Affinage

PPP1R9A

Neurabin-1 · UniProt Q9ULJ8

Length
1098 aa
Mass
123.3 kDa
Annotated
2026-04-28
11 papers in source corpus 7 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPP1R9A (neurabin I) is a neuronal scaffolding protein that couples protein phosphatase 1 (PP1) to the actin cytoskeleton to regulate spine morphogenesis, filopodium formation, and neuritogenesis. Its N-terminal F-actin-binding domain targets it to actin filaments, while a conserved KIKF motif (residues 457–460) recruits PP1 (preferentially PP1γ1 and PP1α) with nanomolar affinity (Ki ≈ 2.7 nM), and the resulting complex drives actin rearrangement essential for filopodium induction (PMID:10504266, PMID:12052877, PMID:12016225). This PP1-anchoring function is dynamically controlled: PKA phosphorylation of Ser461 within the KIKF motif dissociates PP1, whereas Cdk5 phosphorylation regulates neurabin I's F-actin association and downstream Rac1 activation to influence neuronal morphology and migration (PMID:12052877, PMID:17699587). Neurabin I also scaffolds the GTPase Rac3 at growth cones to mediate neuritogenesis, functioning as a multivalent organizer of actin-based signaling in developing neurons (PMID:16525023).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1999 High

    Establishing that neurabin I is a potent PP1 inhibitor whose binding is negatively regulated by PKA phosphorylation at Ser461 answered how PP1 activity is locally controlled at actin-rich neuronal structures.

    Evidence Reconstituted PP1 inhibition assay (Ki = 2.7 nM), HPLC-MS phosphosite identification, S461E phosphomimetic mutagenesis

    PMID:10504266

    Open questions at the time
    • Physiological consequences of Ser461 phosphorylation in neurons not tested
    • Whether PP1 isoform selectivity exists was unknown
  2. 1999 Medium

    Identification of Bau, a splice form lacking actin-binding and p70S6K-binding domains, as a Bin1-interacting nuclear/cytosolic protein that suppresses transformation revealed an unexpected non-neuronal tumor-suppressive role for the PPP1R9A locus.

    Evidence Yeast two-hybrid, co-immunoprecipitation, subcellular fractionation, transformation suppression assay

    PMID:10427963

    Open questions at the time
    • No independent replication of Bin1 interaction
    • Mechanism of transformation suppression not defined
    • Relevance to endogenous tumor suppression in vivo unknown
  3. 2002 High

    Systematic domain analysis and PP1-motif mutagenesis demonstrated that neurabin I's F-actin-binding domain directs cytoskeletal localization, its KIKF motif recruits catalytically active PP1 to drive filopodium formation, and PKA phosphorylation at Ser461 releases PP1 — establishing the tripartite regulatory circuit of actin-scaffolding, phosphatase targeting, and kinase-mediated disassembly.

    Evidence GFP-fusion domain deletions, immune complex phosphatase assays, site-directed mutagenesis, pharmacological PP1 inhibition (okadaic acid/calyculin A) in COS7, HEK293, and hippocampal neurons

    PMID:12052877

    Open questions at the time
    • In vivo spine phenotype of PP1-binding mutant not shown
    • p70S6K functional role at neurabin I not further resolved
  4. 2002 High

    Demonstrating that neurabin I preferentially binds PP1γ1 and PP1α over PP1β, with selectivity conferred by flanking sequences and PP1 C-terminal tails, resolved how specificity among PP1 holoenzymes is achieved at the actin cytoskeleton.

    Evidence Immunoprecipitation from rat brain, recombinant peptide binding assays, PP1 chimera analysis, PP1γ knockout mouse brain co-IP

    PMID:12016225

    Open questions at the time
    • Structural basis of isoform selectivity not resolved
    • Functional consequence of isoform switching (e.g., in PP1γ KO) on spine morphology not tested
  5. 2006 High

    Identifying Rac3 as a direct neurabin I partner at growth cones, with a Rac3-binding domain deletion abolishing neuritogenesis rescue, established neurabin I as a scaffold linking small GTPase signaling to actin at the growth cone.

    Evidence Yeast two-hybrid, co-fractionation, co-localization, antisense knockdown and domain-mutant rescue in neurons

    PMID:16525023

    Open questions at the time
    • Whether Rac3 scaffolding is independent of PP1 binding unclear
    • Downstream effectors of the neurabin I–Rac3 complex not identified
  6. 2007 High

    Showing that Cdk5 phosphorylates neurabin I to regulate its F-actin association and influence neuronal migration in vivo added a second kinase input (alongside PKA) that bidirectionally tunes neurabin I function, and linked neurabin I to Rac1 activation.

    Evidence In vitro Cdk5 kinase assay, phosphosite mutagenesis, gain/loss-of-function in cortical neurons, in utero electroporation, Rac1 activation assay

    PMID:17699587

    Open questions at the time
    • Exact Cdk5 phosphosite(s) on neurabin I not fully mapped by MS in this study
    • Relationship between Cdk5 phosphorylation and PP1 binding not tested
    • Whether Rac1 activation is direct or via intermediate effectors unclear
  7. 2018 Medium

    Discovery that hyper-N-glycosylated neurabin I (at Asn1277) serves as a B-cell receptor autoantigen driving BCR signaling and proliferation in primary CNS lymphoma revealed an unanticipated role for post-translationally modified neurabin I in lymphomagenesis.

    Evidence BCR immunoprecipitation/antigen identification, BCR transfection into lymphoma lines, BCR pathway activation assays, epitope-toxin conjugate cytotoxicity

    PMID:30249786

    Open questions at the time
    • Single study; not independently replicated
    • Mechanism generating atypical glycosylation unknown
    • Whether glyco-neurabin I is presented on normal CNS cell surfaces unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple kinase inputs (PKA, Cdk5), PP1 isoform selectivity, Rac3 scaffolding, and actin binding are integrated at the structural level to coordinate spine morphogenesis and neuronal migration remains unresolved.
  • No high-resolution structure of full-length neurabin I or its PP1 holoenzyme
  • In vivo conditional knockout phenotype in adult neurons not reported in this literature
  • Functional interplay between Rac3 and Rac1 signaling through neurabin I not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 4 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
GO:0005856 cytoskeleton 3 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
BIN1CDK5PPP1CAPPP1CCRAC3

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Neurabin I (PPP1R9A) recruits active PP1 via a PP1-docking sequence (457)KIKF(460); mutation of this motif or pharmacological PP1 inhibition abolishes neurabin I-induced filopodium formation and restores stress fibers, establishing that the neurabin I/PP1 complex controls actin rearrangement and spine morphology. Immune complex phosphatase assays, GFP-fusion cell imaging, site-directed mutagenesis of PP1-binding motif, okadaic acid/calyculin A treatment in Cos7, HEK293, and hippocampal neurons Molecular and cellular biology High 12052877
2002 The N-terminal F-actin-binding domain of neurabin I dictates its localization to the actin cytoskeleton and promotes disassembly of stress fibers, while deletion of the C-terminal coiled-coil and SAM domains abolishes dimerization and induces filopodium extension. GFP-fusion domain deletion analysis and fluorescence microscopy in Cos7, HEK293, and hippocampal neurons Molecular and cellular biology High 12052877
2002 PKA phosphorylation of neurabin I at serine-461 (within the PP1-binding motif) impairs PP1 binding, and in vitro studies showed the actin-binding domain attenuates PKA phosphorylation of neurabin I; p70S6K is excluded from neurabin I/PP1 complexes and requires displacement of PP1 for its own recruitment to neurabin I. In vitro kinase assays, co-immunoprecipitation, phospho-site mutagenesis (S461E), immune complex assays Molecular and cellular biology High 12052877
1999 Neurabin I binds and inhibits PP1 (Ki = 2.7 nM) via residues 456-460; PKA phosphorylates neurabin I at serine-461 (within the PP1-binding motif), and this phosphorylation significantly reduces PP1 binding and inhibitory potency (~35-fold reduction with S461E phosphomimetic mutant). Overlay assay, yeast two-hybrid, co-precipitation, co-immunoprecipitation, GST-fusion PP1 inhibition assay, in vitro PKA kinase assay, HPLC-MS phosphosite identification, S461E mutagenesis Biochemistry High 10504266
2002 Neurabin I preferentially recruits PP1gamma1 and PP1alpha isoforms over PP1beta from brain extracts; sequences flanking the conserved PP1-binding motif and C-terminal sequences unique to PP1 isoforms both contribute to this selectivity. In PP1gamma null mice, neurabins show enhanced association with PP1alpha but not PP1beta. Immunoprecipitation from rat brain extracts, in vitro binding assays with recombinant peptides and chimeric neurabins, PP1/PP2A chimera assays, immunoprecipitation from PP1gamma knockout mouse brain The Journal of biological chemistry High 12016225
2007 Cdk5 directly phosphorylates neurabin I and controls its association with F-actin; mutation of the Cdk5 phosphorylation site reduces the phenotypic consequences of neurabin I overexpression (altered neuronal morphology and migration defects) both in vitro and in vivo, and neurabin I expression levels affect Rac1 activation in neurons. In vitro kinase assay, site-directed mutagenesis of Cdk5 site, gain/loss-of-function in cortical and hippocampal neurons, in utero electroporation, Rac1 activation assay Molecular biology of the cell High 17699587
2006 Neurabin I directly interacts with the neuronal GTPase Rac3 (identified by yeast two-hybrid), colocalizes with Rac3 at growth cones, and is required for Rac3-induced neuritogenesis; neurabin I mediates this process by anchoring Rac3 to growth cone F-actin, as a Rac3-binding domain deletion mutant fails to rescue neuritogenesis. Yeast two-hybrid, co-fractionation, co-localization by light microscopy, antisense oligonucleotide knockdown, rescue with wild-type vs. Rac3-binding domain mutant neurabin I Molecular biology of the cell High 16525023
1999 Bau, a splice form of neurabin I (PPP1R9A) lacking actin- and p70S6K-binding domains, interacts with the tumor suppressor Bin1 via its U3 region, localizes to the nucleus and cytosol, and suppresses oncogene-mediated cell transformation and tumor cell growth. Yeast two-hybrid identification, co-immunoprecipitation, subcellular fractionation/localization, transformation suppression assay Cell adhesion and communication Medium 10427963
2018 Neurabin I is atypically hyper-N-glycosylated at ASN1277, rendering it immunogenic and acting as a B-cell receptor autoantigen that drives BCR pathway activation and proliferation in primary CNS lymphoma cells. BCR immunoprecipitation/antigen identification, BCR transfection into lymphoma cell lines, BCR pathway activation assays, epitope-toxin conjugate cytotoxicity assay Blood Medium 30249786

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Targeting protein phosphatase 1 (PP1) to the actin cytoskeleton: the neurabin I/PP1 complex regulates cell morphology. Molecular and cellular biology 101 12052877
2002 The neuronal actin-binding proteins, neurabin I and neurabin II, recruit specific isoforms of protein phosphatase-1 catalytic subunits. The Journal of biological chemistry 75 12016225
1999 Regulation of neurabin I interaction with protein phosphatase 1 by phosphorylation. Biochemistry 71 10504266
2007 Neurabin-I is phosphorylated by Cdk5: implications for neuronal morphogenesis and cortical migration. Molecular biology of the cell 32 17699587
2018 Hyper-N-glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma. Blood 29 30249786
2015 Altered prefrontal cortical MARCKS and PPP1R9A mRNA expression in schizophrenia and bipolar disorder. Schizophrenia research 25 25757715
2006 Rac3-induced neuritogenesis requires binding to Neurabin I. Molecular biology of the cell 16 16525025
2011 Assessment of genomic imprinting of PPP1R9A, NAP1L5 and PEG3 in pigs. Genetika 11 21675243
2011 Molecular cloning, mRNA expression and imprinting status of PEG3, NAP1L5 and PPP1R9A genes in pig. Genes & genetic systems 9 21498922
2020 Integration of the B-Cell Receptor Antigen Neurabin-I/SAMD14 Into an Antibody Format as New Therapeutic Approach for the Treatment of Primary CNS Lymphoma. Frontiers in oncology 5 33282736
1999 Bau, a splice form of Neurabin-I that interacts with the tumor suppressor Bin1, inhibits malignant cell transformation. Cell adhesion and communication 4 10427963