Affinage

PPP1R1B

Protein phosphatase 1 regulatory subunit 1B · UniProt Q9UD71

Length
204 aa
Mass
23.0 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 42 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP1R1B (DARPP-32) is a phosphorylation-state-controlled signaling integrator in dopaminoceptive neurons that converts upstream neuromodulatory inputs into bidirectional control of protein phosphatase-1 (PP-1) and PKA activity (PMID:6087160, PMID:10604473). When phosphorylated on Thr34 by PKA — the terminal step of a dopamine→cAMP→PKA cascade engaged downstream of D1 receptors — it becomes a nanomolar inhibitor of PP-1, an inhibition that requires both the phospho-Thr34 active-site contact and an N-terminal RKKIQF motif (Phe11, Ile9) for a two-site interaction with the phosphatase (PMID:6087160, PMID:6319627, PMID:9108011, PMID:10075680). The N-terminal region shares sequence identity with phosphatase inhibitor-1, defining a common structural basis for PP-1 inhibition (PMID:3511054). A distinct phosphorylation by Cdk5 at Thr75 instead converts DARPP-32 into a competitive inhibitor of PKA, so the protein operates as a reciprocal molecular switch between the two states (PMID:10604473). These states are tuned by additional kinases and phosphatases — CK2 phosphorylates Ser45/Ser102 and accelerates PKA phosphorylation of Thr34 (PMID:2557337, PMID:2145398), calcineurin (PP2B) is the principal Thr34 phosphatase (PMID:9334390, PMID:10217279), and a Ca2+-sensing PR72/PP2A complex dephosphorylates Thr75 (PMID:17535922) — allowing DARPP-32 to integrate dopamine, glutamate, GABA, adenosine, opioid, and serotonergic signals into graded phosphatase/kinase control (PMID:9334390, PMID:12181566, PMID:15657149, PMID:7931332, PMID:10336688). In vivo, DARPP-32 is essential for molecular, electrophysiological, and behavioral responses to dopamine and psychoactive drugs, acting through site-specific Thr34 and Thr75 phosphorylation to govern responses to cocaine, antidepressants, and L-DOPA-induced dyskinesia (PMID:9694658, PMID:11880651, PMID:16123776, PMID:17596448). Beyond neurons, DARPP-32 and its truncated isoform t-DARPP function in epithelial cancers, where they physically partner with EGFR/ERBB3, IGF1R, CXCR4, and IKKα to activate AKT, STAT3, and NF-κB2 signaling and to promote survival, invasion, angiogenesis, and drug resistance (PMID:21741919, PMID:31235784, PMID:25779598, PMID:23160836, PMID:29782621, PMID:19301121, PMID:19593441).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1984 High

    Established the core biochemical function: that a neuronal phosphoprotein acts as a phosphorylation-dependent inhibitor of PP-1, defining DARPP-32 as a signaling effector rather than a passive substrate.

    Evidence In vitro phosphatase inhibition assay with purified DARPP-32 and PP-1; biochemical purification and hydrodynamic characterization

    PMID:6087160 PMID:6319628

    Open questions at the time
    • Did not define the responsible kinase or the phosphorylated residue
    • No structural model of the DARPP-32/PP-1 contact
  2. 1984 High

    Identified the activating kinase and signaling input, linking dopamine to DARPP-32 via a cAMP/PKA cascade and showing PKA (and PKG) phosphorylate a single threonine.

    Evidence In vitro PKA/PKG kinase assay with phosphopeptide mapping; intact striatal cell [32P] labeling with dopamine and 8-bromo-cAMP

    PMID:6319627 PMID:6501303

    Open questions at the time
    • Exact residue identity not yet assigned at sequence level
    • Phosphatase responsible for reversal unknown
  3. 1986 High

    Resolved the molecular basis of inhibition by determining the full sequence, mapping the PKA site to Thr34, and revealing homology to inhibitor-1.

    Evidence Edman degradation of bovine DARPP-32 peptides; sequence comparison with inhibitor-1

    PMID:3511054

    Open questions at the time
    • Did not define which N-terminal residues contact PP-1
    • Other phosphorylation sites and their kinases unknown
  4. 1989 High

    Showed multi-site regulation by identifying CK2 phosphorylation at Ser45/Ser102 that primes Thr34 phosphorylation, introducing hierarchical control of inhibitory potency.

    Evidence In vitro CK2 kinase assay with phosphopeptide sequencing; intact slice labeling; kinetic analysis; endogenous striatal CK2 characterization

    PMID:2145398 PMID:2557337

    Open questions at the time
    • Physiological trigger of CK2 activity in neurons not defined
    • Functional impact of Ser45 vs Ser102 not separated in vivo
  5. 1997 High

    Defined the structural determinants of PP-1 inhibition, establishing a two-site mechanism requiring both phospho-Thr34 and an N-terminal RKKIQF motif.

    Evidence Synthetic peptide competition and DARPP-32 mutagenesis with in vitro PP-1 inhibition assays

    PMID:10075680 PMID:9108011

    Open questions at the time
    • No co-crystal structure of the DARPP-32/PP-1 complex
    • Whether the two sites engage PP-1 simultaneously in cells untested
  6. 1997 High

    Demonstrated bidirectional dopaminergic control, with D1 increasing and D2 decreasing Thr34 phosphorylation via a Ca2+/calcineurin pathway, and identified calcineurin as the principal Thr34 phosphatase.

    Evidence Striatal slice [32P] assays with D1/D2 pharmacology, calcineurin inhibitors, and Ca2+-free media

    PMID:10217279 PMID:9334390

    Open questions at the time
    • Spatial coupling of calcineurin to DARPP-32 not resolved
    • Contribution of PP2A versus calcineurin quantitatively uncertain
  7. 1999 High

    Revealed the second, opposing switch state: Cdk5 phosphorylation at Thr75 converts DARPP-32 into a competitive PKA inhibitor, making it a reciprocal kinase/phosphatase integrator.

    Evidence In vitro Cdk5 kinase assay, intact brain cell labeling, Cdk5 inhibitor and mutant mice, Ca2+ current electrophysiology

    PMID:10604473

    Open questions at the time
    • Phosphatase reversing Thr75 not yet identified at this stage
    • Crosstalk dynamics between Thr34 and Thr75 states unresolved
  8. 1998 High

    Established physiological necessity in vivo by showing DARPP-32 knockout disrupts dopaminergic molecular, electrophysiological, and behavioral responses.

    Evidence Targeted knockout mouse with behavioral, electrophysiological, and biochemical readouts

    PMID:9694658

    Open questions at the time
    • Did not separate Thr34 from Thr75 contributions
    • Cell-type-specific roles not resolved
  9. 2002 High

    Mapped DARPP-32 downstream effectors and broadened its signaling inputs, linking it to GABA(A), NMDA, AMPA-receptor regulation and to adenosine, serotonergic, and antidepressant pathways through site-specific phosphorylation.

    Evidence DARPP-32 knockout mice, slice electrophysiology, phospho-specific immunoblots, and pharmacology across striatal, accumbens, and cortical preparations

    PMID:10336688 PMID:10805695 PMID:11880651 PMID:12068305 PMID:12181566 PMID:15657149 PMID:7931332

    Open questions at the time
    • Quantitative integration of competing inputs at single-neuron resolution incomplete
    • Direct substrate phosphorylation by PP-1/PKA versus indirect effects not always separated
  10. 2007 High

    Identified the Ca2+-sensing Thr75 phosphatase, showing a PR72/PP2A complex with functional EF-hands dephosphorylates Thr75 in response to glutamate-driven Ca2+.

    Evidence PR72 overexpression/RNAi, EF-hand mutagenesis, in vitro PP2A assay, and striatal slice phosphorylation with glutamate receptor pharmacology

    PMID:17535922

    Open questions at the time
    • Stoichiometry and assembly of the PR72/PP2A/DARPP-32 module unresolved
    • Whether PR72 directly binds DARPP-32 not shown
  11. 2008 High

    Resolved cell-type-specific regulation, showing psychostimulants and antipsychotics drive Thr34 phosphorylation in opposite striatal neuron populations, and dissected site-specific behavioral roles.

    Evidence BAC transgenic and T34A/T75A knock-in mice with FACS-based phospho-analysis and behavioral assays

    PMID:16123776 PMID:17596448 PMID:18622401

    Open questions at the time
    • Molecular basis of divergent D1 versus D2 neuron responses not fully defined
    • Link from H3/ERK cascade to specific transcriptional programs incomplete
  12. 2009 Medium

    Extended DARPP-32 function beyond neurons to epithelial and reproductive contexts, showing canonical Thr34/PP-1 signaling controls cell migration and sexual behavior.

    Evidence Wnt-5a/Frizzled-3 signaling with siRNA and Cdc42 assays in MCF-7 cells; DDR1-dependent migration with DARPP-32 mutants; antisense and knockout for progesterone-facilitated receptivity

    PMID:10669419 PMID:17027969 PMID:19651774

    Open questions at the time
    • Antimigratory cancer findings rest largely on single-lab cell models
    • Generality across epithelial cell types not established
  13. 2014 Medium

    Placed DARPP-32 in a Ca2+/apoptosis feedback module, showing Bcl-2 docks DARPP-32 with calcineurin on the InsP3R to create a negative-feedback loop that limits apoptosis.

    Evidence Reciprocal co-immunoprecipitation, Bcl-2/DARPP-32 RNAi, Ca2+ and apoptosis assays

    PMID:24395794

    Open questions at the time
    • Co-IP-based complex not validated structurally
    • Generality beyond the studied cell systems unclear
  14. 2018 Medium

    Defined oncogenic protein-complex partners through which DARPP-32/t-DARPP activate survival and invasion pathways, including EGFR/ERBB3, IGF1R, CXCR4, IKKα, SRp20, and downstream AKT/STAT3/NF-κB2 signaling.

    Evidence Co-immunoprecipitation, proximity ligation, shRNA/siRNA, organoids, knock-in/knockout and xenograft/orthotopic mouse models, and human tumor tissue analysis

    PMID:12124342 PMID:16061638 PMID:19301121 PMID:19593441 PMID:21741919 PMID:23160836 PMID:25779598 PMID:26119931 PMID:27590997 PMID:29782621 PMID:31235784 PMID:32768595

    Open questions at the time
    • Most interactions established by Co-IP in single labs without structural mapping
    • Whether catalytic phosphatase-inhibitory activity is required for many cancer phenotypes is inconsistent across studies
    • t-DARPP versus full-length contributions not always separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the competing Thr34 and Thr75 phosphorylation states, their kinases, and their phosphatases are spatially and temporally coordinated at the level of individual synapses or signaling complexes remains unresolved, as does the structural basis of the many cancer-associated receptor complexes.
  • No structural model of DARPP-32 bound to PP-1 or to cancer receptor partners
  • Quantitative model integrating all kinase/phosphatase inputs at single-cell resolution lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
CDK5CSNK2A1CXCR4EGFRERBB3IGF1RPPP1CAPPP3CA

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 Phosphorylated DARPP-32 is a potent inhibitor of protein phosphatase-1 (PP-1) at nanomolar concentrations; inhibitory activity requires the phosphorylated (not dephosphorylated) form of the protein. In vitro phosphatase inhibition assay with purified DARPP-32 and PP-1 Nature High 6087160
1984 DARPP-32 is phosphorylated on a single threonine residue (Thr34) by both cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) in vitro, with kinetic parameters compatible with a physiological role for both kinases. In vitro kinase assay with purified PKA and PKG; two-dimensional phosphopeptide mapping; stoichiometry determination The Journal of biological chemistry High 6501303
1984 DARPP-32 is phosphorylated in intact striatal cells by dopamine and by 8-bromo-cAMP, and in cell-free preparations by cAMP-dependent protein kinase, establishing a dopamine→cAMP→PKA→DARPP-32 signaling axis in dopaminoceptive neurons. Intact cell radiolabeling with [32P]; cell-free kinase assay The Journal of neuroscience High 6319627
1984 DARPP-32 is an elongated monomeric protein of 202 residues with a calculated mass of ~22.6 kDa (anomalously high apparent MW on SDS-PAGE); it is highly hydrophilic with a high proline/glutamate content and a stretch of 16 consecutive acidic residues. Protein purification (435-fold), SDS-PAGE, hydrodynamic measurements (Stokes radius, sedimentation coefficient), amino acid composition The Journal of neuroscience High 6319628
1986 The complete amino acid sequence of bovine DARPP-32 was determined; the phosphorylation site for PKA is Thr34; the NH2-terminal region of DARPP-32 shares significant sequence identity with protein phosphatase inhibitor-1, suggesting a common structural basis for PP-1 inhibitory activity. Protein sequencing by automated Edman degradation of overlapping peptides from multiple enzymatic/chemical cleavages; sequence comparison The Journal of biological chemistry High 3511054
1989 Casein kinase II (CK2) phosphorylates DARPP-32 in vitro at Ser45 and Ser102 (main site in intact cells is Ser102); phosphorylation by CK2 does not directly affect PP-1 inhibitory potency but facilitates subsequent phosphorylation of Thr34 by PKA (~2.2-fold increase in Vmax). In vitro kinase assay with purified CK2; phosphopeptide sequencing; manual Edman degradation; [32P]-labeling of intact caudate-putamen slices; kinetic analysis with synthetic peptides The Journal of biological chemistry High 2557337
1999 Cyclin-dependent kinase 5 (Cdk5) phosphorylates DARPP-32 at Thr75 in vitro and in intact brain cells, converting DARPP-32 into an inhibitor of PKA by a competitive mechanism; this is distinct from the PP-1 inhibitory function conferred by Thr34 phosphorylation. In vitro kinase assay; intact brain cell [32P] labeling; Cdk5-specific inhibitor treatment; Cdk5 mutant mice; electrophysiological measurement of voltage-gated Ca2+ currents Nature High 10604473
1997 The NH2-terminal motif RKKIQF (residues 6–11) of DARPP-32 is required for PP-1 inhibition; Phe11 and Ile9 play critical roles. Peptides containing this motif antagonize inhibition of PP-1 by phospho-DARPP-32 and compete with PP-1 targeting/binding proteins, suggesting two-site interaction of phospho-DARPP-32 with PP-1 (active-site interaction via phospho-Thr34, and remote-site interaction via RKKIQF motif). Synthetic peptide competition assays; mutagenesis of DARPP-32; in vitro PP-1 inhibition assays Proceedings of the National Academy of Sciences of the United States of America High 9108011
1999 Detailed mutagenesis of phospho-DARPP-32 identified Phe11, Ile9 (critical), Lys7 (lesser), Pro33, Pro35, and phospho-Thr34 as key residues for PP-1 inhibition; the spacing between residues 7–11 and phospho-Thr34 is also important. The KKIQF motif in DARPP-32 and IKGI in inhibitor-2 represent distinct NH2-terminal motifs critical for PP-1 inhibition. Site-directed mutagenesis; in vitro PP-1 inhibition assays (IC50 measurements); peptide competition The Journal of biological chemistry High 10075680
1997 Dopamine exerts bidirectional control of DARPP-32 phosphorylation: D1 receptor activation increases Thr34 phosphorylation (via PKA), while D2 receptor activation decreases Thr34 phosphorylation via a calcium-dependent calcineurin pathway (blocked by cyclosporin A and Ca2+-free/EGTA medium). Mouse striatal slice preparation; [32P] phosphorylation assay; pharmacological D1/D2 agonist/antagonist treatment; calcineurin inhibitor (cyclosporin A); Ca2+-free medium The Journal of neuroscience High 9334390
1999 Calcineurin (PP2B) is the primary phosphatase responsible for dephosphorylating Thr34-phospho-DARPP-32 in neostriatal neurons, acting synergistically with PP2A (not PP-1); cyclosporin A (calcineurin inhibitor) produced a ~17-fold increase in phospho-DARPP-32 in striatal slices. Mouse neostriatal slice phosphorylation assay; pharmacological inhibitors (cyclosporin A, okadaic acid, calyculin A); Ca2+-free/EGTA medium Journal of neurochemistry High 10217279
1998 DARPP-32 knockout mice show profound deficits in molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication, establishing DARPP-32 as central to the efficacy of dopaminergic neurotransmission in vivo. Targeted gene disruption (knockout mouse); behavioral assays; electrophysiology; biochemical assays Science High 9694658
2000 D1 dopamine receptor stimulation reduces GABA-evoked currents in neostriatal medium spiny neurons through a PKA/DARPP-32/PP1 signaling cascade targeting GABA(A) receptor beta1/beta3 subunits; phosphorylation of beta1/beta3 subunits was attenuated in DARPP-32 mutant neurons. Whole-cell voltage-clamp recordings; immunoprecipitation of radiolabeled proteins; DARPP-32 knockout mice; single-cell RT-PCR Journal of neurophysiology High 10805695
2000 DARPP-32 is required for progesterone-facilitated sexual receptivity in female rats and mice; progesterone increases hypothalamic cAMP levels and PKA activity, leading to Thr34-DARPP-32 phosphorylation; DARPP-32 is an obligate intermediate in progestin receptor-regulated sexual behavior. Antisense oligonucleotides to DARPP-32 in rats; DARPP-32 null mutant mice; behavioral assays; cAMP and PKA activity measurements; phospho-DARPP-32 immunoblot Science High 10669419
2002 DARPP-32 mediates the stimulant action of caffeine (via adenosine A2A receptor blockade) by increasing Thr75 phosphorylation; this occurs through inhibition of PP2A-catalyzed dephosphorylation of Thr75 rather than through stimulation of Cdk5. DARPP-32 knockout mice; locomotor activity assays; phospho-specific immunoblot of striatal tissue; pharmacological A2A antagonist/agonist treatment Nature High 12181566
2002 Fluoxetine regulates DARPP-32 phosphorylation at multiple sites (increases Thr34 and Ser137, decreases Thr75) in prefrontal cortex, hippocampus, and striatum; DARPP-32 mediates fluoxetine-induced phosphorylation of AMPA receptor GluR1 at Ser845 and the antidepressant behavioral response, as shown by attenuation in DARPP-32 knockout mice. In vivo drug administration; DARPP-32 knockout mice; phospho-specific immunoblots; animal test of antidepressant efficacy Proceedings of the National Academy of Sciences of the United States of America High 11880651
2002 Prior D1 receptor activation and consequent DARPP-32 phosphorylation (with subsequent NR1-NMDA receptor phosphorylation) strongly reduces ethanol inhibition of NMDA responses in nucleus accumbens; this regulation was absent in DARPP-32 knockout mice. Rat/mouse nucleus accumbens slice electrophysiology; DARPP-32 knockout mice; pharmacological D1 receptor activation Nature neuroscience High 12068305
2005 Glutamate regulates DARPP-32 phosphorylation at Thr34 and Thr75 through at least five distinct signaling cascades with different time dependencies: (1) NMDA/AMPA/mGluR5→nNOS/NO/cGMP/PKG→Thr34 increase; (2) NMDA/AMPA→Ca2+/PP2B→Thr34 decrease; (3) mGluR5/PLC/ERK→Thr34 rephosphorylation; (4) NMDA/AMPA→Ca2+/PP2A→Thr75 decrease; (5) mGluR1/PLC→Thr75 increase. Mouse neostriatal slice phosphorylation assay; selective receptor antagonists; phospho-specific immunoblots; NOS/NO pathway inhibitors Proceedings of the National Academy of Sciences of the United States of America High 15657149
2007 The PR72/B'' regulatory subunit of PP2A mediates Ca2+-dependent dephosphorylation of DARPP-32 at Thr75; PR72 contains two EF-hand Ca2+-binding sites and EF-hand 1 is necessary for Ca2+-dependent regulation of PP2A activity both in vitro and in vivo; this PP2A/PR72 complex is required for glutamate (AMPA/NMDA receptor)-induced Thr75 dephosphorylation. Overexpression and RNAi knockdown of PR72; in vitro PP2A assay; mutagenesis of EF-hand Ca2+-binding sites; striatal slice phosphorylation assay; glutamate receptor pharmacology Proceedings of the National Academy of Sciences of the United States of America High 17535922
2006 Phosphorylation of DARPP-32 at Thr34 is required for cocaine-induced conditioned place preference, acute locomotor response, and immediate early gene induction (c-fos, arc) in striatum; Thr75 phosphorylation is required for locomotor sensitization to repeated cocaine but not for acute locomotor response or conditioned place preference. Knock-in mice with T34A or T75A point mutations in DARPP-32; behavioral assays (CPP, locomotor activity, sensitization); striatal gene expression analysis Neuropsychopharmacology High 16123776
2007 Sensitized cAMP/PKA/DARPP-32 signaling in L-DOPA-induced dyskinesia leads to sequential phosphorylation of ERK1/2, MSK-1, and histone H3 in striatal medium spiny neurons; genetic inactivation of DARPP-32 reduces dyskinesia, and pharmacological inhibition of MEK counteracts LID induction. DARPP-32 knockout mice; L-DOPA-treated mouse model of dyskinesia; phospho-specific immunoblots; MEK inhibitor (SL327) treatment; c-Fos expression analysis The Journal of neuroscience High 17596448
2008 Cocaine (psychostimulant) and haloperidol (antipsychotic) exert opposing, cell-type-specific effects on DARPP-32 Thr34 phosphorylation: cocaine preferentially increases phospho-Thr34 in striatonigral (D1) neurons, while haloperidol preferentially increases it in striatopallidal (D2) neurons. BAC transgenic mice enabling cell-type-selective DARPP-32 phosphorylation analysis; phospho-specific immunoblots from FACS-sorted neuronal populations Nature neuroscience High 18622401
2009 Wnt-5a triggers cAMP elevation and Thr34-DARPP-32 phosphorylation in breast cancer cells via Frizzled-3/Gαs/PKA signaling; phospho-Thr34-DARPP-32 interacts with PP1, potentiates CREB phosphorylation, reduces Cdc42 activity and filopodia formation, and thereby inhibits MCF-7 breast cancer cell migration. Recombinant Wnt-5a treatment; siRNA knockdown of Frizzled-3, Gαs, DARPP-32; PKA inhibitors; dominant-negative CREB expression; cAMP imaging; Cdc42 activity assay; phalloidin staining; migration assay The Journal of biological chemistry High 19651774
2006 DARPP-32 expression in non-transformed mammary cells inhibits cell migration downstream of the collagen receptor DDR1; phosphorylation of Thr34 (but not Thr75) is necessary for this antimigratory effect; co-expression of DDR1 and DARPP-32 is required for migration inhibition. Transfection of MCF7 and MDA-MB-231 cells with DARPP-32 mutants; cell migration assay; immunoblot analysis Experimental cell research Medium 17027969
2014 Bcl-2 binds DARPP-32 and docks it with calcineurin (CaN) in a complex on the InsP3R, creating a negative feedback loop: PKA phosphorylates InsP3R and DARPP-32; phospho-DARPP-32 inhibits PP1, enhancing InsP3R phosphorylation and Ca2+ release; elevated Ca2+ activates CaN, which dephosphorylates DARPP-32 to dampen further Ca2+ release. Knockdown of Bcl-2 or DARPP-32 disrupts this feedback and increases apoptosis. Co-immunoprecipitation; RNAi knockdown of Bcl-2 and DARPP-32; Ca2+ measurement; apoptosis assay; T-cell activation experiments Proceedings of the National Academy of Sciences of the United States of America Medium 24395794
2015 DARPP-32 interacts physically with adducins (cytoskeletal actin-capping proteins) via the adducin MARCKS domain; this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75-DARPP-32 facilitates β-adducin Ser713 phosphorylation through inhibition of a PKA/PP2A cascade. This pathway is implicated in environmental enrichment-induced changes in nucleus accumbens dendritic spines and cocaine locomotor responses. Co-immunoprecipitation; DARPP-32 T75A knock-in mice; phospho-specific immunoblots; dendritic spine analysis; cocaine locomotor assay Nature communications Medium 26639316
2011 DARPP-32 colocalizes with EGFR on the cell membrane in a complex with EGFR and ERBB3; overexpression of DARPP-32 stabilizes EGFR, increases EGFR-ERBB3 interaction and phosphorylation, activates AKT (Ser473), and confers resistance to gefitinib in gastric cancer cells. Co-immunoprecipitation; immunofluorescence colocalization; clonogenic survival assay; Annexin-V apoptosis assay; shRNA knockdown; mouse xenograft model Gastroenterology Medium 21741919
2013 DARPP-32 physically interacts with IGF1R and promotes its phosphorylation (Y1135), leading to activation of downstream SRC and STAT3 (Y705 phosphorylation, nuclear localization, transcription activation); in DARPP-32 knockout/TFF1 knockout double-mutant mice, IGF1R and STAT3 phosphorylation is absent, and gastric neoplasia development is delayed. Proximity ligation assay; co-immunoprecipitation; 3D gastric organoids; double-knockout mouse model (TFF1 KO × DARPP-32 KO); immunohistochemistry of human gastric cancer tissue arrays Oncogene Medium 31235784
2015 DARPP-32 regulates ANGPT2-mediated tumor angiogenesis through a STAT3-dependent (not NF-κB-dependent) mechanism; this effect is independent of Thr34-mediated PP1 inhibition, as T34A mutant and truncated t-DARPP produce similar ANGPT2 induction; DARPP-32 activates STAT3 phosphorylation and nuclear localization. DARPP-32 overexpression/knockdown; quantitative RT-PCR; immunoblot; luciferase reporter; HUVEC tube formation assay; STAT3 inhibitor/siRNA; in vivo xenograft tumor model; immunohistochemistry of human gastric cancer tissues Gut Medium 25779598
2015 DARPP-32 forms a protein complex with SRp20 splicing factor (co-immunoprecipitation), regulates SRp20 protein stability (via alternative splicing inhibitor digitoxin experiments), and thereby controls CD44E (CD44 V8-V10) splice variant expression to promote gastric cancer cell proliferation in vitro and tumor growth in vivo. siRNA/shRNA knockdown; splicing luciferase reporter; co-immunoprecipitation; immunoprecipitation with digitoxin; tumor xenograft model; SRp20 reconstitution rescue experiment; human gastric cancer tissue analysis Oncogene Medium 26119931
2012 DARPP-32 forms a protein complex with CXCR4 (co-immunoprecipitation and immunofluorescence); DARPP-32 prolongs CXCR4 protein half-life, reduces CXCL12-induced CXCR4 ubiquitination, and promotes gastric cancer cell invasion through CXCR4-dependent activation of the MT1-MMP/MMP-2 pathway. Reciprocal co-immunoprecipitation; immunofluorescence; CXCR4 antagonist (AMD3100) and siRNA; MMP-2 activity assay; Matrigel invasion assay; impedance-based invasion assay; DARPP-32 overexpression/knockdown Molecular cancer research Medium 23160836
2018 DARPP-32 physically interacts with IKKα (inhibitory kappa B kinase-α), and this interaction promotes NSCLC cell migration through non-canonical NF-κB2 signaling; abrogation of DARPP-32 expression reduces tumor growth in orthotopic mouse models. Co-immunoprecipitation; shRNA knockdown; orthotopic mouse tumor model; NF-κB2 signaling analysis; patient tissue immunohistochemistry Communications biology Medium 29782621
2016 H. pylori infection induces DARPP-32 expression through NF-κB transcriptional activation: ChIP and deletion-based luciferase reporter identified the DARPP-32 promoter region −996 to −1008 bp (containing NF-κB-binding sites) as the key regulatory element; DARPP-32 induction counteracts H. pylori-induced cell death through AKT activation. Luciferase reporter assays with DARPP-32 promoter deletions; ChIP assay; H. pylori infection of gastric cancer cells and mice; ATP-Glo and clonogenic survival assays; immunohistochemistry of gastric cancer tissues Gut Medium 27590997
2020 Loss of HIF1A in pancreatic cancer cells increases PPP1R1B expression; elevated PPP1R1B promotes p53 degradation by stabilizing phosphorylation of MDM2 at Ser166; knockdown of PPP1R1B reduces the ability of pancreatic cancer cells to form lung metastases in mice. KPC mouse models with pancreas-specific HIF1A deletion; shRNA knockdown of PPP1R1B; immunoblot; in vivo lung metastasis assay; liquid chromatography-mass spectrometry Gastroenterology Medium 32768595
2005 DARPP-32 and its truncated isoform t-DARPP exert antiapoptotic effects in gastrointestinal cancer cells through a p53-independent mechanism involving preservation of mitochondrial transmembrane potential and increased Bcl-2 levels; antiapoptotic activity required intact phosphorylation sites. Overexpression of DARPP-32 and t-DARPP with phosphorylation site mutations; TUNEL and Annexin-V apoptosis assays; mitochondrial membrane potential assay; siRNA knockdown; luciferase reporters for p53/p21 Cancer research Medium 16061638
2002 The truncated isoform t-DARPP lacks the Thr34 phosphorylation site (PP-1 inhibitory site) but retains the Thr75 site (PKA inhibitory site); both full-length DARPP-32 and t-DARPP are overexpressed in gastric cancers. cDNA cloning; RT-PCR; Western blotting; tumor tissue array analysis Cancer research Medium 12124342
2009 t-DARPP overexpression in breast cancer cells is sufficient to confer trastuzumab resistance and sustain Akt phosphorylation; the Thr75 residue in t-DARPP is required for both Akt activation and trastuzumab resistance; full-length DARPP-32 co-expression reverses these effects. t-DARPP also increases CREB binding activity. Gene silencing (RNAi); transfection of t-DARPP and DARPP-32 cDNAs; T75 mutagenesis; trastuzumab resistance assay; Akt phosphorylation immunoblot; CREB DNA binding assay Breast cancer research and treatment / PloS one Medium 19301121 19593441
1990 Casein kinase II activity identified in caudate-putamen cytosol phosphorylates DARPP-32 on the same seryl residue as purified CK2; CK2-like immunoreactivity colocalizes with DARPP-32 in medium-sized striatonigral neurons; ~45% of total CK2 activity is cytosolic in rat caudate-putamen. Biochemical kinase characterization; excitotoxic lesions (kainic acid); immunocytochemistry; subcellular fractionation Journal of neurochemistry Medium 2145398
1994 GABA increases Thr34-phosphorylation of DARPP-32 in striatal and substantia nigra slices through GABA-A receptors (blocked by bicuculline); the mechanism is consistent with GABA reducing calcineurin-mediated dephosphorylation rather than directly activating PKA (cAMP was not elevated). Striatal and substantia nigra slice [32P] phosphorylation assay; GABA-A/B receptor antagonists; pharmacological synergy with forskolin/L-DOPA Journal of neurochemistry Medium 7931332
1999 Mu-opioid receptors (via DAMGO) specifically inhibit D1-stimulated DARPP-32 phosphorylation in striatonigral neurons, while delta-opioid receptors (via DPDPE) specifically inhibit A2A-stimulated DARPP-32 phosphorylation in striatopallidal neurons; kappa-opioid receptors had no effect. Rat striatal slice phosphorylation assay with selective opioid receptor agonists; D1 and A2A receptor pharmacology The European journal of neuroscience Medium 10336688
2009 DARPP-32 co-immunoprecipitates with all five dopamine receptor subtypes (D1–D5) from rat brain cortex and striatum, suggesting direct or indirect physical association in neurons. Co-immunoprecipitation from brain tissue lysates; western blot; immunohistochemistry Neuroscience research Low 19465068
1992 In choroid plexus epithelial cells, DARPP-32 is phosphorylated in response to factors that increase cAMP (forskolin, isoproterenol, VIP) or cGMP (ANP) or activate other pathways (5-HT), but not by dopamine, indicating context-specific regulation of DARPP-32 by non-dopaminergic signals. Phosphorylation state-specific monoclonal antibody; intact choroid plexus cell phosphorylation assay; cAMP/cGMP measurements The Journal of neuroscience Medium 1494946

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 DARPP-32: an integrator of neurotransmission. Annual review of pharmacology and toxicology 564 14744247
1984 DARPP-32, a dopamine-regulated neuronal phosphoprotein, is a potent inhibitor of protein phosphatase-1. Nature 543 6087160
1984 DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. The Journal of neuroscience : the official journal of the Society for Neuroscience 538 6319625
1999 Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 474 10604473
1998 DARPP-32: regulator of the efficacy of dopaminergic neurotransmission. Science (New York, N.Y.) 384 9694658
2007 Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. The Journal of neuroscience : the official journal of the Society for Neuroscience 351 17596448
1997 Bidirectional regulation of DARPP-32 phosphorylation by dopamine. The Journal of neuroscience : the official journal of the Society for Neuroscience 320 9334390
1984 DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular distribution in the rat brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 277 6319627
1986 DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein: regional, tissue, and phylogenetic distribution. The Journal of neuroscience : the official journal of the Society for Neuroscience 216 3711991
2008 Cell type-specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs. Nature neuroscience 195 18622401
2002 Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac). Proceedings of the National Academy of Sciences of the United States of America 187 11880651
1984 DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. II. Purification and characterization of the phosphoprotein from bovine caudate nucleus. The Journal of neuroscience : the official journal of the Society for Neuroscience 175 6319628
2007 Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. The Journal of clinical investigation 164 17290303
1989 Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II. The Journal of biological chemistry 144 2557337
2002 Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia. Archives of general psychiatry 139 12150646
2002 Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. Nature 134 12181566
2006 DARPP-32 is a robust integrator of dopamine and glutamate signals. PLoS computational biology 130 17194217
2005 DARPP-32 mediates the actions of multiple drugs of abuse. The AAPS journal 128 16353915
1992 Phosphorylation of DARPP-32 and protein phosphatase inhibitor-1 in rat choroid plexus: regulation by factors other than dopamine. The Journal of neuroscience : the official journal of the Society for Neuroscience 128 1494946
1984 DARPP-32, a dopamine- and adenosine 3':5'-monophosphate-regulated neuronal phosphoprotein. II. Comparison of the kinetics of phosphorylation of DARPP-32 and phosphatase inhibitor 1. The Journal of biological chemistry 128 6501303
1999 Characterization of the inhibition of protein phosphatase-1 by DARPP-32 and inhibitor-2. The Journal of biological chemistry 127 10075680
1999 Expression of the striatal DARPP-32/ARPP-21 phenotype in GABAergic neurons requires neurotrophins in vivo and in vitro. The Journal of neuroscience : the official journal of the Society for Neuroscience 126 10377350
2000 D(1) dopamine receptor activation reduces GABA(A) receptor currents in neostriatal neurons through a PKA/DARPP-32/PP1 signaling cascade. Journal of neurophysiology 123 10805695
2002 DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens. Nature neuroscience 120 12068305
2020 Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis. Gastroenterology 119 32768595
1989 Dopamine- and cAMP-regulated phosphoprotein (DARPP-32) and dopamine DA1 agonist-sensitive Na+,K+-ATPase in renal tubule cells. Proceedings of the National Academy of Sciences of the United States of America 110 2573060
1990 Distribution of DARPP-32 in the basal ganglia: an electron microscopic study. Journal of neurocytology 107 2191086
1999 Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons. Journal of neurochemistry 106 10217279
1997 Characterization of the interaction between DARPP-32 and protein phosphatase 1 (PP-1): DARPP-32 peptides antagonize the interaction of PP-1 with binding proteins. Proceedings of the National Academy of Sciences of the United States of America 103 9108011
2000 Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. Science (New York, N.Y.) 102 10669419
2000 N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice. Neuroreport 102 11117485
2005 Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades. Proceedings of the National Academy of Sciences of the United States of America 99 15657149
1986 DARPP-32, a dopamine- and cyclic AMP-regulated neuronal phosphoprotein. Primary structure and homology with protein phosphatase inhibitor-1. The Journal of biological chemistry 99 3511054
2004 The role of DARPP-32 in the actions of drugs of abuse. Neuropharmacology 98 15464122
2002 Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP. Cancer research 95 12124342
2002 DARPP-32 mediates serotonergic neurotransmission in the forebrain. Proceedings of the National Academy of Sciences of the United States of America 93 11880652
2007 The B''/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A. Proceedings of the National Academy of Sciences of the United States of America 84 17535922
2006 Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 83 16123776
2004 Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon. International journal of oncology 83 15010812
1992 Immunocytochemical localization of DARPP-32, a dopamine and cyclic-AMP-regulated phosphoprotein, in the primate brain. The Journal of comparative neurology 75 1328330
1990 Characterization in mammalian brain of a DARPP-32 serine kinase identical to casein kinase II. Journal of neurochemistry 72 2145398
2008 Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior. Journal of neurochemistry 71 18554320
2003 MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. International journal of oncology 71 12739007
2019 LncRNA KCNQ1OT1 enhanced the methotrexate resistance of colorectal cancer cells by regulating miR-760/PPP1R1B via the cAMP signalling pathway. Journal of cellular and molecular medicine 63 30997746
2009 Wnt-5a-induced phosphorylation of DARPP-32 inhibits breast cancer cell migration in a CREB-dependent manner. The Journal of biological chemistry 63 19651774
1999 Neuronal and behavioural abnormalities in striatal function in DARPP-32-mutant mice. The European journal of neuroscience 62 10103106
2013 Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression. Molecular psychiatry 60 23295814
2009 The biological basis of anger: associations with the gene coding for DARPP-32 (PPP1R1B) and with amygdala volume. Behavioural brain research 57 19463699
2005 Darpp-32: a novel antiapoptotic gene in upper gastrointestinal carcinomas. Cancer research 57 16061638
2011 Purmorphamine increases DARPP-32 differentiation in human striatal neural stem cells through the Hedgehog pathway. Stem cells and development 56 21345011
2011 Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology 54 21833500
1994 Expression of mRNAs encoding ARPP-16/19, ARPP-21, and DARPP-32 in human brain tissue. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 8120638
1990 Distribution and cellular localization of DARPP-32 mRNA in rat brain. Brain research. Molecular brain research 52 2160041
2006 Psychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons. Neuroscience and biobehavioral reviews 51 16730373
2000 DARPP-32 knockout mice exhibit impaired reversal learning in a discriminated operant task. Brain research 51 10837805
2012 DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families. Behavioral and brain functions : BBF 50 22559203
2017 Toll-like receptor-4 regulates anxiety-like behavior and DARPP-32 phosphorylation. Brain, behavior, and immunity 48 29221855
2016 Helicobacter pylori-induced cell death is counteracted by NF-κB-mediated transcription of DARPP-32. Gut 48 27590997
2009 Both t-Darpp and DARPP-32 can cause resistance to trastuzumab in breast cancer cells and are frequently expressed in primary breast cancers. Breast cancer research and treatment 47 19301121
2006 Phosphorylation of DARPP-32 regulates breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. Experimental cell research 47 17027969
1990 Rat DARPP-32: cloning, sequencing, and characterization of the cDNA. Journal of molecular neuroscience : MN 47 1979497
1988 DARPP-32 and phosphatase inhibitor-1, two structurally related inhibitors of protein phosphatase-1, are both present in striatonigral neurons. Journal of neurochemistry 47 3335843
2009 Darpp-32 and its truncated variant t-Darpp have antagonistic effects on breast cancer cell growth and herceptin resistance. PloS one 44 19593441
2015 Gastric tumour-derived ANGPT2 regulation by DARPP-32 promotes angiogenesis. Gut 43 25779598
2014 Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival. Proceedings of the National Academy of Sciences of the United States of America 43 24395794
2004 DARPP-32 and modulation of cAMP signaling: involvement in motor control and levodopa-induced dyskinesia. Parkinsonism & related disorders 43 15196506
1988 Cloning of cDNA for DARPP-32, a dopamine- and cyclic AMP-regulated neuronal phosphoprotein. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 3339428
2008 The leukocytes expressing DARPP-32 are reduced in patients with schizophrenia and bipolar disorder. Progress in neuro-psychopharmacology & biological psychiatry 41 19059449
2013 PPP1R1B-STARD3 chimeric fusion transcript in human gastric cancer promotes tumorigenesis through activation of PI3K/AKT signaling. Oncogene 39 24276243
2007 Activation of the cAMP/PKA/DARPP-32 signaling pathway is required for morphine psychomotor stimulation but not for morphine reward. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 39 17251906
2011 DARPP-32 increases interactions between epidermal growth factor receptor and ERBB3 to promote tumor resistance to gefitinib. Gastroenterology 38 21741919
1999 Mu- and delta-opioid receptor agonists inhibit DARPP-32 phosphorylation in distinct populations of striatal projection neurons. The European journal of neuroscience 38 10336688
2020 Ppp1r1b-lncRNA inhibits PRC2 at myogenic regulatory genes to promote cardiac and skeletal muscle development in mouse and human. RNA (New York, N.Y.) 37 31953255
2017 Potential for targeting dopamine/DARPP-32 signaling in neuropsychiatric and neurodegenerative disorders. Expert opinion on therapeutic targets 35 28052701
2000 Dopamine D(1) receptor-induced gene transcription is modulated by DARPP-32. Journal of neurochemistry 35 10854268
2018 DARPP-32 in the orchestration of responses to positive natural stimuli. Journal of neurochemistry 34 30043390
2015 DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons. Nature communications 34 26639316
2005 Nicotine regulates DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) phosphorylation at multiple sites in neostriatal neurons. The Journal of pharmacology and experimental therapeutics 33 16040813
2012 DARPP-32 to quantify intracerebral hemorrhage-induced neuronal death in basal ganglia. Translational stroke research 31 23543809
2016 DARPP-32: from neurotransmission to cancer. Oncotarget 30 26872373
2007 Regulation of DARPP-32 phosphorylation by Delta9-tetrahydrocannabinol. Neuropharmacology 30 17686497
2000 DARPP-32 and CREB are present in type 2 iodothyronine deiodinase-producing tanycytes: implications for the regulation of type 2 deiodinase activity. Brain research 30 10799680
2019 Activation of IGF1R by DARPP-32 promotes STAT3 signaling in gastric cancer cells. Oncogene 29 31235784
2006 DRD2/DARPP-32 expression correlates with lymph node metastasis and tumor progression in patients with esophageal squamous cell carcinoma. World journal of surgery 29 16850143
1994 Phosphorylation of DARPP-32 is regulated by GABA in rat striatum and substantia nigra. Journal of neurochemistry 28 7931332
2009 Colocalization of dopamine receptor subtypes with dopamine and cAMP-regulated phosphoprotein (DARPP-32) in rat brain. Neuroscience research 27 19465068
2018 DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration. Communications biology 26 29782621
2012 Regulation of CXCR4-mediated invasion by DARPP-32 in gastric cancer cells. Molecular cancer research : MCR 26 23160836
2005 DARPP-32 genomic fragments drive Cre expression in postnatal striatum. Genesis (New York, N.Y. : 2000) 26 15830379
2004 DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma. British journal of cancer 26 15188007
2020 DARPP-32 40 years later. Advances in pharmacology (San Diego, Calif.) 25 33706939
2017 The involvement of DARPP-32 in the pathophysiology of schizophrenia. Oncotarget 25 28881851
2007 DARPP-32 and NCS-1 expression is not altered in brains of rats treated with typical or atypical antipsychotics. Neurochemical research 25 17763944
1993 Comparison of the immunocytochemical localization of DARPP-32 and I-1 in the amygdala and hippocampus of the rhesus monkey. The Journal of comparative neurology 25 8408754
2019 The expression of tyrosine hydroxylase and DARPP-32 in the house crow (Corvus splendens) brain. The Journal of comparative neurology 24 30697741
2015 Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastric tumorigenesis. Oncogene 24 26119931
2005 Overexpression of DARPP-32 in colorectal adenocarcinoma. International journal of clinical practice 24 15707466
1999 Requirement for DARPP-32 in mediating effect of dopamine D2 receptor activation. The European journal of neuroscience 24 10383649
2018 Darpp-32 and t-Darpp protein products of PPP1R1B: Old dogs with new tricks. Biochemical pharmacology 23 30552871
2011 Altered DARPP-32 expression in the superior temporal gyrus in schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry 23 21453742

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