Affinage

PTPN5

Tyrosine-protein phosphatase non-receptor type 5 · UniProt P54829

Length
565 aa
Mass
63.5 kDa
Annotated
2026-06-10
100 papers in source corpus 19 papers cited in narrative 19 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

PTPN5 (STEP) is a brain-enriched non-receptor tyrosine phosphatase that acts as a central brake on synaptic signaling by dephosphorylating and inactivating the kinases ERK1/2, p38, Fyn, and Pyk2 and by dephosphorylating glutamate receptor subunits to drive their endocytosis (PMID:22090472, PMID:22544749). STEP directly binds NMDA receptors and controls their constitutive surface trafficking, and dephosphorylates GluN2B (pTyr1472) and GluA2 to promote receptor internalization, thereby opposing synaptic strengthening (PMID:16819973, PMID:20427654, PMID:26391783). The membrane-associated isoform STEP61 is an intrinsic endoplasmic reticulum membrane protein, its unique N-terminal region (transmembrane, PEST, and polyproline domains) conferring membrane association while lowering catalytic activity relative to the cytosolic STEP46 isoform (PMID:8987810). STEP activity and abundance are tightly controlled: PKA phosphorylation at Ser221 inactivates the enzyme (PMID:24466306), calcium-activated calpain cleaves STEP61 to a ~33 kDa fragment (PMID:10537058), oxidative stress drives inactivating intermolecular disulfide oligomerization via Cys65/Cys76 (PMID:21198639), and ubiquitin-proteasome turnover is mediated by the E3 ligase parkin and promoted by PSD-95, which also excludes STEP61 from the postsynaptic density (PMID:25583483, PMID:27457929). STEP61 abundance is further set by activity-dependent local translation downstream of beta1-adrenergic/ERK/mTOR signaling, forming a negative feedback loop on ERK (PMID:17623046). Dysregulated elevation of STEP61 — through impaired ubiquitination — causes pathological NMDAR loss in Alzheimer's disease, Parkinson's disease, and schizophrenia models, while reduced STEP61 activity contributes to inflammatory pain hypersensitivity (PMID:20427654, PMID:25583483, PMID:27752082, PMID:31135041). Crystallographic and fragment-based studies have defined the active site and an allosteric site, enabling both small-molecule inhibitors and a first-in-class allosteric activator (PMID:16441242, PMID:30207464).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Established why STEP61 differs from its cytosolic counterpart by showing its unique N-terminal region targets it to the ER membrane and tunes down its catalytic activity, defining the isoform basis for compartmentalized phosphatase action.

    Evidence Transfection, subcellular fractionation, sucrose gradients, EM and immunocytochemistry in striatal/fibroblast systems

    PMID:8987810

    Open questions at the time
    • Did not identify physiological substrates dephosphorylated at the ER
    • Functional role of PEST/polyproline domains in turnover not yet tested
  2. 1999 High

    Answered how calcium signaling acutely controls STEP by showing calpain cleaves STEP61 into STEP33 in response to calcium influx and glutamate, linking the phosphatase to excitatory neurotransmission.

    Evidence Calcium ionophore/thapsigargin treatment, calpain inhibitor and EGTA blockade, in vitro calpain cleavage of fusion protein and PSDs

    PMID:10537058

    Open questions at the time
    • Catalytic activity and substrate specificity of the STEP33 fragment not fully defined
    • In vivo consequences of cleavage not established
  3. 2006 High

    Demonstrated that STEP binds NMDARs directly and non-redundantly controls their surface trafficking, establishing receptor regulation as a core function and solving high-resolution structures that defined the active site for drug design.

    Evidence Direct binding assays, surface biotinylation, chronic knockdown electrophysiology; X-ray crystallography in two forms with inhibitor screening

    PMID:16441242 PMID:16819973

    Open questions at the time
    • Precise binding interface on the receptor not mapped
    • Early inhibitors lacked validated cellular selectivity
  4. 2007 Medium

    Identified an activity-dependent feedback circuit by showing STEP translation is induced through beta1-adrenergic co-activation of ERK and PI3K-Akt-mTOR pathways, positioning STEP as a negative regulator of ERK signaling.

    Evidence Pharmacological pathway inhibition (SL327, LY294002, rapamycin) plus anisomycin/actinomycin in slices and primary neurons

    PMID:17623046

    Open questions at the time
    • mRNA localization machinery not identified
    • In vivo behavioral relevance of induced translation not shown
  5. 2010 High

    Connected STEP61 to disease by showing amyloid-beta stabilizes STEP61 by impairing its proteasomal degradation, and that STEP61 is required for Abeta-induced NMDAR internalization, defining a pathogenic mechanism in Alzheimer's models.

    Evidence STEP KO cultures, surface biotinylation, proteasome inhibition, ubiquitin detection, Tg2576 mice and human AD brain

    PMID:20427654

    Open questions at the time
    • E3 ligase responsible for Abeta-sensitive degradation not identified here
    • Link between receptor loss and cognitive deficit not directly tested
  6. 2011 High

    Revealed redox regulation of STEP by showing oxidative stress drives inactivating disulfide-bonded oligomerization through Cys65/Cys76, and consolidated the substrate set (ERK, p38, Fyn, Pyk2, NMDARs, AMPARs) and regulatory logic in a synthesis.

    Evidence pNPP/ERK activity assays, H2O2 treatment, cysteine mutagenesis, non-reducing immunoblots; review integration of regulatory mechanisms

    PMID:21198639 PMID:22090472

    Open questions at the time
    • Physiological oxidant source in vivo not defined
    • Reversibility of oligomerization in neurons not quantified
  7. 2012 High

    Defined Pyk2 as a direct STEP substrate dephosphorylated at Tyr402, extending STEP's reach to a kinase controlling PSD targeting and downstream adhesion signaling.

    Evidence Co-IP, in vitro phosphatase assay, STEP KO mice, KCl depolarization, fractionation showing altered paxillin/ASAP1

    PMID:22544749

    Open questions at the time
    • Stoichiometry of Pyk2 dephosphorylation in vivo not measured
    • Behavioral consequence of Pyk2 dysregulation not addressed
  8. 2013 Medium

    Showed that Abeta acting through alpha7 nicotinic receptors elevates and activates STEP61 to suppress ERK/CREB signaling, linking receptor-level Abeta sensing to STEP-mediated transcriptional dampening.

    Evidence APP/PS1 mice, Abeta-treated neurons, alpha-bungarotoxin pharmacology, STEP61 siRNA, immunoblotting

    PMID:24123152

    Open questions at the time
    • Mechanism coupling alpha7 nAChR to STEP61 expression unresolved
    • Single-lab correlative pathway
  9. 2014 Medium

    Established PKA phosphorylation of Ser221 as an inactivating switch with a behavioral role, showing PKA inhibition in striatum raises STEP activity and impairs motor learning.

    Evidence Rotarod task, intrastriatal Rp-cAMPS, phospho-STEP61(Ser221) immunoblotting

    PMID:24466306

    Open questions at the time
    • Direct in vivo demonstration of PKA-STEP causality limited to pharmacology
    • Substrates mediating motor-learning effect not pinpointed
  10. 2015 High

    Defined parkin as a direct E3 ligase for STEP61 and PSD-95 as a binding partner that both degrades STEP61 and excludes it from the PSD, explaining how STEP61 abundance and synaptic localization are controlled and linking its dysregulation to Parkinson's disease.

    Evidence Ubiquitination assays with WT/mutant parkin, PARK2 KO rat and MPTP models, human PD tissue; PSD-95 co-IP, ubiquitination, KO mice, synaptic vs extrasynaptic NMDAR electrophysiology

    PMID:25583483 PMID:27457929

    Open questions at the time
    • Whether parkin and PSD-95 act in the same or parallel degradation routes not resolved
    • Cooperativity between PKA, calpain and ubiquitin pathways not integrated
  11. 2015 Medium

    Implicated STEP61 in homeostatic plasticity and behavior, showing activity-dependent changes in STEP61 set GluN2B/GluA2 phosphorylation during synaptic scaling and that elevated STEP61 suppresses CREB-dependent BDNF transcription, driving PCP-induced deficits.

    Evidence Hippocampal cultures with activity paradigms, mEPSC recording; PCP cultures/mice, CREB and BDNF analysis, knockdown/TC-2153 rescue, behavior

    PMID:26391783 PMID:26450419

    Open questions at the time
    • Signal coupling neuronal activity to STEP61 level changes not defined
    • Single-lab behavioral correlations
  12. 2015 Medium

    Showed STEP61 tonically restrains ERK and Fyn in spinal dorsal horn neurons, and that loss of GABAergic inhibition disrupts these interactions to drive GluN2B accumulation and pain, establishing STEP61 as an inhibitory gatekeeper of nociceptive plasticity.

    Evidence Intrathecal bicuculline/muscimol, co-IP, immunohistochemistry, viral STEP61 overexpression, behavioral pain testing

    PMID:25478941

    Open questions at the time
    • Co-IP interactions not reciprocally validated
    • Direct substrate dephosphorylation kinetics in spinal neurons not measured
  13. 2016 High

    Provided convergent evidence that pathological STEP61 elevation, via reduced ubiquitination, causes NMDAR loss and behavioral deficits in schizophrenia models that are reversible by STEP inhibition, generalizing the disease mechanism across NMDAR-hypofunction disorders.

    Evidence Nrg1+/- and ErbB2/4 mice, SZ patient hiPSC neurons, genetic and TC-2153 STEP inhibition, surface biotinylation, behavior, ubiquitination assays

    PMID:27752082

    Open questions at the time
    • Upstream cause of reduced STEP61 ubiquitination in SZ not identified
    • Translation of TC-2153 efficacy to clinical setting not addressed
  14. 2018 High

    Achieved pharmacological control over STEP by identifying a selective allosteric activator binding outside the active site, validated structurally and enzymatically, opening a route to enhance STEP activity therapeutically.

    Evidence Fragment screening, X-ray crystallography, 15N NMR, enzymatic selectivity panels, molecular dynamics

    PMID:30207464

    Open questions at the time
    • Cellular and in vivo efficacy of the activator not established
    • Specificity across full PTP family in cells not shown
  15. 2019 High

    Demonstrated that BDNF/KCC2-dependent disinhibition downregulates STEP61 activity as a necessary and sufficient step priming GluN2B-NMDAR potentiation in inflammatory pain, establishing STEP61 downregulation as a causal node in nociceptive sensitization.

    Evidence Rodent pain models, human ex vivo spinal cord BDNF model, KCC2 blockade, STEP61 knockdown/overexpression, GluN2B phosphorylation, electrophysiology, behavior

    PMID:31135041

    Open questions at the time
    • Molecular mechanism by which disinhibition lowers STEP61 activity not defined
    • Therapeutic window of STEP modulation in pain not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers (PKA phosphorylation, calpain cleavage, redox oligomerization, parkin/PSD-95-mediated degradation, and local translation) are integrated and prioritized at individual synapses in real time remains unresolved.
  • No unified quantitative model of competing STEP regulatory inputs
  • Spatiotemporal dynamics of STEP activity at single synapses not measured
  • Causal hierarchy among regulatory mechanisms in vivo unknown

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 2
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 2
Partners
FYNMAPK1/ERKNMDAR (GLUN2B/GRIN2B)PARK2 (PARKIN)PSD-95 (DLG4)PYK2 (PTK2B)

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 STEP61 is an intrinsic membrane protein of striatal neurons associated with the endoplasmic reticulum. The novel N-terminal region unique to STEP61 (containing two putative transmembrane domains, two PEST sequences, and two polyproline-rich domains) is responsible for membrane association and also reduces enzymatic activity compared to the cytosolic isoform STEP46. Transfection experiments in fibroblasts, subcellular fractionation, sucrose density gradients, immunocytochemical labeling, electron microscopy, structural analysis The Journal of neuroscience High 8987810
1999 STEP61 is proteolytically cleaved by calpain in response to calcium influx, generating a smaller ~33 kDa isoform (STEP33). Calcium ionophore or thapsigargin treatment triggers cleavage blocked by the calpain inhibitor calpeptin or EGTA. Glutamate exposure in primary neurons also induces this cleavage. Transfection in NT2/D1 neuronal precursor cells, calcium ionophore treatment, calpain inhibitor experiments, in vitro calpain treatment of STEP61 fusion protein and purified postsynaptic densities, immunoblotting Journal of neurochemistry High 10537058
2006 STEP binds directly to NMDA receptors in the absence of other synaptic proteins, and STEP's phosphatase activity controls constitutive trafficking and surface expression of NMDARs, affecting receptor functional properties and downstream signaling. Chronic reduction of STEP levels cannot be compensated by other phosphatases. Direct binding assay, surface biotinylation, electrophysiology, chronic knockdown in neurons The European journal of neuroscience Medium 16819973
2006 Crystal structures of PTPN5 (STEP) were solved in two distinct crystal forms. PTPN5 crystallized with a sulphate ion near the active site and the WPD loop in a unique conformation ending in a 3(10)-helix not seen in other PTPs. Two classes of small-molecule inhibitors (cyclopenta[c]quinolinecarboxylic acids and 2,5-dimethylpyrrolyl benzoic acids) were identified. X-ray crystallography (two crystal forms), compound library screening (~24,000 compounds), structure-activity relationship analysis, docking The Biochemical journal High 16441242
2007 STEP translation is induced by beta1-adrenergic receptor stimulation via co-activation of both the ERK and PI3K-Akt-mTOR pathways (blocked by MEK inhibitor SL327, PI3K inhibitor LY294002, or mTOR inhibitor rapamycin). This is a translation-dependent (not transcription-dependent) mechanism, suggesting STEP participates in a negative feedback loop on ERK. Pharmacological inhibition in corticostriatal slices and primary neuronal cultures, isoproterenol stimulation, anisomycin/actinomycin D treatment, immunoblotting Journal of neurochemistry Medium 17623046
2010 Amyloid-beta increases STEP61 levels in Alzheimer's disease models (Tg2576 mice and cortical cultures) by reducing its ubiquitin-proteasome-mediated degradation. Elevated STEP61 dephosphorylates GluN2B at pTyr1472, reducing NR1/NR2B surface expression. In STEP knockout cultures, Abeta treatment failed to induce NMDA receptor internalization, demonstrating STEP61 is required for Abeta-induced NMDAR endocytosis. Biotinylation assays for surface receptor expression, STEP KO cultures, proteasome inhibition, ubiquitin conjugate detection, Tg2576 mouse cortex analysis, human AD brain analysis The Journal of neuroscience High 20427654
2011 STEP61 undergoes homodimerization under basal conditions in neurons via intermolecular disulfide bond formation between Cys65 and Cys76 in its N-terminal hydrophobic region. Oxidative stress (H2O2) significantly increases formation of STEP61 dimers and higher-order oligomers, leading to a significant reduction in STEP61 enzymatic activity toward both pNPP and ERK substrates. In vitro phosphatase activity assays (pNPP and ERK substrates), H2O2 treatment of neurons, site-directed mutagenesis of cysteine residues, immunoblotting under reducing/non-reducing conditions Journal of neurochemistry High 21198639
2011 STEP is a brain-specific phosphatase whose targets include ERK1/2, p38, Fyn, Pyk2, NMDARs, and AMPARs. STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to their inactivation, while STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis. STEP activity is regulated by phosphorylation (by PKA), cleavage, dimerization, ubiquitination, and local translation. Review synthesizing multiple experimental findings; regulatory mechanisms established by cited original experiments Pharmacological reviews Medium 22090472
2012 Pyk2 (proline-rich tyrosine kinase 2) is a direct substrate of STEP. STEP binds to and dephosphorylates Pyk2 at Tyr402. STEP KO mice show enhanced phosphorylation of Pyk2 at Tyr402 and of downstream Pyk2 substrates paxillin and ASAP1. STEP opposes Pyk2 activation after KCl depolarization and blocks Pyk2 translocation to postsynaptic densities. Co-immunoprecipitation, in vitro phosphatase assay, STEP KO mouse analysis, KCl depolarization of cortical slices, immunoblotting, subcellular fractionation The Journal of biological chemistry High 22544749
2013 STEP61 negatively regulates Abeta-mediated ERK/CREB signaling via alpha7 nicotinic acetylcholine receptors. Abeta binding to alpha7 nAChRs increases STEP61 expression and active (dephosphorylated) STEP61; this is blocked by the alpha7 nAChR antagonist alpha-bungarotoxin. Knockdown of STEP61 enhances ERK1/2 and CREB activation in Abeta-treated neurons. APP/PS1 transgenic mouse model, Abeta1-42 treatment of cortical neurons, alpha-bungarotoxin pharmacology, STEP61 siRNA knockdown, immunoblotting Journal of neuroscience research Medium 24123152
2014 PKA phosphorylates STEP61 at Ser221, inactivating it. During motor skill learning on the rotarod task, phospho-STEP61 (Ser221) levels are differentially modulated in hippocampus, motor cortex, and striatum. Pharmacological inhibition of PKA in dorsal striatum reduces pSTEP61(Ser221), promotes STEP61 activity, and impairs motor learning. Rotarod behavioral task in mice, intrastriatal injection of PKA inhibitor Rp-cAMPS, immunoblotting for phospho-STEP61 Ser221 PloS one Medium 24466306
2015 Parkin (PARK2 E3 ubiquitin ligase) ubiquitinates STEP61 and regulates its levels through the proteasome. Clinically relevant parkin mutants fail to ubiquitinate STEP61. Acute downregulation of parkin or PARK2 KO in rat striatum elevates STEP61. Elevated STEP61 in PD models is associated with decreased ERK1/2 phosphorylation and pCREB. Cellular ubiquitination assays with wild-type and mutant parkin, acute parkin knockdown, PARK2 KO rat striatum analysis, MPTP-lesioned mouse model, human sporadic PD brain tissue analysis, immunoblotting Proceedings of the National Academy of Sciences of the United States of America High 25583483
2015 STEP61 levels and activity are regulated by prolonged changes in neuronal activity as part of homeostatic synaptic plasticity. Prolonged activity blockade decreases STEP61 level/activity and increases tyrosine phosphorylation of GluN2B and GluA2 (STEP61 substrates); increasing STEP61 activity blocks synaptic scaling. Prolonged activity enhancement increases STEP61 level/activity and reduces GluN2B/GluA2 phosphorylation in a STEP61-dependent manner. Rat dissociated hippocampal cultures, activity blockade/enhancement paradigms, immunoblotting, electrophysiology (mEPSC recording), pharmacological manipulation of STEP61 Molecular brain Medium 26391783
2015 STEP61 inhibition (genetic knockdown or pharmacological TC-2153) prevents PCP-induced reduction of BDNF expression by restoring CREB-dependent BDNF transcription. PCP increases STEP61 levels, which inhibits CREB phosphorylation and downstream BDNF expression; STEP61 knockdown rescues BDNF levels and normalizes PCP-induced behavioral deficits in vivo. PCP-treated cortical cultures and mice, STEP61 knockdown/TC-2153 pharmacology, CREB phosphorylation analysis, BDNF mRNA/protein measurement, behavioral testing (hyperlocomotion, cognitive tasks) Cellular and molecular life sciences Medium 26450419
2016 STEP61 binds directly to PSD-95 but not to other PSD-95 family members. PSD-95 expression destabilizes STEP61 via ubiquitination and proteasomal degradation, and excludes STEP61 from the PSD. Knockdown of PSD-95 or PSD-95 KO mice show increased STEP61 in the PSD fraction. Only extrasynaptic (not synaptic) NMDAR expression and currents are increased upon STEP knockdown, consistent with STEP61's exclusion from the PSD by PSD-95. Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, PSD-95 KO mice, PSD-95 knockdown, electrophysiology (synaptic vs. extrasynaptic NMDAR currents) Proceedings of the National Academy of Sciences of the United States of America High 27457929
2016 STEP61 is elevated in schizophrenia models (Nrg1+/- mice, ErbB2/4 mice, hiPSC-derived neurons from SZ patients). Elevated STEP61 causes loss of NMDARs from synaptic membranes via dephosphorylation of GluN2B and inactivation of ERK1/2 and Fyn. Genetic reduction or pharmacological inhibition of STEP prevents NMDAR loss and reverses behavioral deficits. The elevated STEP61 reflects reduced ubiquitination and degradation. Nrg1+/- and ErbB2/4 KO mouse models, hiPSC-derived neurons from SZ patient cohorts, genetic STEP reduction, TC-2153 pharmacological inhibition, surface receptor biotinylation, behavioral testing, ubiquitination assays Molecular psychiatry High 27752082
2018 A first-in-class small molecule allosteric activator of STEP (PTPN5) was identified that binds to the phosphatase domain at a site distinct from the active site. Allosteric binding was confirmed by X-ray crystallography and 15N NMR. Molecular dynamics simulations indicate activation occurs via a long-range allosteric mechanism. The activator shows selectivity for STEP over other PTPs. X-ray crystallography, 15N NMR, enzymatic activity assays with selectivity panel, molecular dynamics simulations, fragment screening Journal of medicinal chemistry High 30207464
2019 In rodent inflammatory pain and human spinal cord ex vivo models, BDNF-mediated KCC2-dependent disinhibition downregulates STEP61 activity. Decreased STEP61 activity is necessary and sufficient to prime subsequent phosphorylation and potentiation of GluN2B-NMDARs by BDNF at lamina I synapses. Blocking disinhibition reversed the downregulation of STEP61 and inflammation-mediated behavioral hypersensitivity. Rodent nerve injury and inflammatory pain models, human ex vivo spinal cord BDNF model, KCC2 blockade, STEP61 knockdown/overexpression, GluN2B phosphorylation assays, electrophysiology, behavioral testing Brain High 31135041
2015 STEP61 tonically interacts with and negatively controls ERK and Fyn kinase activity in spinal dorsal horn neurons under physiological conditions. Impaired GABAergic inhibition disrupts STEP61 interaction with these substrates, allowing ERK and Fyn hyperactivation, subsequent tyrosine phosphorylation and synaptic accumulation of GluN2B-NMDARs, and pain hypersensitivity. Overexpression of wild-type STEP61 blocked bicuculline-induced allodynia and alleviated chronic inflammatory pain. Intrathecal bicuculline/muscimol administration, co-immunoprecipitation, immunoblotting, immunohistochemistry, STEP61 overexpression (viral), behavioral pain testing Anesthesiology Medium 25478941

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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2003 Transitional B cells: step by step towards immune competence. Trends in immunology 184 12810111
2010 Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61. The Journal of neuroscience : the official journal of the Society for Neuroscience 178 20427654
1999 Cell migration as a five-step cycle. Biochemical Society symposium 162 10320942
2014 The meiotic checkpoint network: step-by-step through meiotic prophase. Cold Spring Harbor perspectives in biology 155 25274702
2015 A step-by-step protocol for assaying protein carbonylation in biological samples. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 145 26706659
2010 DNA interstrand crosslink repair in mammalian cells: step by step. Critical reviews in biochemistry and molecular biology 141 20039786
2022 Mitochondrial event as an ultimate step in ferroptosis. Cell death discovery 134 36209144
2011 Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. Pharmacological reviews 131 22090472
2017 A step-by-step microRNA guide to cancer development and metastasis. Cellular oncology (Dordrecht, Netherlands) 126 28748501
2014 Geroconversion: irreversible step to cellular senescence. Cell cycle (Georgetown, Tex.) 115 25483060
2019 Recombination in Enteroviruses, a Multi-Step Modular Evolutionary Process. Viruses 104 31540135
2016 PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61. Proceedings of the National Academy of Sciences of the United States of America 103 27457929
2007 Taking it step by step: mechanistic insights from structural studies of ubiquitin/ubiquitin-like protein modification pathways. Current opinion in structural biology 97 17919899
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2016 A 15-step synthesis of (+)-ryanodol. Science (New York, N.Y.) 84 27563092
2003 Egress: a receptor-regulated step in lymphocyte trafficking. Immunological reviews 84 12969317
2009 Step-by-step evolution of vertebrate blood coagulation. Cold Spring Harbor symposia on quantitative biology 79 19667012
2008 Protein kinase A-dependent step(s) in hepatitis C virus entry and infectivity. Journal of virology 75 18579596
2007 Dasatinib: a new step in molecular target therapy. Annals of oncology : official journal of the European Society for Medical Oncology 74 17591830
1995 5-Aminolevulinate synthase and the first step of heme biosynthesis. Journal of bioenergetics and biomembranes 73 7592562
2020 Viral RNA recognition by LGP2 and MDA5, and activation of signaling through step-by-step conformational changes. Nucleic acids research 72 33137199
1996 STEP61: a member of a family of brain-enriched PTPs is localized to the endoplasmic reticulum. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 8987810
2020 Squalene: More than a Step toward Sterols. Antioxidants (Basel, Switzerland) 70 32748847
2012 Striatal-enriched protein-tyrosine phosphatase (STEP) regulates Pyk2 kinase activity. The Journal of biological chemistry 70 22544749
1996 Myotonic dystrophy: will the real gene please step forward! Human molecular genetics 66 8875246
2014 Variability of the reverse transcription step: practical implications. Clinical chemistry 65 25361949
2010 A step-by-step guide to visual circuit assembly in Drosophila. Current opinion in neurobiology 65 20800474
2023 Step by step: towards a better understanding of the genetic architecture of Alzheimer's disease. Molecular psychiatry 64 37131074
2020 An Optimised Step-by-Step Protocol for Measuring Relative Telomere Length. Methods and protocols 62 32260112
2015 Gene set analysis: A step-by-step guide. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 61 26059482
2004 A DNA enzyme that mimics the first step of RNA splicing. Nature structural & molecular biology 60 14758353
2015 First-Step Mutations during Adaptation Restore the Expression of Hundreds of Genes. Molecular biology and evolution 59 26500250
2006 Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases. The Biochemical journal 58 16441242
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2000 MUM1: a step ahead toward the understanding of lymphoma histogenesis. Leukemia 58 10764139
2019 Loss of STEP61 couples disinhibition to N-methyl-d-aspartate receptor potentiation in rodent and human spinal pain processing. Brain : a journal of neurology 52 31135041
2015 Are epigenetic drugs for diabetes and obesity at our door step? Drug discovery today 49 26697737
2022 Break-induced replication: unraveling each step. Trends in genetics : TIG 48 35459559
2020 Clonal Hematopoiesis: A New Step Linking Inflammation to Heart Failure. JACC. Basic to translational science 48 32140625
2015 STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 48 25583483
2001 Evolution of the two-step model for UV-mutagenesis. Mutation research 47 11341996
2021 Multi-step vs. single-step resistance evolution under different drugs, pharmacokinetics, and treatment regimens. eLife 46 34001313
2016 Biomarkers in DILI: One More Step Forward. Frontiers in pharmacology 46 27597831
2011 A review of recent experiments on step-to-step "hand-off" of the DNA intermediates in mammalian base excision repair pathways. Molekuliarnaia biologiia 45 21954590
2019 Stimulus-Responsive Regulation of Enzyme Activity for One-Step and Multi-Step Syntheses. Advanced synthesis & catalysis 41 31244574
2015 Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity. Molecular brain 40 26391783
2011 Endospanins regulate a postinternalization step of the leptin receptor endocytic pathway. The Journal of biological chemistry 40 21454707
2022 Step by step: cells with multiple functions in cortical circuit assembly. Nature reviews. Neuroscience 38 35422526
2013 Step-by-step mechanism of DNA damage recognition by human 8-oxoguanine DNA glycosylase. Biochimica et biophysica acta 38 24096108
2023 The next step in Mendelian randomization. eLife 37 36891986
2015 One-Step Protein Conjugation to Upconversion Nanoparticles. Analytical chemistry 37 26429146
2022 Transcription factors perform a 2-step search of the nucleus. Genetics 35 35939561
2017 Step by Step, Cell by Cell: Quantification of the Bacterial Cell Cycle. Trends in microbiology 35 28094092
2021 Tau internalization: A complex step in tau propagation. Ageing research reviews 33 33571704
1999 Calcium-dependent cleavage of striatal enriched tyrosine phosphatase (STEP). Journal of neurochemistry 33 10537058
2021 Step-by-Step Evolution of Telomeres: Lessons from Yeasts. Genome biology and evolution 32 33537752
2017 RNA Chaperones Step Out of Hfq's Shadow. Trends in microbiology 32 28189381
2020 Protein stability during nebulization: Mind the collection step! European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 31 32289493
2018 Allosteric Activation of Striatal-Enriched Protein Tyrosine Phosphatase (STEP, PTPN5) by a Fragment-like Molecule. Journal of medicinal chemistry 31 30207464
2016 Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models. Molecular psychiatry 31 27752082
2021 Regulating immune memory and reversing tumor thermotolerance through a step-by-step starving-photothermal therapy. Journal of nanobiotechnology 29 34593005
2020 Livestock Gene Editing by One-step Embryo Manipulation. Journal of equine veterinary science 29 32563448
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2018 Mammalian Sperm Protamine Extraction and Analysis: A Step-By-Step Detailed Protocol and Brief Review of Protamine Alterations. Protein and peptide letters 26 29651936
2014 Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders. Neuroscience research 26 25218562
2022 G6b-B regulates an essential step in megakaryocyte maturation. Blood advances 25 35134123
2020 Regulation of glutamate receptors by striatal-enriched tyrosine phosphatase 61 (STEP61 ). The Journal of physiology 25 32170729
2013 Tyrosine phosphatase STEP61 negatively regulates amyloid β-mediated ERK/CREB signaling pathways via α7 nicotinic acetylcholine receptors. Journal of neuroscience research 25 24123152
2010 The initiation step of eukaryotic DNA replication. Sub-cellular biochemistry 25 20012578
2018 Two-step mechanism and step-arrest mutants of Runella slithyformis NAD+-dependent tRNA 2'-phosphotransferase Tpt1. RNA (New York, N.Y.) 24 29884622
2017 Two-step ATP-driven opening of cohesin head. Scientific reports 24 28607419
2014 Transient expression assays in grapevine: a step towards genetic improvement. Plant biotechnology journal 24 25431200
2011 Oxidative stress-induced oligomerization inhibits the activity of the non-receptor tyrosine phosphatase STEP61. Journal of neurochemistry 24 21198639
2024 Seaweed Proteins: A Step towards Sustainability? Nutrients 23 38674814
2010 Bile duct ligation: step-by-step to cholangiocyte inflammatory tumorigenesis. European journal of gastroenterology & hepatology 23 19641467
2020 Targeting a critical step in fungal hexosamine biosynthesis. The Journal of biological chemistry 22 32341126
2019 RNA Polymerase: Step-by-Step Kinetics and Mechanism of Transcription Initiation. Biochemistry 22 30950601
2015 GABAergic inhibition regulated pain sensitization through STEP61 signaling in spinal dorsal horn of mice. Anesthesiology 22 25478941
2024 The step-by-step assembly mechanism of secreted flavivirus NS1 tetramer and hexamer captured at atomic resolution. Science advances 21 38691607
2017 Striatal-enriched Tyrosine Protein Phosphatase (STEP) in the Mechanisms of Depressive Disorders. Current protein & peptide science 21 28699511
2015 Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice. Cellular and molecular life sciences : CMLS 21 26450419
2020 Step by step evolution of Indeterminate Domain (IDD) transcriptional regulators: from algae to angiosperms. Annals of botany 19 32206771
2016 Seizure-Induced Regulations of Amyloid-β, STEP61, and STEP61 Substrates Involved in Hippocampal Synaptic Plasticity. Neural plasticity 19 27127657
2019 One-Step verse Step-Up Laparoscopic-Assisted Necrosectomy for Infected Pancreatic Necrosis. Digestive surgery 18 31269486
2022 Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution. Biomedicines 17 35327450
2014 Regulation of tyrosine phosphatase STEP61 by protein kinase A during motor skill learning in mice. PloS one 17 24466306
2014 Enhanced sampling simulations of DNA step parameters. Journal of computational chemistry 17 25303338
2021 Breakdown of Filamentous Myofibrils by the UPS-Step by Step. Biomolecules 16 33467597
2007 Translation of striatal-enriched protein tyrosine phosphatase (STEP) after beta1-adrenergic receptor stimulation. Journal of neurochemistry 16 17623046
2023 Structures illustrate step-by-step mitochondrial transcription initiation. Nature 15 37821701
2021 The Journey from Two-Step to Multi-Step Phosphorelay Signaling Systems. Current genomics 15 34045924
2021 Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm. Biomedicines 15 34356863
2016 Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring. PloS one 15 26872063

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