Affinage

PTP4A1

Protein tyrosine phosphatase type IVA 1 · UniProt Q93096

Length
173 aa
Mass
19.8 kDa
Annotated
2026-06-10
61 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTP4A1 (PRL-1) is a small, farnesylated dual-specificity protein phosphatase that couples growth-factor and cytoskeletal signaling, magnesium homeostasis, and metabolic control, and acts as a positive regulator of cell motility, invasion, and metastasis in a catalytic-activity-dependent manner (PMID:8196618, PMID:12782572). Its C-terminal CAAX farnesylation directs association with the plasma membrane, early endosomes, and the endoplasmic reticulum, whereas loss of prenylation redirects the protein to the nucleus; during mitosis it relocalizes farnesylation-independently to centrosomes and the spindle, where catalytic and prenylation mutants cause mitotic delay and chromosome segregation defects (PMID:10747914, PMID:12235145). Crystallographic and kinetic work shows PTP4A1 forms membrane-binding trimers and that catalysis proceeds through a phosphocysteine intermediate requiring active-site Cys104 plus an unusual general-acid Asp72 and backdoor Cys49, a mechanism distinct from classical PTPs; the same Cys49–Cys104 pair forms an intramolecular disulfide that reversibly inactivates the enzyme under oxidative stress (PMID:16142898, PMID:17673310, PMID:40398601). Beyond catalysis, PTP4A1 acts through direct protein interactions: it binds the SH3 domain of p115 RhoGAP via a non-canonical interface to activate ERK1/2 and RhoA (PMID:22009749), binds SRC in a phosphatase-independent manner to drive ERK/SMAD3-dependent TGFβ fibrotic signaling (PMID:29057934), and engages the CBS/Bateman module of CNNM2/CNNM3 through its catalytic domain to counteract CNNM-mediated inhibition of the TRPM7 magnesium channel, thereby controlling intracellular magnesium and mitochondrial metabolism (PMID:27899452, PMID:36972446). PTP4A1 also has defined dephosphorylation substrates with tissue-specific outputs: it dephosphorylates cytohesin-2 at Tyr381 to negatively regulate Schwann cell myelination (PMID:35077201) and dephosphorylates USF1 at Ser309 to induce A20 and restrain endothelial NF-κB-driven inflammation and atherogenesis (PMID:36534975), and it activates a CREBH/FGF21 axis in liver to prevent diet-induced hepatosteatosis and glucose dysregulation (PMID:36793871). In cancer contexts it promotes proliferation, EMT, and invasion through PI3K/AKT signaling and PTEN suppression (PMID:27655691, PMID:40747713).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 High

    Established PRL-1 as a bona fide protein tyrosine phosphatase whose enzymatic activity drives altered growth, answering whether the immediate-early gene encoded a functional catalytic enzyme.

    Evidence Active-site Cys→Ala mutagenesis, in vitro phosphatase assay, and overexpression in transfected cells with nuclear localization

    PMID:8196618

    Open questions at the time
    • No physiological substrate identified
    • Mechanism linking activity to transformed phenotype unresolved
  2. 1999 Medium

    Identified how PRL-1 expression is induced, showing Egr-1 directly transactivates the promoter during mitogenic and regenerative stimulation.

    Evidence EMSA, reporter assays with mutated Egr-1 site, Northern blot of regenerating liver

    PMID:9988683

    Open questions at the time
    • Does not address protein-level regulation or downstream targets
    • Single-lab transcriptional study
  3. 2000 High

    Defined the basis of PRL-1 membrane targeting, establishing that C-terminal farnesylation governs plasma-membrane/endosomal localization versus default nuclear localization.

    Evidence Metabolic prenylation labeling, immunogold EM, FTI-277 inhibition, and CAAX mutagenesis

    PMID:10747914

    Open questions at the time
    • Functional consequence of each localization not fully resolved
    • Trafficking machinery unidentified
  4. 2001 Medium

    Provided the first candidate nuclear substrate by mapping a direct interaction with transcription factor ATF-7 and showing in vitro dephosphorylation.

    Evidence Yeast two-hybrid, domain mapping, in vitro dephosphorylation assay

    PMID:11278933

    Open questions at the time
    • Physiological relevance in cells not established
    • ATF-7 phosphosite not defined
  5. 2002 High

    Connected localization to cell-cycle function, showing PRL-1 moves to centrosomes/spindle in mitosis and that catalytic and farnesylation mutants cause mitotic defects.

    Evidence Endogenous immunofluorescence across cell cycle, conditional catalytic and CAAX mutant expression in HeLa

    PMID:12235145

    Open questions at the time
    • Mitotic substrate unknown
    • Mechanism of spindle recruitment unresolved
  6. 2003 High

    Demonstrated that PRL-1 catalytic activity is required for pro-motility and metastatic behavior, linking the enzyme to cancer cell invasion in vivo.

    Evidence Stable CHO lines, motility/invasion assays, catalytically inactive mutant, mouse metastasis model

    PMID:12782572

    Open questions at the time
    • Direct substrate driving migration not identified
    • Pathway intermediates undefined at this stage
  7. 2005 High

    Resolved the structure and redox regulation of the catalytic domain, defining a membrane-binding trimer and a Cys49–Cys104 disulfide that blocks catalysis.

    Evidence X-ray crystallography of native and mutant PRL-1, kinetics, and cell-based disulfide assays

    PMID:15571731 PMID:16142898

    Open questions at the time
    • Physiological trigger of oxidation in vivo not yet defined
    • Functional role of trimerization in cells unclear
  8. 2007 Medium

    Placed PRL-1 upstream in adhesion/invasion signaling and confirmed oxidative-stress regulation in a native tissue context.

    Evidence shRNA knockdown in A549 with Src/Rac1/Cdc42/FAK readouts; H2O2 disulfide experiments in cells and isolated retina

    PMID:17234774 PMID:17673310

    Open questions at the time
    • Direct dephosphorylation events not established in the invasion pathway
    • Redox studies single-lab
  9. 2008 Medium

    Identified a p53 feedback loop, showing PRL-1 lowers p53 via PIRH2 and Akt/MDM2 while p53 transcriptionally controls PRL-1.

    Evidence Overexpression/siRNA, ubiquitination and proteasome assays, reporter assays, p53 response element mapping

    PMID:18997816

    Open questions at the time
    • Direct phosphatase substrate in the pathway not defined
    • Single-lab mechanistic study
  10. 2011 High

    Defined a non-catalytic scaffolding mechanism whereby PRL-1 binds the p115 RhoGAP SH3 domain to simultaneously activate ERK1/2 and RhoA.

    Evidence Peptide binding, co-IP, crystallography of PRL-1·peptide complex, GAP and signaling assays

    PMID:22009749

    Open questions at the time
    • In vivo physiological output of this complex not addressed
    • Interplay with catalytic substrates unresolved
  11. 2013 Medium

    Showed in Drosophila that membrane-localized PRL suppresses growth and antagonizes Src, with CAAX-independent Src inhibition revealing functional complexity.

    Evidence Transgenic overexpression, CAAX deletion mutant, genetic epistasis with Src

    PMID:23577193

    Open questions at the time
    • Direct biochemical link to Src not defined here
    • Reconciliation with pro-oncogenic roles in mammals incomplete
  12. 2016 High

    Defined the structural basis of CNNM engagement, showing the PRL-1 catalytic domain binds the CNNM2 Bateman module in a heterotetramer.

    Evidence X-ray crystallography of PRL-1–CNNM2BAT complex with interface mutagenesis (Asp-558)

    PMID:27899452

    Open questions at the time
    • Functional output of the complex not yet established in this study
    • Competition with substrate binding unresolved here
  13. 2016 Medium

    Extended PRL-1 oncogenic signaling to PI3K/AKT, linking it to proliferation and EMT in cholangiocarcinoma.

    Evidence Overexpression/knockdown in ICC cells, in vivo tumor model, Western blot of AKT/GSK3β/CyclinD1/Zeb1/Snail

    PMID:27655691

    Open questions at the time
    • Mechanism connecting PTP4A1 to PI3K/AKT not defined here
    • Direct substrate unidentified
  14. 2017 High

    Established a phosphatase-independent SRC-binding mechanism driving TGFβ/ERK/SMAD3 fibrotic signaling and distinguished PTP4A1 from PTP4A2.

    Evidence Reciprocal co-IP, phosphatase-dead mutant, SMAD3 readouts, bleomycin fibrosis mouse model

    PMID:29057934

    Open questions at the time
    • Structural basis of PTP4A1-SRC binding not resolved
    • How catalytic and scaffolding roles are balanced unclear
  15. 2018 Medium

    Localized PRL-1 to the immunological synapse and tied its activity to actin dynamics and IL-2 secretion in T cells.

    Evidence Live imaging, IS immunofluorescence, pharmacological PRL inhibition, IL-2 assays

    PMID:30515156

    Open questions at the time
    • No T-cell substrate identified
    • Inhibitor specificity caveats
  16. 2019 High

    Showed in Drosophila that Prl-1 modulates insulin-receptor signaling in an axon-branch-specific, UTR-dependent manner to control synapse number.

    Evidence Loss/gain-of-function genetics, InR epistasis, mRNA UTR deletion, locomotor assays

    PMID:31048465

    Open questions at the time
    • Mammalian relevance of neuronal role untested in corpus
    • Biochemical InR-pathway substrate undefined
  17. 2022 High

    Identified cytohesin-2 Tyr381 as a direct substrate and placed PTP4A1 opposite SH2B1 in negative control of Schwann cell myelination.

    Evidence In vitro dephosphorylation, Schwann cell-specific KD mice, cytohesin-2 Y381F knockin mice, Arf6 activity assays

    PMID:35077201

    Open questions at the time
    • Upstream signals controlling PTP4A1 in Schwann cells unknown
    • Generalization to other myelinating contexts untested
  18. 2023 High

    Defined multiple in vivo physiological substrates and axes — USF1-Ser309/A20/NF-κB in endothelial anti-inflammation, CREBH/FGF21 in hepatosteatosis prevention, and PRL-CNNM-TRPM7 in magnesium/metabolic control.

    Evidence KO and transgenic/liver-specific OE mice, ChIP and reporter assays, magnesium reporter, co-IP, atherosclerosis and metabolic models

    PMID:36534975 PMID:36793871 PMID:36972446 PMID:37773151

    Open questions at the time
    • Tissue specificity of substrate selection mechanism unclear
    • How a single phosphatase coordinates these distinct programs unresolved
  19. 2024 Medium

    Demonstrated that the oxidized, catalytically inactive form retains biological function by forming a phosphatase-independent complex with Src kinases.

    Evidence Biochemical preparation of oxidized/reduced forms and Src complex assays in systemic sclerosis context

    PMID:38147218

    Open questions at the time
    • Single-lab biochemical characterization
    • In vivo relevance of the oxidized-Src complex not fully established
  20. 2025 High

    Dissected the unusual catalytic mechanism (Asp72 general acid, backdoor Cys49, phosphocysteine intermediate) and showed it differs from classical PTPs and sterically gates CNNM binding.

    Evidence C49S/D72A mutagenesis, in vitro kinetics, crystal structure of phosphocysteine intermediate

    PMID:40398601

    Open questions at the time
    • Physiological control of the catalytic-vs-CNNM-binding switch unresolved
    • How intermediate stabilization affects substrate range unknown
  21. 2025 Medium

    Added a PTEN-suppression mechanism and an inhibitable RhoA-dependent adhesion role in cancer metastasis.

    Evidence Co-IP and immunofluorescence with PTEN, PI3K/AKT readouts; peritoneal adhesion assays with CMPD-43 inhibitor and RhoA assay

    PMID:40747713 PMID:41769321

    Open questions at the time
    • Whether PTEN is a direct dephosphorylation substrate not established
    • Inhibitor specificity and target engagement limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PTP4A1 selects among its many substrates and binding partners across tissues, and how localization, redox state, and the catalytic/scaffolding switch are coordinated to specify distinct biological outputs, remains unresolved.
  • No unifying model integrating catalytic, scaffolding, and redox functions
  • Substrate-selection determinants in vivo unknown
  • Spatial regulation across compartments incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016787 hydrolase activity 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 2 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 3 R-HSA-1640170 Cell Cycle 1 R-HSA-382551 Transport of small molecules 1
Partners
ARHGAP5ATF7CNNM2CNNM3PKM2PTENSRCTRPM7

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 PRL-1 encodes a 20-kDa protein tyrosine phosphatase with a conserved active-site cysteine; mutation of this active-site cysteine abolishes phosphatase activity. PRL-1 can dephosphorylate phosphotyrosine substrates in vitro and is located primarily in the cell nucleus. Overexpression causes altered cellular growth, morphology, and transformed phenotype. Active-site mutagenesis (Cys→Ala), in vitro phosphatase assay, nuclear localization by subcellular fractionation/immunofluorescence, stable transfection overexpression Molecular and cellular biology High 8196618
2000 PRL-1 is prenylated (farnesylated) at its C-terminal CAAX motif, and this prenylation is required for its primary association with the plasma membrane and early endosomal compartment. When farnesylation is inhibited by FTI-277 or the CAAX motif is mutated, PRL-1 relocalizes to the nucleus. Metabolic labeling for prenylation, immunofluorescence and electron microscope immunogold labeling, farnesyltransferase inhibitor (FTI-277) treatment, C-terminal prenylation mutant expression, brefeldin A and wortmannin treatments The Journal of biological chemistry High 10747914
2002 PRL-1 localizes to the endoplasmic reticulum in a farnesylation-dependent manner in non-mitotic cells, and relocalizes to centrosomes and the mitotic spindle (farnesylation-independently) during mitosis. Expression of a catalytic domain mutant delays mitotic progression; expression of a farnesylation-site mutant causes chromosomal bridges and lagging chromosomes in anaphase without affecting spindle checkpoint function. Immunofluorescence of endogenous PRL-1 across cell cycle stages, conditional expression of catalytic mutant and farnesylation mutant in HeLa cells, cell cycle analysis The Journal of biological chemistry High 12235145
2003 PRL-1 expression in CHO cells enhances cell motility and invasive activity; catalytically inactive PRL-1 mutant has significantly reduced migration-promoting activity. PRL-1-expressing cells, but not controls, form metastatic tumors in mice. Stable CHO cell lines, motility and invasion assays, catalytically inactive mutant, in vivo mouse metastasis model Cancer research High 12782572
2005 Crystal structure of PRL-1 reveals it forms a trimer burying ~1140 Ų per dimer interface, creating a membrane-binding surface. The active site places PRL-1 among dual-specificity phosphatases with closest structural similarity to Cdc14. Native PRL-1 crystallizes in an oxidized form where an intramolecular disulfide between active-site Cys104 and neighboring Cys49 blocks substrate binding and catalysis; biochemical and cell-based studies confirm this disulfide as a redox regulatory mechanism. X-ray crystallography (native and C104S mutant with sulfate), kinetic analysis, biochemical disulfide assays in solution and in cells Biochemistry High 16142898
2005 Crystal structure of human PRL-1 at 2.7 Å shows a shallow, hydrophobic active-site pocket with a sulfate ion stabilizing the active conformation. PRL-1 forms a trimer in the crystal, and a trimer is also detected in the membrane fraction of cells, suggesting oligomerization may regulate PRL-1 activity. X-ray crystallography (2.7 Å), cell fractionation to detect trimers in membrane fraction Journal of molecular biology High 15571731
2001 PRL-1 physically interacts with the transcription factor ATF-7 (a bZIP protein related to ATF/CREB family); the interaction was mapped to ATF-7's bZIP region and PRL-1's phosphatase domain. PRL-1 can dephosphorylate ATF-7 in vitro. Yeast two-hybrid, domain-mapping, in vitro dephosphorylation assay The Journal of biological chemistry Medium 11278933
1999 Egr-1 directly binds the proximal PRL-1 promoter and transactivates PRL-1 gene expression in response to mitogen stimulation and partial hepatectomy; mutation of the Egr-1 site abolishes this induction. Electrophoretic mobility shift assay (EMSA), reporter gene assays with wild-type and mutant Egr-1 site, Northern blot of regenerating liver The Journal of biological chemistry Medium 9988683
2007 PRL-1 knockdown in A549 lung cancer cells decreases c-Src and p130Cas expression, reduces Rac1 and Cdc42 activation, and elevates FAK Tyr397 phosphorylation, resulting in reduced invasion and increased cell-substrate adhesion. These results place PRL-1 upstream of c-Src, Rac1, and Cdc42 in adhesion/invasion signaling. Stable shRNA knockdown, invasion and adhesion assays, Western blot for c-Src/p130Cas/FAK phosphorylation, GTPase activation assays, immunofluorescence Cancer research Medium 17234774
2008 PRL-1 overexpression reduces p53 protein levels through ubiquitination and proteasomal degradation, achieved via two independent pathways: induction of PIRH2 transcription and MDM2 phosphorylation through Akt signaling. Conversely, PRL-1 siRNA increases p53 levels. PRL-1 is itself transcriptionally regulated by p53 via a response element in the first intron, forming a negative feedback loop. Overexpression and siRNA knockdown, p53 ubiquitination assay, proteasome inhibitor experiments, reporter assays for PIRH2 and MDM2, identification of p53 response element Oncogene Medium 18997816
2011 PRL-1 binds the SH3 domain of p115 RhoGAP via a non-canonical interaction in which a PxxP ligand-binding groove of the SH3 domain occupies a folded groove within PRL-1. This interaction prevents p115 RhoGAP from binding MEKK1, thereby activating ERK1/2; simultaneously, PRL-1 binding inhibits the GAP activity of p115 RhoGAP, activating RhoA. Peptide binding/pulldown, co-IP in vitro and in cells, X-ray crystallography of PRL-1·peptide complex, GAP activity assay, ERK1/2 and RhoA activation assays The Journal of biological chemistry High 22009749
2016 Crystal structure of PRL-1 in complex with the Bateman module (CBS domains) of CNNM2 reveals a heterotetrameric assembly: one CNNM2BAT homodimer bound to two independent PRL-1 molecules. The interaction is mediated via PRL-1's catalytic domain, with CNNM2 Asp-558 in the CBS2 loop being critical for the interface. X-ray crystallography of PRL-1–CNNM2BAT complex, mutagenesis of interface residues (Asp-558) The Journal of biological chemistry High 27899452
2017 PTP4A1 promotes TGFβ signaling in dermal fibroblasts by enhancing ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, PTP4A1 directly interacts with SRC and inhibits basal SRC activation independently of its phosphatase activity. PTP4A2, by contrast, minimally interacts with SRC and does not promote this SRC-ERK-SMAD3 pathway. Co-IP of PTP4A1 with SRC, siRNA knockdown, TGFβ pathway readouts (SMAD3 nuclear translocation, target gene expression), bleomycin fibrosis mouse model, comparison with catalytically inactive mutant Nature communications High 29057934
2007 PRL-1 phosphatase activity in retinal cones and cone-derived cells is reversibly inhibited by oxidative stress through formation of an intramolecular disulfide bond between active-site Cys104 and Cys49. This was observed in vitro, in cell culture, and in isolated retinas exposed to hydrogen peroxide. In vitro phosphatase activity assay under H2O2 treatment, cell culture oxidative stress experiments, isolated retina experiments, inhibition by glutathione system blockade Biochimica et biophysica acta Medium 17673310
2019 Drosophila Prl-1 (ortholog of PRL-1) is an axon-intrinsic factor that promotes synapse formation in a spatially restricted manner on a specific axon collateral. Prl-1 modulates insulin receptor (InR) signaling within a single contralateral axon compartment to control synapse number. The axon branch-specific localization and function of Prl-1 depend on its mRNA untranslated regions. Loss-of-function genetics (Drosophila null mutants), overexpression of Prl-1, behavioral (locomotor) assays, genetic epistasis with InR pathway, mRNA UTR deletion analysis Science High 31048465
2013 In Drosophila, overexpression of PRL under normal conditions suppresses growth in a CAAX motif-dependent manner (requiring membrane localization at the apical lateral membrane), and PRL can counteract the oncogenic activity of Src. PRL lacking the CAAX motif retains the ability to inhibit Src function even when associating non-specifically with the plasma membrane. Transgenic Drosophila overexpression, CAAX motif deletion mutant, genetic epistasis with Src, tissue growth assays PloS one Medium 23577193
2016 PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma (ICC) via PI3K/AKT signaling; downstream effectors include phosphorylation of GSK3β, upregulation of CyclinD1, and EMT transcription factors Zeb1 and Snail. Forced overexpression and knockdown of PTP4A1 in ICC cells, in vitro proliferation/invasion assays, in vivo tumor model, Western blot for PI3K/AKT pathway components Oncotarget Medium 27655691
2018 PRL-1 redistributes to the immunological synapse (IS) in two stages during T cell activation: initially accumulating at scanning membranes enriched in CD3 and actin, then delivered from pericentriolar CD3ζ-containing vesicles. At the established IS, PRL-1 distributes to LFA-1 and CD3ε sites. PRL-1 regulates actin dynamics during IS assembly and IL-2 secretion; pharmacological inhibition of PRL catalytic activity reduces IL-2 secretion. Live imaging, immunofluorescence at immunological synapse, pharmacological inhibition of PRL phosphatase activity, IL-2 secretion assays Frontiers in immunology Medium 30515156
2022 PTP4A1 dephosphorylates cytohesin-2 at Tyr381, and this dephosphorylation negatively regulates Schwann cell myelination. The adaptor SH2B1 maintains Tyr381 phosphorylation, opposing PTP4A1. Schwann cell-specific knockdown of PTP4A1 increases cytohesin-2 phosphorylation and myelin thickness; SH2B1-specific loss reduces myelin thickness and cytohesin-2 phosphorylation. Knockin mice with Y381F (non-phosphorylatable) cytohesin-2 show reduced myelin thickness and Arf6 activity. In vitro dephosphorylation assay in HEK293T cells, Schwann cell-specific knockdown mice, cytohesin-2 Y381F knockin mice, myelin thickness measurements, Arf6 activity assay Science signaling High 35077201
2023 PRL-1/2 counteract the CNNM family's inhibition of TRPM7 magnesium channel function. PRL-2 overexpression prevents CNNM3 from interacting with TRPM7, thereby enhancing TRPM7 activity and magnesium influx. ARL15 small GTPase promotes CNNM3/TRPM7 complex formation to reduce TRPM7 activity, and PRL-2 counteracts this. PRL-1/2 promote TRPM7-induced cell signaling; co-targeting TRPM7 and PRL-1/2 disrupts mitochondrial function and sensitizes cells to magnesium depletion. Genetically encoded intracellular magnesium reporter, co-IP for protein complex formation, overexpression/knockdown of PRL-1/2, CNNM3, ARL15, TRPM7; cell signaling and metabolic stress assays Proceedings of the National Academy of Sciences of the United States of America High 36972446
2023 PTP4A1 dephosphorylates USF1 at Ser309 in endothelial cells, increasing USF1 transcriptional activity. This induces TNFAIP3/A20 transcription and subsequent NF-κB inhibition, reducing cell adhesion molecule expression. Ptp4a1 knockout mice show exacerbated IL-1β-induced CAM expression; Ptp4a1 transgenic mice show reduced CAMs. PTP4A1 deficiency in ApoE KO mice worsens diet-induced atherogenesis. shRNA knockdown and overexpression in endothelial cells, Ptp4a1 KO and transgenic mice, chromatin immunoprecipitation, luciferase reporter assays, immunostaining, ApoE KO atherosclerosis model Cardiovascular research High 36534975
2023 PTP4A1 promotes hepatosteatosis prevention by activating the CREBH/FGF21 transcriptional axis. Ptp4a1 knockout mice develop exacerbated glucose dysregulation and hepatosteatosis on a high-fat diet; liver-specific PTP4A1 overexpression rescues this. Mechanistically, lipid accumulation in PTP4A1-deficient hepatocytes reduces GLUT2 at the plasma membrane, impairing glucose uptake. Ptp4a1 KO mice, adeno-associated virus liver-specific PTP4A1 expression, adenovirus FGF21 rescue, glucose/insulin tolerance tests, hyperinsulinemic-euglycemic clamp, co-IP, luciferase reporter assay Theranostics High 36793871
2023 PTP4A1 binds pyruvate kinase isoenzyme M2 (PKM2) to promote its expression and binds aconitase 2 (ACO2) to enhance its degradation, thereby regulating mitochondrial metabolic reprogramming and invasive capacity in OSCC cells. Co-IP of PTP4A1 with PKM2 and ACO2, overexpression/knockdown in OSCC cells, in vitro invasion assays, in vivo tumor model Cell death discovery Medium 37773151
2025 Mutagenesis studies identify an aspartic acid (D72) and the backdoor cysteine (C49) in the PRL-1 catalytic site as required for phosphocysteine hydrolysis. A C49S/D72A double mutant stabilizes the phosphocysteine intermediate for weeks. The crystal structure of cysteine-phosphorylated PRL-1 (PTP4A1) confirms that phosphocysteine sterically interferes with CNNM binding. The D72A mutation increases initial catalytic rate for all three PRL paralogs, in contrast to the homologous mutation in PTP1B/PTPN12 which disrupts catalysis, revealing a mechanistic difference between PRLs and classical PTPs. Site-directed mutagenesis (C49S, D72A), in vitro enzyme assays, X-ray crystallography of phosphocysteine-intermediate form The Journal of biological chemistry High 40398601
2025 PTP4A1 promotes cancer–mesothelial cell adhesion in a peritoneal metastasis model; a small molecule inhibitor of PTP4A1 (CMPD-43) reduces RhoA activity and inhibits heterotypic cancer–mesothelial cell adhesion. Peritoneal mesothelial cell proteomics, heterotypic adhesion assay, small molecule inhibitor treatment, RhoA activity assay Aging and cancer Medium 41769321
2025 PTP4A1 physically interacts with PTEN (validated by co-IP and immunofluorescence), suppresses PTEN phosphorylation, and thereby promotes PI3K/AKT/GSK3α pathway activation to drive ICC cell proliferation, migration, and invasion. Co-immunoprecipitation, immunofluorescence co-localization, Western blot for PTEN phosphorylation and PI3K/AKT pathway, in vitro and in vivo functional assays Oncology reports Medium 40747713
2024 PTP4A1 is catalytically active in its reduced form. The oxidized form (Cys104-Cys49 disulfide) retains biological function by forming a kinase-phosphatase complex with Src kinases, establishing a phosphatase-activity-independent function for oxidized PTP4A1 in systemic sclerosis. Preparation and characterization of oxidized and reduced PTP4A1 protein forms, complex formation assay with Src kinase, functional studies in SSc context Methods in molecular biology Medium 38147218

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. Molecular and cellular biology 247 8196618
2003 PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer research 234 12782572
2000 Prenylation-dependent association of protein-tyrosine phosphatases PRL-1, -2, and -3 with the plasma membrane and the early endosome. The Journal of biological chemistry 184 10747914
1998 Mouse PRL-2 and PRL-3, two potentially prenylated protein tyrosine phosphatases homologous to PRL-1. Biochemical and biophysical research communications 164 9514946
2002 The tyrosine phosphatase PRL-1 localizes to the endoplasmic reticulum and the mitotic spindle and is required for normal mitosis. The Journal of biological chemistry 108 12235145
2007 PRL-1 tyrosine phosphatase regulates c-Src levels, adherence, and invasion in human lung cancer cells. Cancer research 75 17234774
2005 Structure and biochemical properties of PRL-1, a phosphatase implicated in cell growth, differentiation, and tumor invasion. Biochemistry 74 16142898
2020 Circular RNA circNRIP1 promotes migration and invasion in cervical cancer by sponging miR-629-3p and regulating the PTP4A1/ERK1/2 pathway. Cell death & disease 72 32457332
2013 MiR-339-5p regulates the growth, colony formation and metastasis of colorectal cancer cells by targeting PRL-1. PloS one 70 23696794
2001 ATF-7, a novel bZIP protein, interacts with the PRL-1 protein-tyrosine phosphatase. The Journal of biological chemistry 68 11278933
2005 Trimeric structure of PRL-1 phosphatase reveals an active enzyme conformation and regulation mechanisms. Journal of molecular biology 65 15571731
2016 Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2. The Journal of biological chemistry 55 27899452
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
1999 Mitogenic up-regulation of the PRL-1 protein-tyrosine phosphatase gene by Egr-1. Egr-1 activation is an early event in liver regeneration. The Journal of biological chemistry 51 9988683
2017 PTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis. Nature communications 49 29057934
1996 Expression of PRL-1 nuclear PTPase is associated with proliferation in liver but with differentiation in intestine. The American journal of physiology 49 8760115
2002 The induction of the immediate-early-genes Egr-1, PAI-1 and PRL-1 during liver regeneration in surgical models is related to increased portal flow. Journal of hepatology 47 12399226
2016 Protein tyrosine phosphatase PTP4A1 promotes proliferation and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma via the PI3K/AKT pathway. Oncotarget 42 27655691
2011 PRL-1 protein promotes ERK1/2 and RhoA protein activation through a non-canonical interaction with the Src homology 3 domain of p115 Rho GTPase-activating protein. The Journal of biological chemistry 42 22009749
2008 New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53. Oncogene 41 18997816
2016 Suppression of cell migration is promoted by miR-944 through targeting of SIAH1 and PTP4A1 in breast cancer cells. BMC cancer 39 27377268
2021 Long non-coding RNA USP30-AS1 aggravates the malignant progression of cervical cancer by sequestering microRNA-299-3p and thereby overexpressing PTP4A1. Oncology letters 35 33986866
2019 Branch-restricted localization of phosphatase Prl-1 specifies axonal synaptogenesis domains. Science (New York, N.Y.) 34 31048465
1996 PRL-1, a protein tyrosine phosphatase, is expressed in neurons and oligodendrocytes in the brain and induced in the cerebral cortex following transient forebrain ischemia. Brain research. Molecular brain research 28 8840018
2017 MicroRNA-1271 functions as a metastasis and epithelial-mesenchymal transition inhibitor in human HCC by targeting the PTP4A1/c-Src axis. International journal of oncology 27 29345291
2007 Oxidative stress-induced expression and modulation of Phosphatase of Regenerating Liver-1 (PRL-1) in mammalian retina. Biochimica et biophysica acta 25 17673310
1998 The gene encoding human nuclear protein tyrosine phosphatase, PRL-1. Cloning, chromosomal localization, and identification of an intron enhancer. The Journal of biological chemistry 25 9642300
2021 Activation of the EGFR-PI3K-CaM pathway by PRL-1-overexpressing placenta-derived mesenchymal stem cells ameliorates liver cirrhosis via ER stress-dependent calcium. Stem cell research & therapy 24 34689832
1995 A 100-kb physical and transcriptional map around the EDH17B2 gene: identification of three novel genes and a pseudogene of a human homologue of the rat PRL-1 tyrosine phosphatase. Human genetics 24 8529999
2006 Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL-1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone. Cell and tissue research 22 16508789
2000 PRL-1 PTPase expression is developmentally regulated with tissue-specific patterns in epithelial tissues. American journal of physiology. Gastrointestinal and liver physiology 22 10960362
2023 PRL-1/2 phosphatases control TRPM7 magnesium-dependent function to regulate cellular bioenergetics. Proceedings of the National Academy of Sciences of the United States of America 20 36972446
2012 Tissue-specific alterations of PRL-1 and PRL-2 expression in cancer. American journal of translational research 20 22347524
2021 LncRNA NEAT1 promotes cell proliferation, migration, and invasion via the miR-186-5p/PTP4A1 axis in cholangiocarcinoma. The Kaohsiung journal of medical sciences 19 33502823
2023 Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation. Cardiovascular research 18 36534975
2018 miR-339-5p Increases Radiosensitivity of Lung Cancer Cells by Targeting Phosphatases of Regenerating Liver-1 (PRL-1). Medical science monitor : international medical journal of experimental and clinical research 18 30462625
1999 Developmental expression of the murine Prl-1 protein tyrosine phosphatase gene. The Journal of experimental zoology 16 10194868
2020 Enhanced PRL-1 expression in placenta-derived mesenchymal stem cells accelerates hepatic function via mitochondrial dynamics in a cirrhotic rat model. Stem cell research & therapy 15 33246509
2013 Drosophila PRL-1 is a growth inhibitor that counteracts the function of the Src oncogene. PloS one 14 23577193
2021 PRL-1 overexpressed placenta-derived mesenchymal stem cells suppress adipogenesis in Graves' ophthalmopathy through SREBP2/HMGCR pathway. Stem cell research & therapy 13 34051850
2012 Increased expression of PRL-1 protein correlates with shortened patient survival in human hepatocellular carcinoma. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 13 22484636
2023 Hepatic PTP4A1 ameliorates high-fat diet-induced hepatosteatosis and hyperglycemia by the activation of the CREBH/FGF21 axis. Theranostics 10 36793871
2022 GINS2 regulates the proliferation and apoptosis of colon cancer cells through PTP4A1. Molecular medicine reports 10 35137928
2024 WTAP promotes proliferation of esophageal squamous cell carcinoma via m6A-dependent epigenetic promoting of PTP4A1. Cancer science 9 38746998
2023 PTP4A1 promotes oral squamous cell carcinoma (OSCC) metastasis through altered mitochondrial metabolic reprogramming. Cell death discovery 9 37773151
2005 Exclusion of four candidate genes, KHDRBS2, PTP4A1, KIAA1411 and OGFRL1, as causative of autosomal recessive retinitis pigmentosa. Ophthalmic research 9 16192744
2022 The adaptor SH2B1 and the phosphatase PTP4A1 regulate the phosphorylation of cytohesin-2 in myelinating Schwann cells in mice. Science signaling 8 35077201
2022 Inhibitory Effect of miR-339-5p on Glioma through PTP4A1/HMGB1 Pathway. Disease markers 7 35872698
2018 Phosphatase of Regenerating Liver-1 (PRL-1) Regulates Actin Dynamics During Immunological Synapse Assembly and T Cell Effector Function. Frontiers in immunology 6 30515156
1996 Localization of the human phosphotyrosine phosphatase-related genes (h-PRL-1) to chromosome bands 1p35-p34, 17q12-q21, 11q24-q25 and 12q24. Human genetics 6 8931711
2022 Long noncoding RNA DLEU2 promotes growth and invasion of hepatocellular carcinoma by regulating miR-30a-5p/PTP4A1 axis. Pathology, research and practice 5 36049439
2022 Circular RNA circ_0000212 accelerates cervical cancer progression by acting as a miR-625-5p sponge to upregulate PTP4A1. Anti-cancer drugs 4 36729102
2023 Increased PRL-1 in BM-derived MSCs triggers anaerobic metabolism via mitochondria in a cholestatic rat model. Molecular therapy. Nucleic acids 3 36865088
2009 1H, 15N, 13C resonance assignments of the reduced and active form of human Protein Tyrosine Phosphatase, PRL-1. Biomolecular NMR assignments 3 19636948
2023 Expression of PTP4A1 in circulating tumor cells and its efficacy evaluation in patients with early- and intermediate-stage esophageal cancer. Medicine 2 38134119
2025 GINS2 promotes oral squamous cell carcinoma progression and immune evasion by recruiting PD-L1+ neutrophils and modulating the PTP4A1/PKM2 axis. Frontiers in immunology 1 41322418
2022 Phosphatase of Regenerating Liver-1 (PRL-1)-Overexpressing Placenta-Derived Mesenchymal Stem Cells Enhance Antioxidant Effects via Peroxiredoxin 3 in TAA-Injured Rat Livers. Antioxidants (Basel, Switzerland) 1 36670907
2025 Structure of the phosphocysteine intermediate of the phosphatase of regenerating liver PTP4A1. The Journal of biological chemistry 0 40398601
2025 PTP4A1 promotes intrahepatic cholangiocarcinoma development and progression by interacting with PTEN and activating the PI3K/AKT/GSKα axis. Oncology reports 0 40747713
2025 Protein Tyrosine Phosphatase 4A1 (PTP4A1) Regulates Early Events in Colorectal Cancer Intraperitoneal Dissemination in the Aged Male Host. Aging and cancer 0 41769321
2024 Preparation of Oxidized and Reduced PTP4A1 for Structural and Functional Studies. Methods in molecular biology (Clifton, N.J.) 0 38147218

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