Affinage

PPP1R1B

Protein phosphatase 1 regulatory subunit 1B · UniProt Q9UD71

Length
204 aa
Mass
23.0 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP1R1B (DARPP-32) is a bifunctional signal integration hub in dopaminoceptive neurons and other cell types that controls the opposing activities of protein phosphatase-1 (PP1) and cAMP-dependent protein kinase (PKA). When phosphorylated at Thr34 by PKA—downstream of D1 dopamine, adenosine A2A, and other cAMP-elevating receptors—DARPP-32 potently inhibits PP1, thereby amplifying PKA-dependent phosphorylation of ion channels (Na⁺, Ca²⁺, NMDA receptors), CREB, and other substrates; conversely, Cdk5 phosphorylation at Thr75 converts DARPP-32 into a competitive inhibitor of PKA, and additional phosphorylation at Ser97 (CK2) governs its nuclear–cytoplasmic shuttling, with dephosphorylation by calcineurin (Thr34) and PP2A/PR72 (Thr75, Ser97) integrating glutamatergic and calcium signals to reset the system (PMID:6087160, PMID:10604473, PMID:27998980, PMID:17535922). Through this multi-site phosphorylation code, DARPP-32 integrates dopamine, glutamate, GABA, adenosine, and serotonin inputs to regulate striatal output, locomotor behavior, reward processing, and neuroendocrine responses including progesterone-facilitated sexual receptivity (PMID:2153935, PMID:16123776, PMID:10669419). Outside the nervous system, DARPP-32 and its N-terminally truncated isoform t-DARPP are overexpressed in gastric, breast, pancreatic, and lung cancers, where they promote survival signaling by interacting with IGF1R to activate STAT3, stabilizing CXCR4 to drive invasion, engaging IKKα for non-canonical NF-κB signaling, and stabilizing MDM2 phosphorylation to degrade p53 (PMID:31235784, PMID:23160836, PMID:29782621, PMID:32768595).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1984 High

    Establishing the core biochemical identity of DARPP-32: PKA phosphorylation at Thr34 converts it into a nanomolar-potency PP1 inhibitor, and its expression maps to dopaminoceptive (D1 receptor-bearing) medium spiny neurons, defining it as a neuron-type-specific signal transduction molecule.

    Evidence In vitro phosphatase assay with purified protein; amino acid sequencing of phosphopeptides; immunocytochemistry across rat and primate brain

    PMID:6087160 PMID:6319625 PMID:6501302

    Open questions at the time
    • No in vivo loss-of-function evidence yet
    • Upstream signaling pathways not yet mapped in intact cells
    • No information on additional phosphorylation sites
  2. 1990 High

    Demonstrating that DARPP-32 is a convergence point for opposing dopamine and glutamate signals: NMDA receptor activation recruits calcineurin to dephosphorylate Thr34, reversing dopamine/cAMP-driven PP1 inhibition.

    Evidence Striatal slice phosphorylation assay with pharmacological receptor activation; electron microscopic immunocytochemistry showing subcellular localization in dendrites, spines, and axon terminals

    PMID:2153935 PMID:2191086

    Open questions at the time
    • Identity of the phosphatase for other DARPP-32 sites unknown
    • No genetic loss-of-function model yet available
  3. 1997 High

    Resolving the downstream electrophysiological consequence: DARPP-32 is required for PKA/D1-mediated potentiation of NMDA receptor currents, with D1 and D2 receptors having opposing effects on Thr34 phosphorylation, and DARPP-32 also functions outside the brain as a glycogen-targeted PP1 regulator in adipocytes.

    Evidence Reconstitution in Xenopus oocytes with antisense knockdown and mRNA injection; mouse striatal slices with selective D1/D2 agonists and calcineurin inhibitors; subcellular fractionation and PP1 activity assay in 3T3-L1 adipocytes

    PMID:9334390 PMID:9368038 PMID:9405704

    Open questions at the time
    • No knock-in point mutations to dissect site-specific contributions in vivo
    • Mechanism of DARPP-32 action on NMDA receptor subunit phosphorylation not resolved
  4. 1998 High

    Extending the input repertoire: adenosine A2A receptors phosphorylate DARPP-32 at Thr34 via cAMP/PKA in striatopallidal neurons, paralleling D1 action in striatonigral neurons; phospho-Thr34-DARPP-32 suppresses voltage-gated Na⁺ currents by maintaining Na⁺ channel phosphorylation.

    Evidence Striatal slice phosphorylation with selective A2A/D1 agonists and PKA inhibitor; whole-cell patch-clamp with intracellular injection of phospho- vs dephospho-DARPP-32

    PMID:9522376 PMID:9749785

    Open questions at the time
    • Identity of the specific Na⁺ channel subunit(s) targeted not determined
    • Relative contribution of A2A vs D1 pathway in vivo not quantified
  5. 1999 High

    Discovering the second functional arm of DARPP-32: Cdk5 phosphorylation at Thr75 converts DARPP-32 from a PP1 inhibitor into a PKA inhibitor, creating a bidirectional switch; genetic knockout confirms DARPP-32 is obligatory for both D1 and D2 regulation of Na⁺/K⁺-ATPase.

    Evidence In vitro kinase assay, striatal slice phosphorylation, Cdk5 knockout mice, and electrophysiology for Thr75; Na⁺/K⁺-ATPase activity assay in DARPP-32 knockout neostriatal cells

    PMID:10383649 PMID:10604473

    Open questions at the time
    • Phosphatase responsible for Thr75 dephosphorylation not yet identified
    • Structural basis for competitive PKA inhibition unknown
  6. 2000 High

    Demonstrating a non-striatal behavioral role: DARPP-32 is an obligate intermediate in progesterone-facilitated sexual receptivity, with progesterone increasing hypothalamic Thr34 phosphorylation via cAMP/PKA.

    Evidence Antisense knockdown in rat hypothalamus and DARPP-32 null mice with behavioral and biochemical readouts

    PMID:10669419

    Open questions at the time
    • Downstream PP1 substrates mediating behavioral receptivity not identified
    • Whether Thr75 also contributes to this behavior not tested
  7. 2002 High

    Identifying the truncated oncogenic isoform t-DARPP in gastric cancer (lacking Thr34 but retaining Thr75), and confirming DARPP-32 requirement for D1-mediated NMDA current potentiation and caffeine's locomotor stimulant effect via Thr75/PP2A regulation.

    Evidence RT-PCR and immunostaining of gastric tumors; DARPP-32 knockout mice with whole-cell patch-clamp for NMDA currents; knockout mice with locomotor testing and PP2A activity dissection

    PMID:12124342 PMID:12181566 PMID:12466426

    Open questions at the time
    • Mechanism by which t-DARPP contributes to tumorigenesis not yet dissected
    • Whether t-DARPP acts solely through PKA inhibition in cancer unclear
  8. 2005 High

    Mapping the full complexity of glutamatergic regulation: at least five distinct receptor cascades (NMDA/AMPA/mGluR1/mGluR5) converge on DARPP-32 Thr34 and Thr75 through NOS/cGMP, calcineurin, ERK, and PP2A; separately, DARPP-32 mediates cocaine's effects on Na⁺ channels in nucleus accumbens, and its cancer role is extended to anti-apoptotic function.

    Evidence Systematic pharmacological dissection in neostriatal slices; voltage-clamp with direct p-Thr34-DARPP-32 application after chronic cocaine; TUNEL/Annexin V apoptosis assays with siRNA and phosphorylation-site mutagenesis in cancer cells

    PMID:15657149 PMID:15726118 PMID:16061638

    Open questions at the time
    • Whether all five glutamate cascades operate simultaneously in single neurons not resolved
    • Structural basis for DARPP-32's anti-apoptotic function independent of PP1 inhibition unclear
  9. 2006 High

    Site-specific knock-in mutations dissect behavioral outputs: Thr34 phosphorylation is specifically required for cocaine-induced reward (conditioned place preference) and immediate early gene induction, while Thr75 phosphorylation selectively mediates locomotor sensitization.

    Evidence T34A and T75A knock-in mice with behavioral testing and striatal immunoblotting

    PMID:16123776

    Open questions at the time
    • Whether Thr34 and Thr75 contribute independently or interact cooperatively in vivo not fully dissected
    • Circuit-level mechanisms of behavioral dissociation not resolved
  10. 2007 High

    Identifying the PP2A regulatory subunit PR72 as the Ca²⁺-sensing dephosphorylase for Thr75, completing the phosphatase side of the Cdk5/Thr75 switch; separately, BDNF-driven DARPP-32 expression requires convergent PI3K/AKT/mTOR and CDK5/p35 pathways.

    Evidence In vitro phosphatase reconstitution with PR72 EF-hand mutants, RNAi in striatal neurons, and slice phosphorylation; pharmacological and viral construct approaches for BDNF regulation

    PMID:17209049 PMID:17535922

    Open questions at the time
    • Whether PR72 also mediates Ser97 dephosphorylation not yet tested at this point
    • Structural basis for PR72/DARPP-32 interaction not resolved
  11. 2009 Medium

    Demonstrating cancer-relevant signaling: t-DARPP confers trastuzumab resistance in HER2+ breast cancer by sustaining Akt phosphorylation; in a separate context, Wnt-5a/Frizzled-3 activates DARPP-32 Thr34 phosphorylation to inhibit breast cancer cell migration via Cdc42 suppression.

    Evidence cDNA transfection with clonogenic survival and Akt immunoblot for trastuzumab resistance; siRNA knockdown of Frizzled-3/Gαs/DARPP-32 with cAMP FRET imaging and migration assay

    PMID:19593441 PMID:19651774

    Open questions at the time
    • Direct physical interaction between t-DARPP and Akt not demonstrated
    • Wnt-5a/DARPP-32 anti-migratory pathway not validated in vivo
  12. 2012 Medium

    Establishing DARPP-32 as a CXCR4 stabilizer: DARPP-32 co-immunoprecipitates with CXCR4, reduces its ubiquitination, prolongs its half-life, and promotes gastric cancer invasion via CXCR4→MT1-MMP→MMP-2.

    Evidence Reciprocal Co-IP, pulse-chase stability assay, ubiquitination assay, Matrigel invasion with siRNA and AMD3100

    PMID:23160836

    Open questions at the time
    • Direct binding domain mapping not performed
    • Whether DARPP-32 phosphorylation state affects CXCR4 interaction not tested
  13. 2015 Medium

    Expanding the cancer signaling repertoire: DARPP-32 activates STAT3 to induce ANGPT2 and tumor angiogenesis (independent of Thr34/PP1 function), promotes TRAIL resistance via Src/STAT3→BCL-xL and NF-κB→FLIP(S), regulates SRp20-dependent CD44 splicing, and PDE10A inhibitor studies confirm Thr34 dependency for D2-MSN selective signaling in vivo; calpain cleavage of DARPP-32 at Thr153 in Alzheimer's disease reduces its PP1 inhibitory and CREB-activating functions.

    Evidence STAT3 inhibitor/knockdown with HUVEC tube formation and xenograft; Annexin V and caspase assays with Src inhibitor; Co-IP with splicing reporters; T34A knock-in mice with FRET biosensors; in vitro calpain cleavage and AD brain immunoblot

    PMID:22589394 PMID:25779598 PMID:26119931 PMID:26178297 PMID:26465004

    Open questions at the time
    • How DARPP-32 activates STAT3 without PP1 inhibition mechanistically unresolved
    • Whether calpain cleavage is causative or consequential in AD pathology unclear
    • SRp20 interaction domain not mapped
  14. 2016 High

    Completing the nuclear translocation model: PP2A/PR72 dephosphorylates Ser97 in a Ca²⁺-dependent manner, driving DARPP-32 nuclear accumulation in its dephospho-Thr34/dephospho-Ser97 form; H. pylori infection induces DARPP-32 transcription via NF-κB to promote gastric cell survival through AKT.

    Evidence In vitro PP2A/PR72 phosphatase assay, striatal neuron nuclear imaging, in vivo phosphorylation; ChIP and promoter deletion mapping with NF-κB site identification

    PMID:27590997 PMID:27998980

    Open questions at the time
    • Nuclear substrates of the dephospho-DARPP-32/PP1 complex not identified
    • Whether PR72-dependent Ser97 dephosphorylation occurs in cancer cells not tested
  15. 2018 Medium

    DARPP-32 physically interacts with IKKα to activate non-canonical NF-κB2 signaling and promote lung cancer cell migration and tumor growth.

    Evidence Co-IP, orthotopic mouse model, migration assay, NF-κB2 pathway immunoblot

    PMID:29782621

    Open questions at the time
    • DARPP-32 domain required for IKKα interaction not mapped
    • Whether this pathway operates in neurons or is cancer-specific not addressed
  16. 2019 High

    Establishing DARPP-32 as a direct IGF1R activator: proximity ligation and reciprocal Co-IP confirm physical association; DARPP-32 promotes IGF1R Y1135 phosphorylation and downstream SRC/STAT3 activation; double-knockout mice confirm in vivo requirement for gastric neoplasia. Separately, Cdk5/Thr75 phosphorylation mediates depressive-like behavior in Huntington's disease via β-adducin and dendritic spine remodeling.

    Evidence Proximity ligation assay, reciprocal Co-IP, TFF1/DARPP-32 double-KO mice, 3D gastric organoids; Hdh+/Q111 × DARPP-32 T75A double knock-in mice with behavioral and spine morphology analysis

    PMID:31060804 PMID:31235784

    Open questions at the time
    • Binding interface between DARPP-32 and IGF1R not structurally resolved
    • Whether Thr34 or Thr75 phosphorylation modulates IGF1R interaction not tested
    • Whether β-adducin is a direct or indirect substrate of the Cdk5/DARPP-32 axis unclear
  17. 2020 Medium

    DARPP-32 stabilizes MDM2 phosphorylation at Ser166 to promote p53 degradation, linking HIF1A loss to DARPP-32 upregulation, p53 suppression, and pancreatic cancer metastasis; a non-coding RNA (Ppp1r1b-lncRNA) from the same locus regulates myogenic differentiation by sequestering EZH2 from MyoD1/Myogenin promoters.

    Evidence shRNA knockdown with MDM2/p53 immunoblot and in vivo metastasis model; GapmeR silencing with ChIRP, H3K27me3 ChIP, and hiPS-derived cardiomyocyte differentiation

    PMID:31953255 PMID:32768595

    Open questions at the time
    • Whether DARPP-32 directly binds MDM2 or acts through an intermediary kinase not resolved
    • Relationship between protein-coding and lncRNA products of the PPP1R1B locus not characterized
    • In vivo relevance of Ppp1r1b-lncRNA outside differentiation models not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the identity of nuclear PP1 substrates regulated by translocated DARPP-32; (2) structural basis for DARPP-32 interactions with IGF1R, CXCR4, and IKKα; (3) whether the multiple cancer-associated signaling functions reflect direct binding or indirect PP1/PKA-mediated effects; (4) whether Thr34 and Thr75 phosphorylation states modulate DARPP-32's oncogenic protein interactions.
  • No structural model of DARPP-32 in complex with any cancer-relevant partner
  • Nuclear PP1 substrates downstream of DARPP-32 unidentified
  • Systematic comparison of phosphorylation-state-dependent interactomes not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 7 R-HSA-1643685 Disease 7 R-HSA-162582 Signal Transduction 6
Partners
CDK5CHUKCXCR4IGF1RPPP1CAPPP2R3APPP3CASRSF3

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 Phosphorylated DARPP-32 (phospho-Thr34) is a potent inhibitor of protein phosphatase-1 (PP-1) at nanomolar concentrations; the dephosphorylated form is inactive as a phosphatase inhibitor. In vitro phosphatase assay with purified DARPP-32 Nature High 6087160
1984 DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) at a single threonine residue (Thr34) within the sequence Arg-Arg-Arg-Pro-Thr(P)-Pro-Ala-Met-Leu-Phe-Arg, sharing homology with phosphatase inhibitor-1 and G-substrate. Protein sequencing of tryptic and chymotryptic phosphopeptides; reverse-phase HPLC; solid-phase sequencing The Journal of biological chemistry High 6501302
1984 DARPP-32 is localized in dopaminoceptive (D1 receptor-bearing) neurons in dopamine-innervated brain regions, including striatal medium spiny neurons, and is present in dendritic cell bodies and terminals projecting to globus pallidus and substantia nigra. Immunocytochemistry in rat and primate brain The Journal of neuroscience High 6319625
1990 Activation of NMDA receptors reverses cAMP-stimulated phosphorylation of DARPP-32 in striatal slices, implicating Ca2+-dependent calcineurin (PP-2B) in dephosphorylation of DARPP-32 at Thr34, thereby counteracting dopamine signaling. Striatal slice phosphorylation assay; pharmacological receptor activation Nature High 2153935
1990 DARPP-32 is present in striatal medium spiny neuron cell bodies, dendrites, dendritic spines, axons, and axon terminals; immunoreactive terminals in globus pallidus and substantia nigra form symmetrical synapses, establishing subcellular localization linked to striatal output pathway function. Electron microscopic immunocytochemistry Journal of neurocytology High 2191086
1997 D1 receptor activation increases DARPP-32 phosphorylation at Thr34 (via cAMP/PKA), while D2 receptor activation decreases it via a calcium-dependent, calcineurin-mediated mechanism; these pathways have opposing effects on DARPP-32 phosphorylation state. Mouse striatal slice phosphorylation assay; selective D1/D2 agonists/antagonists; Ca2+-free/EGTA medium; cyclosporin A The Journal of neuroscience High 9334390
1997 DARPP-32 mediates cAMP/PKA-dependent potentiation of NMDA currents in striatal neurons; antisense knockdown of DARPP-32 abolishes PKA-enhancement of NMDA responses, and adding DARPP-32 cRNA to hippocampal neurons (which lack DARPP-32) reconstitutes this potentiation. Xenopus oocyte two-electrode voltage-clamp; antisense oligodeoxynucleotides; mRNA injection Proceedings of the National Academy of Sciences of the United States of America High 9405704
1998 Adenosine A2A and dopamine D1 receptors stimulate DARPP-32 phosphorylation at Thr34 via cAMP in distinct subpopulations of striatal medium spiny neurons (striatopallidal and striatonigral, respectively); both effects are abolished by the PKA inhibitor Rp-cAMPS. Rat striatal slice phosphorylation assay; selective agonists; cAMP measurement; PKA inhibitor Neuroscience High 9522376
1998 Phospho-DARPP-32 (but not dephospho-DARPP-32) injected into striatal neurons reduces voltage-gated sodium current amplitude, analogous to okadaic acid (PP1/PP2A inhibitor), with no additivity, indicating DARPP-32 inhibits PP1-dependent dephosphorylation of sodium channels. Whole-cell patch-clamp of primary striatal neurons; intracellular injection of phospho- vs dephospho-DARPP-32 The European journal of neuroscience High 9749785
1999 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; decreasing Thr75 phosphorylation (via Cdk5 inhibitor or knockout mice) augments dopamine-induced PKA substrate phosphorylation and peak voltage-gated calcium currents. In vitro kinase assay; striatal slice phosphorylation; Cdk5 inhibitor; genetic knockout mice; electrophysiology Nature High 10604473
1999 DARPP-32 is required for dopamine D2 receptor-mediated inhibition of Na+/K+-ATPase in striatal neurons; both D1 and D2 agonist effects on Na+/K+-ATPase are abolished in DARPP-32 knockout mice. Na+/K+-ATPase activity assay in dissociated neostriatal cells from DARPP-32 knockout mice The European journal of neuroscience High 10383649
2000 DARPP-32 is an obligate intermediate in progesterone-facilitated sexual receptivity; progesterone increases hypothalamic cAMP and PKA activity and enhances phosphorylation of DARPP-32 at Thr34 in the hypothalamus; DARPP-32 null mice show minimal progesterone-facilitated receptivity. Antisense oligonucleotide knockdown in rats; DARPP-32 null mice; PKA activity assay; phosphorylation assay Science High 10669419
2002 Caffeine increases DARPP-32 phosphorylation at Thr75 by inhibiting PP-2A-catalyzed dephosphorylation (not by stimulating Cdk5); caffeine's stimulant effect on motor activity is greatly reduced in DARPP-32 knockout mice. Mouse striatal phosphorylation assay; DARPP-32 knockout mice; Cdk5 inhibitor; locomotor behavior Nature High 12181566
2002 DARPP-32 is required for D1 receptor-mediated enhancement of NMDA currents in striatal neurons; mice lacking DARPP-32 show significantly reduced D1-induced NMDA current potentiation; okadaic acid (PP1 inhibitor) increases D1-induced potentiation, indicating constitutively active PP1 attenuates D1 potentiation. Whole-cell patch-clamp of dissociated striatal neurons from DARPP-32 knockout mice; pharmacological PP1 inhibition Journal of neurophysiology High 12466426
2002 DARPP-32 and a novel truncated isoform t-DARPP are overexpressed in gastric cancers; t-DARPP lacks the Thr34 phosphorylation site for PP1 inhibition but retains the Thr75 PKA-inhibitory site. Quantitative RT-PCR; Western blot; tumor tissue array immunostaining; cDNA characterization Cancer research Medium 12124342
2005 Glutamate regulates DARPP-32 phosphorylation at Thr34 and Thr75 through at least five distinct signaling cascades: NMDA/AMPA/mGluR5 receptors→nNOS/NO/cGMP/PKG (initial Thr34 increase); NMDA/AMPA/Ca2+/PP-2B (subsequent Thr34 decrease); mGluR5/PLC/ERK (rephosphorylation at Thr34); NMDA/AMPA/Ca2+/PP-2A (Thr75 decrease); and mGluR1/PLC (Thr75 increase). Mouse neostriatal slice phosphorylation assays with receptor-selective antagonists and signaling inhibitors Proceedings of the National Academy of Sciences of the United States of America High 15657149
2006 Phosphorylation of DARPP-32 at Thr34 is specifically required for cocaine-induced conditioned place preference, acute locomotor activity, and induction of immediate early genes (c-fos, arc) and DeltaFosB in striatum; Thr75 phosphorylation is required for locomotor sensitization but not acute locomotion or place preference. Knock-in mice with T34A or T75A point mutations; behavioral testing; immunoblotting for gene expression Neuropsychopharmacology High 16123776
2007 The PR72 (B''/PPP2R3A) regulatory subunit of PP2A mediates Ca2+-dependent dephosphorylation of DARPP-32 at Thr75; the first EF-hand of PR72 is required for Ca2+-regulated PP2A activity; PR72-containing PP2A is necessary for glutamate/AMPA/NMDA receptor-regulated Thr75 dephosphorylation. Overexpression and RNAi knockdown in striatal neurons; in vitro phosphatase assay; EF-hand mutagenesis; striatal slice phosphorylation Proceedings of the National Academy of Sciences of the United States of America High 17535922
1994 GABA (acting via GABAA receptors) increases DARPP-32 phosphorylation at Thr34 in striatum and substantia nigra slices by inhibiting calcineurin-mediated dephosphorylation, independently of cAMP elevation. Striatal and substantia nigra slice phosphorylation assay; GABAA/GABAB receptor antagonists; cAMP measurement Journal of neurochemistry Medium 7931332
1997 DARPP-32 in 3T3-L1 adipocytes is induced during adipogenesis and localizes exclusively to particulate/glycogen-enriched fractions; it maintains glycogen-targeted PP1 in a low basal state, and insulin treatment overcomes DARPP-32-mediated PP1 inhibition to stimulate glycogen synthesis. Subcellular fractionation; PP1 activity assay; insulin stimulation; Western blot; glycogen synthesis assay The Journal of biological chemistry Medium 9368038
2005 DARPP-32 and t-DARPP act as antiapoptotic proteins in gastrointestinal cancer cells; expression reduces apoptosis in response to camptothecin, sodium butyrate, and ceramide; this requires intact phosphorylation sites; overexpression preserves mitochondrial transmembrane potential and increases Bcl2; siRNA knockdown reverses Bcl2 elevation. TUNEL and Annexin V apoptosis assays; siRNA; Bcl2 immunoblotting; mitochondrial membrane potential assay; phosphorylation site mutagenesis Cancer research Medium 16061638
2009 Wnt-5a triggers cAMP elevation at the plasma membrane and PKA-dependent Thr34-DARPP-32 phosphorylation via a Frizzled-3/Galpha(s) pathway; phospho-Thr34-DARPP-32 inhibits PP1 and potentiates CREB phosphorylation; this cascade inhibits breast cancer cell migration by reducing Cdc42 activity and filopodia formation. siRNA knockdown of Frizzled-3, Galpha(s), DARPP-32; cAMP FRET imaging; Co-IP; phalloidin staining; Cdc42 activity assay; migration assay; dominant-negative CREB The Journal of biological chemistry High 19651774
2009 t-DARPP overexpression (but not full-length DARPP-32) confers resistance to Herceptin (trastuzumab) and prevents Herceptin-mediated Akt dephosphorylation in Her2-positive breast cancer cells; co-expression of full-length DARPP-32 reverses t-DARPP's effects; t-DARPP promotes CREB DNA-binding activity. cDNA transfection; clonogenic survival; Akt phosphorylation immunoblot; CREB EMSA PloS one Medium 19593441
2012 DARPP-32 co-exists in a protein complex with CXCR4, prolongs CXCR4 protein half-life, reduces CXCR4 ubiquitination after CXCL12 stimulation, and promotes gastric cancer cell invasion via CXCR4→MT1-MMP→MMP-2 activation. Reciprocal Co-IP; immunofluorescence; pulse-chase protein stability assay; ubiquitination assay; Matrigel invasion assay; siRNA; AMD3100 inhibitor Molecular cancer research Medium 23160836
2013 PPP1R1B-STARD3 chimeric fusion transcript (generated by RNA processing without chromosomal rearrangement) activates PI3K/AKT signaling to promote gastric cancer cell proliferation and tumor growth in vivo. Paired-end transcriptome sequencing; RT-PCR; stable overexpression; cell proliferation assay; colony formation; xenograft mouse model; phospho-AKT immunoblot Oncogene Medium 24276243
2015 DARPP-32 regulates ANGPT2 expression and tumor angiogenesis through activation of STAT3 (not NF-κB); DARPP-32-induced ANGPT2 is secreted and functionally active; this effect does not require Thr34-PP1 inhibitory function (T34A mutant and t-DARPP have similar effects). Western blot; STAT3 inhibitor/knockdown; HUVEC tube formation assay; xenograft mouse model; antibody blocking; luciferase reporter; immunofluorescence; co-IP Gut Medium 25779598
2015 DARPP-32 regulates SRp20 splicing factor expression and stability, co-exists in the same protein complex with SRp20, and thereby controls CD44E (CD44 variant) splicing in gastric cancer; loss of DARPP-32 reduces SRp20-dependent CD44E expression and tumor growth. Co-IP; splicing luciferase reporter; immunoprecipitation after splicing inhibition; xenograft mouse model; qRT-PCR; immunoblot Oncogene Medium 26119931
2015 DARPP-32 promotes resistance to TRAIL-induced apoptosis by: (1) activating Src/STAT3 signaling to upregulate BCL-xL and block the intrinsic apoptosis pathway; (2) preventing NF-κB p65 cleavage to maintain FLIP(S) expression and block extrinsic (caspase-8) apoptosis. Stable overexpression/shRNA knockdown; Annexin V; caspase activation assay; Src inhibitor PP1; NF-κB reporter; immunoblot; clonogenic assay Clinical cancer research Medium 22589394
2015 Calpain cleaves DARPP-32 primarily at Thr153 in Alzheimer's disease brains and in neurons treated with amyloid-β or okadaic acid; this cleavage reduces PP1 inhibitory function of DARPP-32 and decreases CREB phosphorylation. Immunoblot of AD brains; primary neuronal treatment with Aβ/okadaic acid; in vitro calpain cleavage assay; CREB phosphorylation measurement Aging cell Medium 26178297
2016 H. pylori infection induces DARPP-32 expression via NF-κB transcriptional activation; ChIP and deletion mapping identify the −996 to −1008 bp NF-κB binding region as the key regulatory element; DARPP-32 induction counteracts H. pylori-induced cell death through AKT activation. Luciferase reporter; deletion constructs; ChIP assay; qRT-PCR; immunoblot; ATP-Glo cell viability; clonogenic assay Gut Medium 27590997
2016 Glutamate activates PP2A/PR72 to dephosphorylate DARPP-32 at Ser97 (the CK2 site) via Ca2+-dependent mechanisms; Ser97 dephosphorylation causes DARPP-32 to translocate to the nucleus in a dephospho-Thr34/dephospho-Ser97 form, counteracting dopamine/D1/PKA signaling. Striatal slice phosphorylation; in vitro PP2A/PR72 phosphatase assay; cultured striatal neuron nuclear localization imaging; in vivo phosphorylation measurement The Journal of biological chemistry High 27998980
2018 DARPP-32 physically interacts with IKKα and promotes non-small cell lung cancer cell migration through non-canonical NF-κB2 signaling; abrogation of DARPP-32 reduces tumor growth in orthotopic mouse models. Co-IP; orthotopic mouse model; migration assay; NF-κB2 pathway analysis; immunoblot Communications biology Medium 29782621
2019 DARPP-32 co-exists in the same protein complex with IGF1R (detected by proximity ligation assay and Co-IP); DARPP-32 binding to IGF1R promotes IGF1R phosphorylation at Y1135 and subsequent SRC and STAT3 activation; in vivo, TFF1 KO/DARPP-32 KO double-knockout mice show no IGF1R or STAT3 phosphorylation and delayed gastric neoplasia. Proximity ligation assay; reciprocal Co-IP; phospho-immunoblot; TFF1 KO/DARPP-32 KO double-knockout mouse model; 3D gastric organoids; tissue microarray Oncogene High 31235784
2020 PPP1R1B promotes degradation of p53 by stabilizing MDM2 phosphorylation at Ser166; loss of HIF1A increases PPP1R1B expression which activates this p53-degradation pathway to promote pancreatic cancer invasion and metastasis. shRNA knockdown; immunoblot; MDM2 phosphorylation assay; lung metastasis in vivo model; KPC mouse model Gastroenterology Medium 32768595
2020 Ppp1r1b-lncRNA (a non-coding RNA transcribed from the PPP1R1B locus) promotes myogenic differentiation by binding EZH2/PRC2 and preventing H3K27me3 at MyoD1, Myogenin, and Tbx5 promoters; silencing the lncRNA impairs myotube formation and cardiomyocyte differentiation. GapmeR silencing; ChIRP assay; H3K27me3 ChIP; EZH2 ChIP; qRT-PCR; immunoblot; hiPS-derived cardiomyocyte differentiation RNA (New York, N.Y.) Medium 31953255
2007 BDNF-induced DARPP-32 protein expression in striatal medium spiny neurons requires both the PI3K/AKT/mTOR and CDK5/p35 signaling pathways, with PI3K upstream of CDK5/p35 (PI3K activation increases p35 protein levels); these pathways act at both transcriptional and translational levels. Pharmacological inhibitors of PI3K, AKT, CDK5; constitutively active and dominant negative viral constructs; DARPP-32 protein and mRNA measurement The Journal of biological chemistry Medium 17209049
2015 PDE10A inhibitor-induced PKA signaling preferentially activates D2 MSNs over D1 MSNs; this selectivity requires DARPP-32's PP1-inhibitory function (Thr34 phosphorylation), as mice with T34A DARPP-32 mutation lose the D2-selective response. In vivo immunohistochemistry; FRET-based cAMP/PKA biosensors in brain slices; T34A knock-in mice eNeuro High 26465004
2005 Repeated cocaine administration decreases calcineurin levels and enhances DARPP-32-mediated PP1 inhibition of sodium channels in nucleus accumbens neurons; phospho-Thr34-DARPP-32 suppresses voltage-gated sodium current (I_Na) by maintaining Na+ channel phosphorylation state. Whole-cell voltage-clamp; Western blot for CaN, DARPP-32, PP1 protein levels; direct application of p-Thr34-DARPP-32 Neuropsychopharmacology Medium 15726118
2019 Cdk5 phosphorylation of DARPP-32 at Thr75 in the nucleus accumbens contributes to depressive-like behavior in Huntington's disease mice (Hdh+/Q111); Thr75Ala knock-in DARPP-32 mutation confers resistance to depressive-like behaviors; β-adducin phosphorylation downstream of Cdk5 mediates structural spine plasticity changes. Hdh+/Q111 × DARPP-32 Thr75Ala double knock-in mice; behavioral tests; phospho-DARPP-32 immunoblot; roscovitine Cdk5 inhibitor infusion; spine morphology analysis Biological psychiatry High 31060804

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 561 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
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