Affinage

PHACTR1

Phosphatase and actin regulator 1 · UniProt Q9C0D0

Round 2 corrected
Length
580 aa
Mass
66.3 kDa
Annotated
2026-04-28
87 papers in source corpus 26 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHACTR1 is an RPEL-motif-containing cofactor of protein phosphatase 1 (PP1) that couples Rho–actin signaling to substrate-specific dephosphorylation, transcriptional regulation, and cytoskeletal remodeling across vascular, immune, and neuronal contexts. In resting cells, G-actin binds the three C-terminal RPEL motifs to retain PHACTR1 in the cytoplasm; Rho-signal-driven G-actin depletion exposes importin α–β binding sites and triggers nuclear accumulation, simultaneously freeing the PP1-interaction surface because G-actin and PP1 bind competitively to the same region (PMID:22976292, PMID:32975518). The PHACTR1/PP1 holoenzyme remodels PP1's hydrophobic groove to create a composite substrate-recognition surface that confers sequence-specific dephosphorylation of cytoskeletal targets such as IRSp53 and spectrin αII; in macrophages this activity maintains myosin light chain phosphorylation required for efferocytosis, while in neurons it recruits PP1 to suppress Slack (KCNT1) channel activity (PMID:32975518, PMID:33630758, PMID:31914597). De novo missense mutations disrupting actin- or PP1-binding cause West syndrome (infantile epileptic spasms), with loss of PHACTR1 impairing cortical neuron migration and synaptic function (PMID:30256902); in endothelial cells under disturbed flow, nuclear PHACTR1 acts as a PPARγ transcriptional corepressor to promote endothelial activation and atherosclerosis (PMID:37199156).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 High

    Establishing PHACTR1 as a PP1-binding, actin-associating protein enriched at synapses answered the initial question of what this brain-expressed protein does biochemically and where it acts.

    Evidence Interaction cloning, in vitro PP1 activity assay, subcellular fractionation and immunohistochemistry in rat brain

    PMID:15107502

    Open questions at the time
    • No structural basis for PP1 or actin binding
    • No in vivo loss-of-function data
    • Neuronal substrates of PHACTR1/PP1 unknown
  2. 2011 Medium

    Demonstrating that VEGF/NRP-1/VEGFR1 signaling induces PHACTR1 in endothelial cells and that PHACTR1 is required for tubulogenesis, survival, and lamellipodial dynamics extended the protein's role beyond neurons into the vasculature and linked it to actin dynamics and PP1 activity in endothelial biology.

    Evidence siRNA knockdown in HUVECs with receptor-specific depletion, PP1 activity assays, tube formation and apoptosis assays, live-cell imaging

    PMID:21798305 PMID:21939755

    Open questions at the time
    • Mechanism connecting PHACTR1 loss to death receptor activation unclear
    • No in vivo endothelial phenotype
    • Whether PP1 catalytic activity mediates tube formation not directly tested
  3. 2012 High

    Resolving how PHACTR1 shuttles between cytoplasm and nucleus answered the key regulatory question: G-actin binding to RPEL motifs competitively blocks both importin α–β-dependent nuclear import and PP1 binding, so Rho-driven G-actin depletion simultaneously drives nuclear entry and enables PP1 engagement.

    Evidence RPEL motif mutagenesis, competitive importin and PP1 binding assays, serum-stimulation nuclear accumulation, siRNA phenotyping in CHL-1 melanoma cells

    PMID:22976292

    Open questions at the time
    • No structural resolution of competitive binding interfaces
    • Whether the mechanism operates equivalently in neurons vs. endothelial cells untested
    • Nuclear PP1 substrates not identified
  4. 2013 Medium

    Identifying TGF-β/miR-584 as an upstream regulatory axis for PHACTR1 expression established a mechanism by which PHACTR1-dependent actin reorganization drives TGF-β-induced cancer cell migration.

    Evidence miR-584 overexpression and PHACTR1 knockdown in breast cancer cells; TGF-β stimulation; phalloidin staining; migration assays

    PMID:23479725

    Open questions at the time
    • Direct miR-584 binding site on PHACTR1 3'UTR not validated by reporter assay in this study
    • Whether PP1 activity is required for this migration phenotype unknown
  5. 2014 Medium

    Showing that PHACTR1 interacts with MRTF-A/B and myocardin via RPEL-containing NLS sequences, and is a direct target of Rho-pathway inhibitor CCG-1423, placed PHACTR1 within the broader RPEL-protein regulatory network.

    Evidence CCG-1423-Sepharose affinity pull-down, competitive G-actin displacement assay

    PMID:24558465

    Open questions at the time
    • Functional consequence of PHACTR1–MRTF interaction not determined
    • Whether CCG-1423 inhibits PHACTR1 function in cells not tested
  6. 2015 High

    Identifying the CAD-risk SNP rs9349379 as a MEF2-dependent enhancer that controls PHACTR1 expression in coronary arteries connected human GWAS genetics to a specific cis-regulatory mechanism.

    Evidence eQTL analysis in human coronary arteries, EMSA, CRISPR/Cas9 deletion of MEF2 site in endothelial cells

    PMID:25838425

    Open questions at the time
    • Whether reduced PHACTR1 expression is the causal mediator of CAD risk at this locus was contested by subsequent work implicating EDN1
    • No functional vascular phenotype tested
  7. 2017 High

    A landmark CRISPR base-editing study demonstrated that rs9349379 acts as a distal enhancer of EDN1 (not PHACTR1) in aortic endothelial cells, raising the possibility that the CAD risk at this locus is mediated through endothelin-1 rather than PHACTR1 in certain vascular beds.

    Evidence CRISPR base editing in iPSC-derived endothelial cells, H3K27ac and DNase I chromatin analysis, aorta eQTL mapping

    PMID:28753427

    Open questions at the time
    • Cell-type and vascular-bed specificity of rs9349379 regulation not fully resolved
    • Does not exclude PHACTR1-mediated contributions in macrophages or non-aortic vessels
  8. 2018 High

    Identification of de novo PHACTR1 missense mutations causing West syndrome, with mutations selectively disrupting actin- or PP1-binding and failing to rescue cortical neuron migration, established PHACTR1 as a disease gene and demonstrated that both binding activities are essential for brain development.

    Evidence Trio WES, co-IP of mutant PHACTR1 with actin/PP1, in utero electroporation rescue in mouse cortex, patch-clamp electrophysiology

    PMID:30256902

    Open questions at the time
    • Downstream substrates mediating migration and synaptic phenotypes not identified
    • Whether PP1 catalytic activity or scaffolding underlies the rescue not distinguished
  9. 2018 Medium

    Demonstrating that PHACTR1 interacts with MRTF-A and p65/NF-κB to promote nuclear translocation of p65 in endothelial cells provided a PP1-independent transcriptional mechanism for PHACTR1's pro-inflammatory role.

    Evidence Co-IP of PHACTR1 with MRTF-A and p65, siRNA knockdown, immunofluorescence for p65 translocation in coronary artery endothelial cells

    PMID:30293016

    Open questions at the time
    • No reciprocal IP for PHACTR1–p65 direct binding
    • Mechanism by which PHACTR1 promotes p65 translocation without affecting IκBα unclear
    • Relationship to PP1 catalytic activity not tested
  10. 2019 High

    Electrophysiological evidence that PHACTR1 recruits PP1 to dephosphorylate the Slack (KCNT1) potassium channel at Ser407, reducing channel current, identified the first ion-channel substrate and demonstrated a neuronal signaling role for the PHACTR1/PP1 holoenzyme.

    Evidence Co-IP of PHACTR1 with Slack, patch-clamp electrophysiology in oocytes/HEK cells, PP1-binding mutant of PHACTR1

    PMID:31914597

    Open questions at the time
    • In vivo neuronal consequence of Slack regulation by PHACTR1 not determined
    • Whether other PHACTR1/PP1 substrates exist in neurons not addressed beyond this channel
  11. 2020 High

    Crystal structures of the PHACTR1/PP1 holoenzyme with dephosphorylated substrates (IRSp53, spectrin αII) provided the definitive structural mechanism: PHACTR1 remodels PP1's hydrophobic groove to create a composite surface conferring sequence-specific substrate recognition and orders-of-magnitude enhanced catalytic efficiency.

    Evidence X-ray crystallography of holoenzyme–product complexes, phosphoproteomics in fibroblasts and neurons, mutagenesis of substrate-contact residues

    PMID:32975518

    Open questions at the time
    • Full substrate repertoire in physiological contexts incompletely mapped
    • Whether actin-bound vs. PP1-bound pools have distinct substrate access in cells not resolved
  12. 2020 Medium

    Showing that macrophage PHACTR1 deficiency drives M1 polarization and foam cell formation via reduced CREB/KLF4 signaling provided a macrophage-intrinsic mechanism linking lower PHACTR1 to atherosclerosis progression.

    Evidence Phactr1−/−/Apoe−/− mice, bone marrow transplant, co-IP of PHACTR1 with CREB, KLF4 rescue

    PMID:32857129

    Open questions at the time
    • Whether PHACTR1-CREB interaction is PP1-dependent not tested
    • Single lab finding awaiting independent replication
  13. 2021 High

    Demonstrating that PHACTR1 prevents MLC dephosphorylation to enable macrophage efferocytosis, and that the rs9349379 risk allele reduces PHACTR1 expression and efferocytic capacity, provided a direct mechanistic link between PHACTR1-directed PP1 activity, apoptotic cell clearance, and CAD risk.

    Evidence Human macrophage efferocytosis assays, hematopoietic-specific Phactr1 KO in Ldlr−/− mice on Western diet, phospho-MLC Western blot, plaque histology

    PMID:33630758

    Open questions at the time
    • Paradox: PHACTR1 here prevents dephosphorylation of MLC whereas it promotes dephosphorylation of other substrates — mechanism of substrate selectivity in macrophages not resolved
    • Whether endothelial and macrophage PHACTR1 effects are additive in atherogenesis not tested in combined models
  14. 2023 High

    Identifying PHACTR1 as a flow-sensitive PPARγ transcriptional corepressor in endothelial cells resolved how nuclear PHACTR1 promotes endothelial activation: under disturbed flow it represses PPARγ anti-inflammatory target genes, and endothelial-specific deletion is atheroprotective.

    Evidence EC-specific and global Phactr1 KO in ApoE−/− mice, partial carotid ligation, immunostaining under flow, PPARγ binding assays, GW9662 pharmacological rescue

    PMID:37199156

    Open questions at the time
    • Whether the corepressor function requires PP1 or is independent not determined
    • Identity of PPARγ target genes most relevant to atheroprotection not fully defined
  15. 2024 Medium

    Multi-omics profiling revealed that PHACTR1 localizes to mitochondria and modulates mitochondrial morphology and bioenergetics via an AKAP1/Drp1 axis, expanding PHACTR1's functional repertoire beyond the actin cytoskeleton and nucleus.

    Evidence Transcriptomics, proteomics, metabolomics, lipidomics in HT1080 OE/KD cells; validation in primary endothelial cells; mitochondrial localization confirmed

    PMID:41554990

    Open questions at the time
    • Whether PP1 activity is required for mitochondrial effects not tested
    • AKAP1/Drp1 interaction with PHACTR1 not validated by reciprocal co-IP or mutagenesis
    • Single study; independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: how PHACTR1 differentially prevents dephosphorylation of MLC in macrophages while promoting dephosphorylation of other cytoskeletal substrates; the relative contributions of endothelial, macrophage, and smooth muscle cell PHACTR1 to CAD in vivo; the full neuronal substrate repertoire and how its disruption causes epileptic spasms; and whether the mitochondrial localization and AKAP1/Drp1 axis represent a physiologically significant function.
  • Substrate selectivity mechanism in distinct cell types unresolved
  • No combined tissue-specific KO studies for atherosclerosis
  • Neuronal substrates beyond Slack channel not validated in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 3 R-HSA-112316 Neuronal System 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
ACTA1AKAP1CREB1KCNT1MRTFAPPARGPPP1CAROCK2
Complex memberships
PHACTR1/PP1 holoenzyme

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 PHACTR1 (Phactr-1) was identified as the founding member of a family of PP1-binding proteins that also bind cytoplasmic actin via RPEL motifs. Phactr-1 was shown to be a potent modulator of PP1 activity in vitro, and the protein is selectively expressed in brain with enrichment at synapses. Interaction cloning, in vitro PP1 activity assay, subcellular fractionation, immunohistochemistry in rat brain Proceedings of the National Academy of Sciences of the United States of America High 15107502
2011 PHACTR1 depletion in HUVECs abolished tube formation and triggered apoptosis via death receptors DR4, DR5, and FAS in a caspase-8-dependent manner, establishing PHACTR1 as a key regulator of endothelial cell survival and tubulogenesis. siRNA knockdown in HUVECs, tube formation assay, flow cytometry for apoptosis, siRNA rescue with death-receptor and caspase-8 siRNAs Biochimie Medium 21798305
2011 PHACTR1 expression in HUVECs is induced by VEGF-A165 and is regulated specifically through NRP-1 and VEGF-R1 (but not NRP-2 or VEGF-R2). Upon VEGF stimulation, Phactr1 promotes tube formation and fine-tunes actin polymerization and lamellipodial dynamics; its depletion decreases PP1 activity and disrupts actin dynamics. siRNA knockdown of NRP-1, NRP-2, VEGFR1, VEGFR2; antagonist peptide blocking; PP1 activity assay; live-cell imaging of lamellipodia; tube formation assay in HUVECs Cellular signalling Medium 21939755
2012 G-actin binding by the three C-terminal RPEL motifs of Phactr1 is required for its cytoplasmic retention in resting cells. Rho-actin signalling (serum stimulation) depletes G-actin and promotes importin α-β-dependent nuclear accumulation of Phactr1. G-actin and importin α-β bind competitively to nuclear import signals flanking the RPEL motifs. Furthermore, G-actin and PP1 bind competitively to the Phactr1 C-terminal region, so that nuclear Phactr1 RPEL mutants that cannot bind G-actin induce aberrant actomyosin structures in a PP1-dependent manner. In CHL-1 melanoma cells, Phactr1 is required for stress fibre assembly, motility, and invasiveness. RPEL motif mutagenesis, importin binding assays, serum-stimulation nuclear accumulation assays, live-cell imaging, siRNA knockdown with motility/invasion assays Journal of cell science High 22976292
2013 TGF-β down-regulates miR-584 in breast cancer cells, relieving repression of PHACTR1 and thereby increasing PHACTR1 expression. Elevated PHACTR1 reorganizes the actin cytoskeleton and is required for TGF-β-induced breast cancer cell migration; overexpression of miR-584 or knockdown of PHACTR1 each blocked this migration. miRNA overexpression, siRNA knockdown, TGF-β stimulation, cell migration assays, phalloidin staining of actin cytoskeleton The Journal of biological chemistry Medium 23479725
2015 Phactr-1 down-expression in endothelial cells activates focal adhesion kinase pathways (FAK/PYK2/Paxillin) and inhibits metabolic stress pathways (AMPK/CREB/eNOS), and induces expression of pro-atherogenic molecules including MMP regulators (TIMP-1/-2, RECK), oxidized LDL receptors (CD36, Clusterin), and inflammatory proteins (Thrombin, PAR-1, ADAM-9/-17). siRNA knockdown of Phactr1 in endothelial cells; antagonist peptide inhibition of VEGF-A165/NRP-1 interaction; Western blot and protein array profiling Biochimie Low 26362351
2015 The CAD-risk SNP rs9349379 in intron 3 of PHACTR1 is an eQTL for PHACTR1 expression in human coronary arteries; alleles at this SNP are differentially bound by the MEF2 transcription factor, and CRISPR/Cas9 deletion of the MEF2-binding site in endothelial cells reduced PHACTR1 expression by ~35%. Genetic fine-mapping, eQTL analysis in human coronary arteries, electrophoretic mobility shift assay with endothelial cell extracts, CRISPR/Cas9 deletion Arteriosclerosis, thrombosis, and vascular biology High 25838425
2016 PHACTR1 is expressed in human atherosclerotic plaque macrophages, foam cells, adventitial lymphocytes, and endothelial cells (but absent from vascular smooth muscle cells). Atherogenic stimuli (oxLDL, TNF-α) regulate PHACTR1 transcription; the CAD risk allele at rs9349379 is associated with reduced PHACTR1 expression in macrophages, paralleling the effect of inflammatory stimulation. Immunohistochemistry, qRT-PCR, immunoblotting, eQTL analysis in primary human macrophages Atherosclerosis Medium 27187934
2017 The CAD/MI risk SNP rs9349379 acts as a distal enhancer of endothelin-1 (EDN1) gene expression ~600 kb upstream. CRISPR-edited stem-cell-derived endothelial cells revealed that rs9349379 regulates EDN1 (not PHACTR1) expression in an aorta-specific enhancer context, providing a mechanistic link between this pleiotropic locus and vascular disease. CRISPR base editing in iPSC-derived endothelial cells, epigenomic chromatin analysis (H3K27ac, DNase I), eQTL mapping in aorta, reporter assays Cell High 28753427
2017 Phactr1 is expressed in mouse brain in a developmental stage-dependent and tissue-dependent manner. In primary hippocampal neurons, Phactr1 is detected in axons, dendrites, and is enriched in synaptosomal and postsynaptic density fractions. In embryonic cortex, Phactr1 accumulates in the nucleus, whereas postnatally it distributes diffusely in the cell body. Western blotting, subcellular fractionation (synaptosomal/PSD), immunohistochemistry in mouse brain, immunofluorescence in cultured hippocampal neurons Neuroscience research Medium 28803787
2017 Phactr1 expression level positively correlates with vascular calcification severity in smooth muscle cells. Stable overexpression of Phactr1 in mESC-derived SMCs enhanced calcium phosphate deposition and osteogenic marker osteopontin expression, while knockdown reduced calcification. Stable lentiviral over- and under-expression of Phactr1 in mouse embryonic stem cell-derived SMCs; osteogenic medium calcification assay; alizarin red staining; RT-PCR for osteopontin Biochemical and biophysical research communications Medium 28720499
2018 De novo missense mutations in PHACTR1 associated with West syndrome (infantile spasms) impair either actin binding (p.Leu500Pro, p.Asn479Ile, p.Ile518Asn) or PP1 binding (p.Arg521Cys) as determined by immunoprecipitation. Acute knockdown of mouse Phactr1 by in utero electroporation caused defects in cortical neuron migration rescued by wild-type but not mutant PHACTR1, and Phactr1-deficient excitatory neurons showed abnormal synaptic electrophysiological properties. Trio whole-exome sequencing, co-immunoprecipitation of mutant PHACTR1 with actin and PP1, in utero electroporation knockdown + rescue in mouse cortex, patch-clamp electrophysiology Brain : a journal of neurology High 30256902
2018 PHACTR1 interacts with MRTF-A and with p65/NF-κB in coronary artery endothelial cells (co-immunoprecipitation). Knockdown of PHACTR1 attenuates nuclear translocation of p65 and NF-κB activity (without affecting IκBα or IKKα/β phosphorylation), reduces ox-LDL-induced ICAM-1, VCAM-1, and VE-cadherin expression, and reduces intracellular ROS. Knockdown of MRTF-A disrupts the PHACTR1–p65 interaction. Co-immunoprecipitation, siRNA knockdown, immunofluorescence for p65 nuclear translocation, flow cytometry for ROS, Western blotting for NF-κB pathway components Atherosclerosis Medium 30293016
2019 Phactr1 physically links Slack (KCNT1) potassium channels to actin via co-immunoprecipitation. Co-expression of Phactr1 reduces Slack current amplitude in a manner dependent on the PP1-binding activity of Phactr1 and a conserved PKC phosphorylation site (S407) on Slack, establishing that Phactr1 regulates Slack channel activity by recruiting PP1 to dephosphorylate the channel. Co-immunoprecipitation, patch-clamp electrophysiology in Xenopus oocytes/HEK cells, Phactr1 PP1-binding mutant FASEB journal High 31914597
2020 Crystal/high-resolution structures of the Phactr1/PP1 holoenzyme bound to dephosphorylated substrates IRSp53 and spectrin αII revealed that Phactr1 remodels PP1's hydrophobic groove to create a composite substrate-recognition surface. Substrate sequences C-terminal to the dephosphorylation site make intimate contacts with this composite surface, conferring sequence specificity and orders-of-magnitude enhanced reactivity toward specific substrates compared to apo-PP1 or other PP1 holoenzymes. Phosphoproteomic identification of Phactr1/PP1 substrates in fibroblasts and neurons included cytoskeletal components and regulators. X-ray crystallography (high-resolution structures of holoenzyme-product complexes), phosphoproteomics in mouse fibroblasts and neurons, in vitro dephosphorylation assays with mutagenesis of substrate contact residues eLife High 32975518
2020 Phactr1 deficiency in macrophages promotes M1 polarization, increased pro-inflammatory cytokine production, and enhanced foam cell formation driven by ox-LDL. Mechanistically, Phactr1 activates CREB signaling by directly binding to CREB and up-regulating phospho-CREB and KLF4 expression; KLF4 overexpression partially rescued the inflammatory and foam cell phenotypes of Phactr1-deficient macrophages. Phactr1-/-/Apoe-/- double-knockout mice, bone marrow transplantation, co-immunoprecipitation of Phactr1 with CREB, Western blot for phospho-CREB, KLF4 overexpression rescue, macrophage polarization assays Clinical science Medium 32857129
2021 PHACTR1 prevents dephosphorylation of myosin light chain (MLC), which is required for actin-mediated apoptotic cell engulfment (efferocytosis) by macrophages. The rs9349379-G/G risk genotype associates with lower PHACTR1 expression in human macrophages and impaired efferocytosis. Hematopoietic Phactr1 deletion in Ldlr-/- mice on a Western diet impaired lesional efferocytosis, increased plaque necrosis, and produced thinner fibrous caps. Human monocyte-derived macrophage efferocytosis assays, Ldlr-/- hematopoietic-specific Phactr1 knockout mouse model, Western diet atherosclerosis model, Western blot for phospho-MLC, plaque histology The Journal of clinical investigation High 33630758
2021 A de novo PHACTR1 missense mutation p.L519R reduces the affinity of PHACTR1 for G-actin and increases its propensity to form complexes with PP1 catalytic subunit (PPP1CA), leading to altered subcellular localization and increased cytoskeletal rearrangements, associated with multifocal epilepsy and infantile spasms. In vitro binding assays, subcellular localization analysis of mutant PHACTR1, functional cytoskeletal assays Clinical genetics Medium 33463715
2021 Phactr1 negatively regulates osteogenesis and promotes adipogenesis of bone marrow mesenchymal stem cells via the RhoA/ROCK2 pathway. Phactr1 and ROCK2 physically interact (co-IP) during osteogenic differentiation, and ROCK2 inhibition (KD025) reproduces the Phactr1-overexpression phenotype of suppressed Runx2 and osteogenesis. Co-immunoprecipitation of Phactr1 and ROCK2, siRNA knockdown and lentiviral overexpression of Phactr1 in BMSCs, osteogenic/adipogenic differentiation assays, alizarin red/Oil red O staining, Western blot for RhoA/ROCK2/Runx2/C-EBPα Journal of molecular histology Medium 34709489
2023 Endothelial PHACTR1 acts as a transcriptional corepressor of PPARγ under disturbed flow conditions. PHACTR1 is enriched in the nucleus of endothelial cells in disturbed-flow regions and shuttles to the cytoplasm under laminar flow. PHACTR1 binds PPARγ through corepressor motifs. Global or EC-specific Phactr1 knockout in ApoE-/- mice significantly reduced atherosclerosis, and PPARγ antagonist GW9662 abolished the protective effect. EC-specific and global Phactr1 knockout in ApoE-/- mice, partial carotid ligation atherosclerosis model, immunostaining for PHACTR1 localization under laminar vs. disturbed flow, RNA-seq of EC-enriched mRNA, PPARγ binding assays (corepressor motif), GW9662 pharmacological rescue Arteriosclerosis, thrombosis, and vascular biology High 37199156
2023 PHACTR1 overexpression promotes invasion, migration, and tumorigenicity of papillary thyroid carcinoma cells by increasing F-actin formation; disruption of F-actin assembly with swinholide A reversed the enhanced migration, placing PHACTR1 function upstream of F-actin polymerization in cancer cell motility. siRNA knockdown and cDNA overexpression in PTC cell lines, Transwell invasion/migration assays, phalloidin-F-actin fluorescence imaging, swinholide A pharmacological rescue Heliyon Medium 37876444
2024 BDNF stimulation of primary cortical neurons causes sustained downregulation of PHACTR1 (and PHACTR2/3 but not PHACTR4) mRNA via the ERK/MAPK pathway; this was blocked by the MEK inhibitor U0126, identifying ERK/MAPK as an upstream regulator of PHACTR1 gene expression in neurons. BDNF stimulation of primary cultured mouse cortical neurons, qRT-PCR for PHACTR family mRNAs, MEK inhibitor U0126 treatment Drug discoveries & therapeutics Low 39183043
2024 AlphaFold-Multimer modeling and analysis of PHACTR1 patient variants indicate that the RPEL3 domain serves as the binding interface for both G-actin and PPP1CA, and these two interactions are competitive. Missense variants in patients with infantile epileptic spasms syndrome map to the RPEL3 domain and impair either G-actin or PPP1CA binding. AlphaFold-Multimer structural prediction, whole-exome sequencing of nine PHACTR1-variant patients, genotype-phenotype correlation Journal of medical genetics Low 38272663
2014 Phactr1 binds directly to MRTF-A, MRTF-B, myocardin, and Phactr1 itself via RPEL-containing nuclear localization sequences, and is a direct target of the Rho-signaling inhibitor CCG-1423 (pull-down with CCG-1423-Sepharose). G-actin binding blocks CCG-1423 interaction with the NLS of RPEL proteins including Phactr1. CCG-1423-Sepharose affinity pull-down assay, competitive G-actin displacement assay PloS one Medium 24558465
2026 Multi-omics profiling (transcriptomics, proteomics, metabolomics, lipidomics) of PHACTR1 overexpression and knockdown in HT1080 cells revealed that PHACTR1 governs cell cycle progression (altering key regulatory proteins), regulates cellular iron-storage proteins (iron metabolism), and localizes to mitochondria where it modulates mitochondrial morphology and bioenergetics through a signaling axis involving AKAP1 and Drp1. Mitochondrial changes correlated with shifts in lipid metabolism. Multi-omics (transcriptomics, proteomics, metabolomics, lipidomics) in PHACTR1 OE/KD HT1080 cells; validation in primary human endothelial cells; mitochondrial localization confirmed; AKAP1/Drp1 interaction identified Communications biology Medium 41554990
2025 The CAD-risk SNP rs6903956 'A' allele enhances HOXA4/MEIS1 transcription factor binding at the locus to drive PHACTR1 transcriptional activation in endothelial cells. iPSC-derived endothelial cells with the 'A' allele show elevated PHACTR1 expression and, under pathological flow, elevated ICAM-1 expression and increased monocyte adhesion compared to the 'G' allele. Single-base editing of iPSC-derived endothelial cells, eQTL analysis, AlphaFold 3 in silico binding modeling, luciferase reporter assays, ICAM-1/monocyte adhesion assays under flow bioRxivpreprint Low 40654905
2024 All four Phactr proteins (Phactr1–4) confer identical sequence specificities on their respective PP1 holoenzymes, as demonstrated by a PP1-PIP fusion approach. This establishes that the composite Phactr/PP1 substrate-recognition surface described for Phactr1 is a conserved property of the Phactr family. PP1-PIP fusion protein approach, substrate phosphoproteomics, in vitro dephosphorylation assays bioRxivpreprint Medium

Source papers

Stage 0 corpus · 87 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature genetics 1493 21378990
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nature genetics 895 19198609
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nature genetics 561 21378988
2010 A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet (London, England) 441 20971364
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2017 A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression. Cell 346 28753427
2013 Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nature genetics 314 23793025
2012 Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations. Stroke 308 23042660
2013 Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. Stroke 269 24262325
2012 Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease. Nature genetics 262 22751097
2012 Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nature genetics 255 22683712
2011 Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction. Circulation 242 22144573
2003 The DNA sequence and analysis of human chromosome 6. Nature 242 14574404
2007 Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC medical genetics 190 17903296
2014 Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection. Nature genetics 167 25420145
2019 Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection. Journal of the American College of Cardiology 155 30621952
2016 PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance. PLoS genetics 139 27792790
2004 Phactrs 1-4: A family of protein phosphatase 1 and actin regulatory proteins. Proceedings of the National Academy of Sciences of the United States of America 136 15107502
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2013 Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction. Atherosclerosis 87 23561647
2014 RPEL proteins are the molecular targets for CCG-1423, an inhibitor of Rho signaling. PloS one 86 24558465
2000 Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 81 11214970
2015 Myocardial Infarction-Associated SNP at 6p24 Interferes With MEF2 Binding and Associates With PHACTR1 Expression Levels in Human Coronary Arteries. Arteriosclerosis, thrombosis, and vascular biology 75 25838425
2013 Genetics of coronary artery calcification among African Americans, a meta-analysis. BMC medical genetics 68 23870195
2011 Genetic susceptibility to coronary heart disease in type 2 diabetes: 3 independent studies. Journal of the American College of Cardiology 67 22152955
2011 Neuropilin-1 regulates a new VEGF-induced gene, Phactr-1, which controls tubulogenesis and modulates lamellipodial dynamics in human endothelial cells. Cellular signalling 66 21939755
2013 MicroRNA-584 and the protein phosphatase and actin regulator 1 (PHACTR1), a new signaling route through which transforming growth factor-β Mediates the migration and actin dynamics of breast cancer cells. The Journal of biological chemistry 64 23479725
2012 G-actin regulates the shuttling and PP1 binding of the RPEL protein Phactr1 to control actomyosin assembly. Journal of cell science 55 22976292
2011 Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis. Biochimie 55 21798305
2012 Genome-wide association study in a Lebanese cohort confirms PHACTR1 as a major determinant of coronary artery stenosis. PloS one 47 22745674
2021 Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis. The Journal of clinical investigation 44 33630758
2016 Genetic and environmental risk factors for atherosclerosis regulate transcription of phosphatase and actin regulating gene PHACTR1. Atherosclerosis 37 27187934
2015 Disruption of phactr-1 pathway triggers pro-inflammatory and pro-atherogenic factors: New insights in atherosclerosis development. Biochimie 35 26362351
2018 De novo PHACTR1 mutations in West syndrome and their pathophysiological effects. Brain : a journal of neurology 34 30256902
2017 Coronary artery disease associated gene Phactr1 modulates severity of vascular calcification in vitro. Biochemical and biophysical research communications 34 28720499
2020 Molecular basis for substrate specificity of the Phactr1/PP1 phosphatase holoenzyme. eLife 28 32975518
2018 PHACTR1 regulates oxidative stress and inflammation to coronary artery endothelial cells via interaction with NF-κB/p65. Atherosclerosis 23 30293016
2018 PHACTR1 splicing isoforms and eQTLs in atherosclerosis-relevant human cells. BMC medical genetics 18 29884117
2020 Genetic deficiency of Phactr1 promotes atherosclerosis development via facilitating M1 macrophage polarization and foam cell formation. Clinical science (London, England : 1979) 17 32857129
2019 Phosphatase Actin Regulator-1 (PHACTR-1) Knockdown Suppresses Cell Proliferation and Migration and Promotes Cell Apoptosis in the bEnd.3 Mouse Brain Capillary Endothelial Cell Line. Medical science monitor : international medical journal of experimental and clinical research 16 30772888
2016 PHACTR1 Gene Polymorphism Is Associated with Increased Risk of Developing Premature Coronary Artery Disease in Mexican Population. International journal of environmental research and public health 15 27517945
2015 The rs12526453 Polymorphism in an Intron of the PHACTR1 Gene and Its Association with 5-Year Mortality of Patients with Myocardial Infarction. PloS one 15 26086777
2023 Endothelial PHACTR1 Promotes Endothelial Activation and Atherosclerosis by Repressing PPARγ Activity Under Disturbed Flow in Mice. Arteriosclerosis, thrombosis, and vascular biology 14 37199156
2022 PHACTR-1 (Phosphatase and Actin Regulator 1) Deficiency in Either Endothelial or Smooth Muscle Cells Does Not Predispose Mice to Nonatherosclerotic Arteriopathies in 3 Transgenic Mice. Arteriosclerosis, thrombosis, and vascular biology 14 35387477
2019 Phactr1 regulates Slack (KCNT1) channels via protein phosphatase 1 (PP1). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 31914597
2022 PHACTR1, a coronary artery disease risk gene, mediates endothelial dysfunction. Frontiers in immunology 13 36091033
2019 PHACTR1 gene polymorphism with the risk of coronary artery disease in Chinese Han population. Postgraduate medical journal 13 30777881
2018 Expression and purification of human phosphatase and actin regulator 1 (PHACTR1) in plant-based systems. Protein expression and purification 13 29894805
2017 Expression analyses of Phactr1 (phosphatase and actin regulator 1) during mouse brain development. Neuroscience research 13 28803787
2017 PHACTR1 and SLC22A3 gene polymorphisms are associated with reduced coronary artery disease risk in the male Chinese Han population. Oncotarget 12 27893421
2023 PHACTR1 modulates vascular compliance but not endothelial function: a translational study. Cardiovascular research 10 35653516
2021 A Study of Associations Between rs9349379 (PHACTR1), rs2891168 (CDKN2B-AS), rs11838776 (COL4A2) and rs4880 (SOD2) Polymorphic Variants and Coronary Artery Disease in Iranian Population. Biochemical genetics 9 34109516
2016 Possible role of intronic polymorphisms in the PHACTR1 gene on the development of cardiovascular disease. Medical hypotheses 9 27876132
2021 Mutation in PHACTR1 associated with multifocal epilepsy with infantile spasms and hypsarrhythmia. Clinical genetics 8 33463715
2020 PHACTR1 is associated with disease progression in Chinese Moyamoya disease. PeerJ 7 32411507
2022 PECAM1, COL4A2, PHACTR1, and LMOD1 Gene Polymorphisms in Patients with Unstable Angina. Journal of clinical medicine 6 35054067
2018 PHACTR1 genotype predicts coronary artery disease in patients with familial hypercholesterolemia. Journal of clinical lipidology 6 29784573
2023 Genetic Variants in PHACTR1 & LPL Mediate Restenosis Risk in Coronary Artery Patients. Vascular health and risk management 5 36814994
2020 Associations between PHACTR1 gene polymorphisms and pulse pressure in Chinese Han population. Bioscience reports 5 32420588
2024 Genotype and phenotype correlation of PHACTR1-related neurological disorders. Journal of medical genetics 4 38272663
2021 The association of polymorphism in PHACTR1 rs9349379 and rs12526453 with coronary artery atherosclerosis or coronary artery calcification. A systematic review. Coronary artery disease 3 33660664
2021 PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice. Scientific reports 3 33727568
2021 Phactr1 negatively regulates bone mass by inhibiting osteogenesis and promoting adipogenesis of BMSCs via RhoA/ROCK2. Journal of molecular histology 3 34709489
2020 Differential expression of PHACTR1 in atheromatous versus normal carotid artery tissue. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 3 31980275
2024 Circular RNA hsa_circ_0002268 (PHACTR1) Is Specific to Gestational Diabetes Mellitus in a Polish Pregnant Population. International journal of molecular sciences 2 39000149
2024 PHACTR1 and APOC1 genetic variants are associated with multi-vessel coronary artery disease. Lipids in health and disease 2 39395990
2023 PHACTR1 promotes the mobility of papillary thyroid carcinoma cells by inducing F-actin formation. Heliyon 2 37876444
2023 Mechanism of PWAR6 regulating cisplatin drug sensitivity in non-small cell lung cancer through miR-577/PHACTR1. Gene 2 37923092
2022 Genome-Wide Transcriptional Profiling Reveals PHACTR1 as a Novel Molecular Target of Resveratrol in Endothelial Homeostasis. Nutrients 2 36364780
2019 PHACTR1 haplotypes are associated with carotid plaque presence and affect PHACTR1 mRNA expression in carotid plaque tissue. Gene 2 31200082
2024 The BDNF-ERK/MAPK axis reduces phosphatase and actin regulator1, 2 and 3 (PHACTR1, 2 and 3) mRNA expressions in cortical neurons. Drug discoveries & therapeutics 1 39183043
2022 Epileptic Encephalopathy with Variants in the PHACTR1 and AFF2 Genes: A Case Report. Cytogenetic and genome research 1 36535243
2021 Association of PHACTR1 intronic variants with the first myocardial infarction and their effect on PHACTR1 mRNA expression in PBMCs. Gene 1 33460763
2026 Multi-omic analysis of human PHACTR1 signaling networks. Communications biology 0 41554990
2025 Coronary Artery Disease Risk Variant rs6903956 Links to Endothelial Dysfunction via PHACTR1 Regulation. bioRxiv : the preprint server for biology 0 40654905
2025 Genetic Basis of Hypsarrhythmia: Expanding the PHACTR1 Spectrum and Pathway to Targeted Therapy. Clinical genetics 0 41054829
2024 Association of PHACTR1 with Coronary Artery Calcium Differs by Sex and Cigarette Smoking. Journal of cardiovascular development and disease 0 39057616
2024 Correction: Dłuski et al. Circular RNA hsa_circ_0002268 (PHACTR1) Is Specific to Gestational Diabetes Mellitus in a Polish Pregnant Population. Int. J. Mol. Sci. 2024, 25, 7040. International journal of molecular sciences 0 39769512
2022 Associations of RPEL1 and miR-1307 gene polymorphisms with disease susceptibility, glucocorticoid efficacy, anxiety, depression, and health-related quality of life in Chinese systemic lupus erythematosus patients. Lupus 0 36194484