular retention, rather than affecting its shedding. High-throughput screening for PRL-3 inhibitors, siRNA knockdown, co-immunoprecipitation (ULBP2-HSP60), phospho-tyrosine Western blot, flow cytometry Journal of immunology Medium 25687758
2016 PRL-3 promotes epithelial lumen disruption and ectopic lumen formation in polarized epithelial MDCK and Caco2 cysts by accelerating cytokinesis and causing midbody mispositioning, without altering mitotic spindle orientation or asymmetric abscission. 3D cyst culture, time-lapse microscopy, cytokinesis timing measurement, spindle orientation assay, midbody localization analysis, catalytic mutant comparison Journal of cell science Medium 27656108
2017 PRL-3 interacts with integrin β1 and FAK-pY397 in focal adhesion structures (co-immunoprecipitation). PRL-3 plasma membrane anchorage (via CAAX prenylation) is required for PRL-3-induced migration; a prenylation-deficient mutant abolishes migration. PRL-3 dephosphorylates integrin β1 in its intracytoplasmic S/T region and regulates integrin β1 clustering in focal adhesions on collagen I but not fibronectin. Co-immunoprecipitation, integrin β1 knockdown, prenylation mutant, phosphorylation analysis, confocal imaging of focal adhesions, migration assay Experimental cell research Medium 28284838
2017 PRL-3 promotes telomere deprotection and chromosomal instability through its association with the shelterin component RAP1, which mediates PRL-3 recruitment to telomeric DNA along with TRF2. PRL-3 overexpression dissociates RAP1 and TRF2 from telomeric DNA in vitro and in cells. Disruption of the PRL-3-RAP1 complex or ectopic TRF2 counteracts PRL-3-induced telomere deprotection. Co-immunoprecipitation (RAP1, TRF2), ChIP at telomeres, in vitro DNA-protein dissociation assay, PRL-3 transgenic mice, DSS-induced colon malignancy model Nucleic acids research Medium 28482095
2018 PRL-3 dephosphorylates FZR1 (a regulatory subunit of APC/C), facilitating APC/C(FZR1) complex assembly, which leads to enhanced ubiquitination and degradation of Aurora kinase A (AURKA). This PRL-3-FZR1-AURKA axis promotes G2-M arrest, chromosomal instability, and self-renewal in colorectal cancer. PRL-3 physically interacts with both AURKA and FZR1. Co-immunoprecipitation (PRL-3-AURKA, PRL-3-FZR1), ubiquitination assay, phosphatase-dead mutant, FZR1 phosphorylation Western blot, APC/C activity assay, xenograft model Cancer research High 30498084
2018 PRL-3 dephosphorylates Leo1 (a component of the PAF complex) on serine residues. Serine-dephosphorylated Leo1 binds directly to β-catenin, promoting nuclear β-catenin accumulation and TCF/LEF target gene transactivation (cyclin D1, c-myc) in AML. SILAC proteomics, Co-IP (Leo1 identified as direct PRL-3 substrate), phosphorylation assay, β-catenin nuclear localization, TCF/LEF reporter assay, in vitro and in vivo rescue experiments Oncogene High 30305722
2014 PRL-3 overexpression in AML increases JMJD2C histone demethylase occupancy on the Leo1 promoter, reducing H3K9me3 repressive marks and promoting Leo1 gene expression. Leo1 mediates PRL-3 oncogenic activities (cytokine-independent growth) and loss of Leo1 destabilizes the PAF complex and downregulates SOX2/SOX4. SILAC proteomics, ChIP (JMJD2C and H3K9me3 at Leo1 promoter), siRNA knockdown, cytokine-independence assay Cancer research Medium 24686170
2016 PRL-3 phosphatase activity dependently upregulates LIN28B, which represses the let-7 miRNA family and induces a stem cell-like transcriptional program in AML cells. This PRL-3/LIN28B/let-7 axis is required for leukemogenesis in vitro and in vivo. Catalytic mutant comparison, LIN28B expression analysis, let-7 miRNA measurement, xenograft mouse model Molecular cancer research Medium 28011885
2021 NSD2 interacts with SMARCA2 (SWI/SNF ATPase) in a non-canonical, SWI/SNF complex-independent manner. The NSD2-SMARCA2 complex binds the PTP4A3 promoter, increases the permissive H3K36me2 histone mark, and transcriptionally activates PTP4A3 expression in t(4;14) multiple myeloma. SILAC mass spectrometry, Co-IP (NSD2-SMARCA2), ChIP (H3K36me2 at PTP4A3 promoter), RNA sequencing, BET inhibitor PFI-3 displacement experiment, xenograft model Cancer research High 33602783
2008 The C-terminal CAAX motif of PRL-3, beyond directing farnesylation, plays an additional regulatory role by inhibiting the catalytic efficiency of PRL-3 in vitro. Truncation and mutation analysis invalidates the hypothesis that the C-terminal polybasic sequence is a nuclear localization signal. Truncated and mutant PRL-3 forms, in vitro phosphatase activity assay, subcellular localization analysis Journal of cellular and molecular medicine Medium 19040419
2016 PRL-3 promotes TNBC cell invasion by upregulating matrix metalloproteinase 10 (MMP10), increases TNBC cell adherence to laminin via focal adhesion pathway engagement (Src, ERK, RhoA, Rac1/2/3 GTPase). Loss of PRL-3 deactivates Src and ERK signaling and rearranges F-actin networks. PRL-3 knockdown/overexpression, Western blot (Src, ERK, RhoA, Rac1/2/3), invasion assay, adhesion assay, MMP10 analysis, F-actin staining Cancer letters Medium 27452906
2013 PRL-3 is downstream of BCR-ABL signaling in CML; inhibition of BCR-ABL by imatinib or BCR-ABL siRNA reduces PRL-3 expression. PRL-3 is required for CML cell proliferation and self-renewal. In imatinib-resistant P210 T315I cells, PRL-3 levels are maintained or increased despite BCR-ABL inhibition. BCR-ABL siRNA, imatinib treatment, PRL-3 shRNA, proliferation and self-renewal assays, Western blot Molecular cancer Medium 22995644
2019 PTP4A3/PRL-3 dephosphorylates CRMP2 on T514. Inhibition of CRMP2 expression in PTP4A3-expressing uveal melanoma cells increases migration and invasiveness, accompanied by shortened actin filaments and increased cytoplasmic stiffness. The inactive phosphatase mutant does not recapitulate these actin/stiffness changes. Phosphorylation analysis (CRMP2-T514), siRNA knockdown, catalytic mutant, in vitro migration/invasion, AFM cell stiffness measurement, in vivo xenograft Scientific reports Medium 30816227
2016 PTP4A3 increases cell membrane accumulation of MMP14 by accelerating vesicular trafficking of MMP14. PTP4A3 and MMP14 co-localize and MMP14 vesicular trafficking is faster in the presence of catalytically active PTP4A3. Inhibition of MMP14 expression in PTP4A3-expressing uveal melanoma cells impairs migration and invasiveness. Flow cytometry of cell surface MMP14, immunofluorescence colocalization, MMP14 vesicular trafficking assay with active vs. inactive PTP4A3, MMP14 siRNA knockdown, in vivo invasiveness assay Investigative ophthalmology & visual science Medium 27096756
2021 PRL-3 directly dephosphorylates p38 MAPK under stress conditions (CoCl2-induced hypoxia, UV, H2O2, and hypoxia), promoting cell survival and apoptosis resistance. This requires catalytic activity (C104S mutant fails to confer resistance). In vivo, cells expressing PRL-3 show higher metastatic burden and lower p38 MAPK phosphorylation. In vitro dephosphorylation assay (PRL-3 + p38 MAPK), catalytic mutant, apoptosis assay under multiple stress conditions, mouse lung metastasis model, phospho-p38 Western blot Free radical biology & medicine High 34662712
2013 Ptp4a3-null colitis-associated colon cancer cells exhibit reduced clonogenicity and fail to form secondary tumors in nude mice, while wild-type Ptp4a3-expressing CD133+ tumor-initiating cells readily form secondary tumors, demonstrating PTP4A3's role in tumor-initiating cell self-renewal. Ptp4a3 knockout mouse model, AOM/DSS-induced tumors, CD133+ cell isolation, limiting dilution clonogenicity assay, secondary tumor transplantation in nude mice Stem cell research High 24950307

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer research 234 12782572
2007 PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. Cancer research 226 17409395
2003 PRL-3 expression in metastatic cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 177 14654542
1998 Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatases homologous to PRL-1. Biochemical and biophysical research communications 164 9514946
2010 PCBP1 suppresses the translation of metastasis-associated PRL-3 phosphatase. Cancer cell 154 20609352
2004 High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases. Clinical cancer research : an official journal of the American Association for Cancer Research 144 15534108
2010 High PTP4A3 phosphatase expression correlates with metastatic risk in uveal melanoma patients. Cancer research 138 21135111
2005 PRL-3 phosphatase is implicated in ovarian cancer growth. Clinical cancer research : an official journal of the American Association for Cancer Research 126 16203771
2001 Role of PRL-3, a human muscle-specific tyrosine phosphatase, in angiotensin-II signaling. Biochemical and biophysical research communications 116 11355880
2010 PRL-3 phosphatase and cancer metastasis. Journal of cellular biochemistry 108 21053359
2004 Expression of PRL-3 phosphatase in human gastric carcinomas: close correlation with invasion and metastasis. Pathobiology : journal of immunopathology, molecular and cellular biology 108 15263806
2008 The metastasis-associated gene Prl-3 is a p53 target involved in cell-cycle regulation. Molecular cell 102 18471976
2004 Structural insights into molecular function of the metastasis-associated phosphatase PRL-3. The Journal of biological chemistry 100 14704153
1992 Detection of prolactin receptor (PRL-R) mRNA in the rat hypothalamus and pituitary gland. Endocrinology 94 1537321
2012 miR-495 and miR-551a inhibit the migration and invasion of human gastric cancer cells by directly interacting with PRL-3. Cancer letters 93 22469786
2006 Synthesis and biological evaluation of rhodanine derivatives as PRL-3 inhibitors. Bioorganic & medicinal chemistry letters 93 16530413
2007 Overexpression and involvement in migration by the metastasis-associated phosphatase PRL-3 in human myeloma cells. Blood 88 17934070
2006 PRL-3 initiates tumor angiogenesis by recruiting endothelial cells in vitro and in vivo. Cancer research 86 17018620
2015 Ubiquitin-Specific Protease 4-Mediated Deubiquitination and Stabilization of PRL-3 Is Required for Potentiating Colorectal Oncogenesis. Cancer research 85 26669864
2009 PRL-3 promotes the motility, invasion, and metastasis of LoVo colon cancer cells through PRL-3-integrin beta1-ERK1/2 and-MMP2 signaling. Molecular cancer 83 19930715
2004 Catalytic domain of PRL-3 plays an essential role in tumor metastasis: formation of PRL-3 tumors inside the blood vessels. Cancer biology & therapy 83 15326366
2010 Stathmin, a new target of PRL-3 identified by proteomic methods, plays a key role in progression and metastasis of colorectal cancer. Journal of proteome research 66 20806969
2009 PRL-3 facilitates angiogenesis and metastasis by increasing ERK phosphorylation and up-regulating the levels and activities of Rho-A/C in lung cancer. Pathology 65 19152186
2013 Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells. The Journal of clinical investigation 64 23867504
2007 High PRL-3 expression in human gastric cancer is a marker of metastasis and grades of malignancies: an in situ hybridization study. Virchows Archiv : an international journal of pathology 64 17235563
2007 Ezrin is a specific and direct target of protein tyrosine phosphatase PRL-3. Biochimica et biophysica acta 64 18078820
2006 Identification of integrin alpha1 as an interacting protein of protein tyrosine phosphatase PRL-3. Biochemical and biophysical research communications 62 16472776
2019 The miR-29c-KIAA1199 axis regulates gastric cancer migration by binding with WBP11 and PTP4A3. Oncogene 61 30626935
2017 CCL26 Participates in the PRL-3-Induced Promotion of Colorectal Cancer Invasion by Stimulating Tumor-Associated Macrophage Infiltration. Molecular cancer therapeutics 60 29051319
2011 PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-AML therapy. PloS one 59 21589872
2009 Down-modulation of keratin 8 phosphorylation levels by PRL-3 contributes to colorectal carcinoma progression. International journal of cancer 58 19115206
2004 Structure of human PRL-3, the phosphatase associated with cancer metastasis. FEBS letters 58 15135076
2013 Targeted deletion of the metastasis-associated phosphatase Ptp4a3 (PRL-3) suppresses murine colon cancer. PloS one 56 23555575
2006 Protein tyrosine phosphatase PRL-3 in malignant cells and endothelial cells: expression and function. Molecular cancer therapeutics 56 16505094
2011 The metastasis-promoting phosphatase PRL-3 shows activity toward phosphoinositides. Biochemistry 53 21806020
2005 Generation of PRL-3- and PRL-1-specific monoclonal antibodies as potential diagnostic markers for cancer metastases. Clinical cancer research : an official journal of the American Association for Cancer Research 52 15788667
2010 Phosphatase PRL-3 is a direct regulatory target of TGFbeta in colon cancer metastasis. Cancer research 51 21084277
2014 Protein-tyrosine phosphatase 4A3 (PTP4A3) promotes vascular endothelial growth factor signaling and enables endothelial cell motility. The Journal of biological chemistry 49 24403062
2013 KCNN4 channels participate in the EMT induced by PRL-3 in colorectal cancer. Medical oncology (Northwood, London, England) 49 23572150
2007 PRL-3 siRNA inhibits the metastasis of B16-BL6 mouse melanoma cells in vitro and in vivo. Molecular medicine (Cambridge, Mass.) 48 17592549
2016 PRL-3 promotes the peritoneal metastasis of gastric cancer through the PI3K/Akt signaling pathway by regulating PTEN. Oncology reports 47 27572739
2013 Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia. EMBO molecular medicine 43 23929599
2019 Interaction with tumor‑associated macrophages promotes PRL‑3‑induced invasion of colorectal cancer cells via MAPK pathway‑induced EMT and NF‑κB signaling‑induced angiogenesis. Oncology reports 42 30864736
2014 A role of autophagy in PTP4A3-driven cancer progression. Autophagy 42 25136802
2012 An epigenetic role for PRL-3 as a regulator of H3K9 methylation in colorectal cancer. Gut 42 22345654
2008 Evaluation of PRL-3 expression, and its correlation with angiogenesis and invasion in hepatocellular carcinoma. International journal of molecular medicine 42 18636172
2007 The value and correlation between PRL-3 expression and matrix metalloproteinase activity and expression in human gliomas. Neuropathology : official journal of the Japanese Society of Neuropathology 40 18021371
2016 PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion. Cancer letters 39 27452906
2017 Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor. Oncotarget 37 29492190
2014 Methylation-associated silencing of miR-495 inhibit the migration and invasion of human gastric cancer cells by directly targeting PRL-3. Biochemical and biophysical research communications 37 25475733
2009 PRL-3 promotes epithelial mesenchymal transition by regulating cadherin directly. Cancer biology & therapy 36 19440036
2018 PRL-3 Promotes Ubiquitination and Degradation of AURKA and Colorectal Cancer Progression via Dephosphorylation of FZR1. Cancer research 35 30498084
2014 Independent oncogenic and therapeutic significance of phosphatase PRL-3 in FLT3-ITD-negative acute myeloid leukemia. Cancer 35 24737397
2018 A loss-of-function genetic screening reveals synergistic targeting of AKT/mTOR and WTN/β-catenin pathways for treatment of AML with high PRL-3 phosphatase. Journal of hematology & oncology 34 29514683
2017 PRL-3 improves colorectal cancer cell proliferation and invasion through IL-8 mediated glycolysis metabolism. International journal of oncology 34 28791350
2015 PRL-3 promotes gastric cancer migration and invasion through a NF-κB-HIF-1α-miR-210 axis. Journal of molecular medicine (Berlin, Germany) 34 26548949
2008 PRL-3 is essentially overexpressed in primary colorectal tumours and associates with tumour aggressiveness. British journal of cancer 34 19002188
2019 Long Noncoding RNA UCA1 Regulates PRL-3 Expression by Sponging MicroRNA-495 to Promote the Progression of Gastric Cancer. Molecular therapy. Nucleic acids 33 31982772
2016 LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML. Molecular cancer research : MCR 32 28011885
2011 PRL-3 promotes the proliferation of LoVo cells via the upregulation of KCNN4 channels. Oncology reports 30 21725609
2016 PRL-3 disrupts epithelial architecture by altering the post-mitotic midbody position. Journal of cell science 29 27656108
2012 The pro-metastasis tyrosine phosphatase, PRL-3 (PTP4A3), is a novel mediator of oncogenic function of BCR-ABL in human chronic myeloid leukemia. Molecular cancer 29 22995644
2019 The Phosphatase PRL-3 Is Involved in Key Steps of Cancer Metastasis. Journal of molecular biology 28 31207239
2016 The phosphatase of regenerating liver-3 (PRL-3) is important for IL-6-mediated survival of myeloma cells. Oncotarget 28 27036022
2014 LEO1 is regulated by PRL-3 and mediates its oncogenic properties in acute myelogenous leukemia. Cancer research 28 24686170
2012 PRL-3 activates NF-κB signaling pathway by interacting with RAP1. Biochemical and biophysical research communications 28 23178297
2011 Therapeutic potential of PRL-3 targeting and clinical significance of PRL-3 genomic amplification in gastric cancer. BMC cancer 27 21466710
2011 VEGF promotes the transcription of the human PRL-3 gene in HUVEC through transcription factor MEF2C. PloS one 26 22073279
2016 Elevated phosphatase of regenerating liver 3 (PRL-3) promotes cytoskeleton reorganization, cell migration and invasion in endometrial stromal cells from endometrioma. Human reproduction (Oxford, England) 25 26874360
2016 Phosphatase of regenerating liver 3 (PRL-3) is overexpressed in human prostate cancer tissue and promotes growth and migration. Journal of translational medicine 25 26975394
2011 Emodin inhibits migration and invasion of DLD-1 (PRL-3) cells via inhibition of PRL-3 phosphatase activity. Bioorganic & medicinal chemistry letters 25 22137788
2016 PTP4A3 is a target for inhibition of cell proliferatin, migration and invasion through Akt/mTOR signaling pathway in glioblastoma under the regulation of miR-137. Brain research 24 27328425
2015 PRL-3 Promotes the Malignant Progression of Melanoma via Triggering Dephosphorylation and Cytoplasmic Localization of NHERF1. The Journal of investigative dermatology 24 25897829
2015 PRL-3 activates mTORC1 in Cancer Progression. Scientific reports 24 26597054
2016 Regulatory mechanisms of phosphatase of regenerating liver (PRL)-3. Biochemical Society transactions 23 27911713
2020 Endosulfan triggers epithelial-mesenchymal transition via PTP4A3-mediated TGF-β signaling pathway in prostate cancer cells. The Science of the total environment 22 32413665
2017 PRL-3/PTP4A3 phosphatase regulates integrin β1 in adhesion structures during migration of human ocular melanoma cells. Experimental cell research 21 28284838
2017 PRL-3 promotes telomere deprotection and chromosomal instability. Nucleic acids research 21 28482095
2012 The phosphatase of regenerating liver 3 (PRL-3) promotes cell migration through Arf-activity-dependent stimulation of integrin α5 recycling. Journal of cell science 21 22595524
2007 PRL-3: a metastasis-associated phosphatase in search of a function. Cells, tissues, organs 21 17587829
2021 SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma. Cancer research 20 33602783
2020 Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) drives migration and progression of T-cell acute lymphoblastic leukemia in vitro and in vivo. Oncogenesis 20 32001668
2020 lncRNA PCBP1-AS1 Aggravates the Progression of Hepatocellular Carcinoma via Regulating PCBP1/PRL-3/AKT Pathway. Cancer management and research 20 32753957
2018 Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia. Oncogene 20 30305722
2022 PRL-3 and MMP9 Expression and Epithelial-Mesenchymal Transition Markers in Circulating Tumor Cells From Patients With Colorectal Cancer: Potential Value in Clinical Practice. Frontiers in oncology 19 35574414
2018 PRL-3 promotes gastric cancer peritoneal metastasis via the PI3K/AKT signaling pathway in vitro and in vivo. Oncology letters 19 29805638
2016 Protein Tyrosine Phosphatase 4A3 (PTP4A3) Promotes Human Uveal Melanoma Aggressiveness Through Membrane Accumulation of Matrix Metalloproteinase 14 (MMP14). Investigative ophthalmology & visual science 19 27096756
2019 Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) promotes the aggressiveness of human uveal melanoma through dephosphorylation of CRMP2. Scientific reports 18 30816227
2015 PRL-3 mediates the protein maturation of ULBP2 by regulating the tyrosine phosphorylation of HSP60. Journal of immunology (Baltimore, Md. : 1950) 18 25687758
2020 PRL-3 facilitates Hepatocellular Carcinoma progression by co-amplifying with and activating FAK. Theranostics 17 32929353
2008 Analysis of molecular determinants of PRL-3. Journal of cellular and molecular medicine 17 19040419
2019 Next-Generation Cell-Active Inhibitors of the Undrugged Oncogenic PTP4A3 Phosphatase. The Journal of pharmacology and experimental therapeutics 16 31601683
2018 A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 29746167
2017 Antibody Array Revealed PRL-3 Affects Protein Phosphorylation and Cytokine Secretion. PloS one 16 28068414
2011 The essential role of FKBP38 in regulating phosphatase of regenerating liver 3 (PRL-3) protein stability. Biochemical and biophysical research communications 16 21320469
2000 Increase in prolactin receptor (PRL-R) mRNA level in the mammary gland after hormonal induction of lactation in virgin ewes. Domestic animal endocrinology 16 10701763
2021 PRL-3 dephosphorylates p38 MAPK to promote cell survival under stress. Free radical biology & medicine 15 34662712
2020 Endosulfan promotes cell migration via PTP4A3-mediated signaling pathways in HUVECs. Ecotoxicology and environmental safety 15 32044604
2014 Investigational inhibitors of PTP4A3 phosphatase as antineoplastic agents. Expert opinion on investigational drugs 15 24625356
2014 Deletion of Ptp4a3 reduces clonogenicity and tumor-initiation ability of colitis-associated cancer cells in mice. Stem cell research 15 24950307

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