Affinage

ARPC2

Actin-related protein 2/3 complex subunit 2 · UniProt O15144

Length
300 aa
Mass
34.3 kDa
Annotated
2026-06-09
20 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARPC2 (p34-Arc) is a structurally essential subunit of the Arp2/3 complex that drives branched actin nucleation and the actin-dependent processes of endocytosis and cell migration (PMID:18381280). Mutagenesis in yeast resolved three distinct functional surfaces on ARPC2: one face and a second site near the ARPC2-ARPC4 contact are both required for actin nucleation and endocytosis, while a third conserved distal surface is required for endocytosis but not nucleation, and purified mutant complexes confirmed loss of actin assembly activity (PMID:18381280). Within the assembled complex ARPC2 is a druggable target: the small molecules benproperine (its active S-stereoisomer engaging residue F225) and pimozide bind directly to defined ARPC2 pockets, increase the lag phase of Arp2/3-dependent actin polymerization, disrupt lamellipodia, and suppress cancer cell migration and metastasis (PMID:30710516, PMID:31571309, PMID:36558913). Pimozide binding additionally blocks vinculin-mediated recruitment of ARPC2 to focal adhesions (PMID:31571309). ARPC2 abundance is controlled at multiple post-transcriptional and transcriptional levels — through an IRES/G-quadruplex element in the longer 5'-UTR splice variant that supports cap-independent translation (PMID:31387452), by RBM3 acting on the 3'-UTR (PMID:30720048), by Nox1/p38 MAPK signaling that upregulates ARPC2 to drive smooth muscle cell migration (PMID:24152438), and by FOXF1-mediated transcriptional repression in fibroblasts (PMID:25260753). Beyond its canonical complex role, ARPC2 regulates TGF-β1-induced nuclear translocation of MRTFA and modulates MRTFA/G-actin complex formation to promote fibrotic gene expression independently of other Arp2/3 subunits (PMID:41898590).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2008 High

    Established whether ARPC2 is a passive scaffold or an active contributor to Arp2/3 nucleation by resolving which of its surfaces are functionally required.

    Evidence Site-directed mutagenesis of conserved residues in yeast with purified mutant complex in vitro actin assays and endocytosis phenotyping

    PMID:18381280

    Open questions at the time
    • Surface assignments derived in yeast; human residue-level function not directly mapped here
    • Does not address how ARPC2 contacts the mother filament structurally
    • No connection to upstream regulatory inputs
  2. 2013 Medium

    Connected ARPC2 expression to a defined signaling axis, showing it is a regulated effector rather than a constitutively constant subunit.

    Evidence Proteomics plus siRNA knockdown of Nox1/ARPC2 and p38 inhibition in vascular smooth muscle cell migration assays

    PMID:24152438

    Open questions at the time
    • Mechanism by which p38 MAPK raises ARPC2 protein is not resolved
    • Single cell type (VSMC)
    • No direct link to transcription versus translation control
  3. 2014 Medium

    Identified a transcriptional repressor of ARPC2 and linked ARPC2 to fibroblast proliferation and collagen output.

    Evidence siRNA knockdown of FOXF1 and ARPC2 with growth and COL1 readouts and epistasis in lung fibroblasts

    PMID:25260753

    Open questions at the time
    • Direct FOXF1 binding to the ARPC2 promoter not demonstrated
    • Mechanism of blunted repression in IPF fibroblasts unclear
  4. 2015 Medium

    Tested whether ARPC2 binding is restricted to actin, finding a microtubule-binding capacity in the plant ortholog.

    Evidence In vitro co-sedimentation of truncated NtARPC2 with microtubules and live-cell GFP imaging in tobacco/Arabidopsis

    PMID:26706062

    Open questions at the time
    • Plant ortholog; relevance to mammalian ARPC2 untested
    • Functional consequence of MT binding not established
  5. 2019 Medium

    Defined how ARPC2 protein levels are tuned post-transcriptionally, identifying both a 5'-UTR IRES/G-quadruplex and a 3'-UTR-dependent RBM3 input.

    Evidence Bicistronic reporters with G-quadruplex structural probing; separately siRNA/3'-UTR binding and epistasis in breast cancer cells

    PMID:30720048 PMID:31387452

    Open questions at the time
    • Physiological trigger for IRES switching beyond cell density not defined
    • Direct RBM3-3'UTR interaction described at abstract level
    • Relationship between the two regulatory layers untested
  6. 2019 High

    Validated ARPC2 as a directly druggable subunit by identifying small molecules that bind it and inhibit Arp2/3 actin polymerization and migration.

    Evidence Affinity pulldown, DARTS, CETSA, SPR, CRISPR point mutants (F225, F247, Y250) plus actin assays and knockdown across benproperine and pimozide studies

    PMID:30710516 PMID:31571309 PMID:36558913

    Open questions at the time
    • Co-crystal structure of compound-bound ARPC2 not reported
    • Selectivity against other actin regulators not fully characterized
  7. 2024 Medium

    Probed the necessity of ARPC2/Arp2/3 in actin pedestal formation, showing Palladin can functionally substitute during EPEC infection.

    Evidence ArpC2-knockout cells rescued by Palladin overexpression with domain-mutant controls and pedestal length quantification

    PMID:39692253

    Open questions at the time
    • Whether substitution generalizes beyond EPEC pedestals unknown
    • Does not address endogenous redundancy in normal cells
  8. 2026 Medium

    Revealed an Arp2/3-independent role for ARPC2 in transcriptional control of fibrosis via MRTFA.

    Evidence ARPC2 overexpression/knockdown with MRTFA nuclear localization imaging, MRTFA/G-actin complex assay, and transcriptomics of ARPC2/ACTR2/MRTFA-depleted cells

    PMID:41898590

    Open questions at the time
    • Molecular basis of ARPC2 acting separately from other subunits unresolved
    • Single lab, recent and unreplicated
    • Direct ARPC2-MRTFA or ARPC2-G-actin interaction not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ARPC2 mechanistically uncouples from the Arp2/3 complex to perform its MRTFA-regulatory and microtubule-associated roles, and whether these are conserved in mammals, remains unresolved.
  • No structural or biochemical model for Arp2/3-independent ARPC2 function
  • Mammalian relevance of MT binding untested
  • Integration of multiple regulatory inputs on ARPC2 abundance not assembled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0005198 structural molecule activity 1
Localization
GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 2
Partners
ARPC4MRTFARBM3VINCULIN
Complex memberships
Arp2/3 complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Mutagenesis of the p35/ARPC2 subunit in S. cerevisiae identified three distinct functional surfaces: one face required for actin nucleation and endocytosis, a second site near the ARPC2-ARPC4 contact required for nucleation and endocytosis, and a third distal conserved surface required for endocytosis but not nucleation. Purified mutant Arp2/3 complexes confirmed loss of actin assembly activity, establishing ARPC2 as a structurally critical subunit for Arp2/3-mediated actin nucleation. Site-directed mutagenesis of conserved solvent-exposed residues, in vitro actin assembly assays with purified mutant Arp2/3 complexes, yeast cell growth and endocytosis phenotype analysis The Journal of biological chemistry High 18381280
2019 Benproperine (Benp) directly binds ARPC2 (identified by affinity column chromatography with Benp-tagged Sepharose beads, validated by pulldown with Benp-biotin, DARTS, and CETSA), inhibits Arp2/3 complex-dependent actin polymerization, disrupts lamellipodial structure, and suppresses cancer cell migration and metastasis. ARPC2 knockdown phenocopied Benp treatment, confirming ARPC2 as the functional target. Affinity column chromatography, pulldown with Benp-biotin, DARTS, CETSA, actin polymerization assay, siRNA knockdown, in vivo metastasis model Biochemical pharmacology High 30710516
2019 Pimozide directly binds ARPC2 (confirmed by DARTS and CETSA), increases the lag phase of Arp2/3 complex-dependent actin polymerization, and inhibits vinculin-mediated recruitment of ARPC2 to focal adhesions. ARPC2 point mutants (F225A, F247A, Y250F) generated by CRISPR/Cas9 revealed a binding pocket on ARPC2 required for pimozide interaction. DARTS, CETSA, actin polymerization assay, CRISPR/Cas9 point-mutant cell lines, focal adhesion immunofluorescence Cancer science High 31571309
2022 S-Benproperine, the active stereoisomer of benproperine, directly binds ARPC2 at residue F225 (ARPC2-F225A mutant abolishes binding by CETSA and DARTS), co-localizes with ARPC2 in cancer cells and tumor tissues, and suppresses actin remodeling including lamellipodium formation. Surface plasmon resonance (SPR), CETSA, DARTS, CRISPR/Cas9 ARPC2-F225A mutant cells, Cy3-conjugated S-Benp co-localization, actin polymerization assay Pharmaceuticals (Basel, Switzerland) High 36558913
2013 NADPH oxidase 1 (Nox1) mediates H2O2-induced upregulation of ARPC2 protein expression in vascular smooth muscle cells (VSMCs) via a p38 MAPK-dependent pathway, and ARPC2 is required downstream of Nox1 for H2O2-stimulated VSMC migration. 2D-DIGE/mass spectrometry proteomics, Western blot, siRNA knockdown of Nox1 and ARPC2, p38 MAPK inhibitor (SB203580), wound-healing scratch assay International journal of molecular sciences Medium 24152438
2019 The longer 5'-UTR splice variant of ARPC2 mRNA harbors an internal ribosome entry site (IRES) containing a guanine-quadruplex (G-quadruplex) motif that promotes cap-independent translation; the shorter variant lacks this activity. At high cell density, relative ARPC2 protein levels increase, consistent with IRES-driven expression under conditions that compromise cap-dependent translation. Bicistronic reporter construct, multiple IRES control assays, chemical probing of RNA structure, G-quadruplex structural analysis, cell density-dependent protein level measurement RNA biology Medium 31387452
2015 Plant ARPC2 protein (a core Arp2/3 complex subunit) directly interacts with microtubules in addition to actin filaments; a putative MT-binding domain was identified by in vitro co-sedimentation of truncated NtARPC2 proteins with microtubules. GFP-ARPC2 decorated microtubules in tobacco BY-2 cells and Arabidopsis root epidermal cells. In vitro co-sedimentation assay with truncated ARPC2 proteins, pharmacological interference with actin/MT dynamics, live-cell GFP imaging Plant science : an international journal of experimental plant biology Medium 26706062
2019 RBM3 upregulates ARPC2 protein expression through a post-transcriptional mechanism involving binding to the 3'-UTR of ARPC2 mRNA, and ARPC2 mediates the pro-proliferative and pro-metastatic effects of RBM3 in breast cancer cells. siRNA knockdown of RBM3 and ARPC2, 3'-UTR binding assay, cell proliferation and migration assays, epistasis (ARPC2 knockdown rescues RBM3 overexpression phenotype) International journal of oncology Medium 30720048
2014 FOXF1 transcriptionally represses ARPC2 expression in normal lung fibroblasts; ARPC2 knockdown inhibits cell growth and COL1 expression, placing ARPC2 downstream of FOXF1 in the regulation of fibroblast proliferation and collagen production. In IPF fibroblasts, FOXF1-mediated repression of ARPC2 is blunted. siRNA knockdown (FOXF1 and ARPC2), gain-of-function/loss-of-function models, cell growth assay, COL1 expression measurement, epistasis analysis American journal of physiology. Lung cellular and molecular physiology Medium 25260753
2026 ARPC2 regulates TGF-β1-induced nuclear translocation of myocardin-related transcription factor-A (MRTFA) and modulates MRTFA/G-actin complex formation in lung fibroblasts, promoting fibrotic gene expression (including ACTA2) at the transcriptional level independently of other ARP2/3 complex components. Transcriptomic analysis showed ARPC2 and MRTFA co-regulate a specific repertoire of fibrotic genes. ARPC2 modulation (overexpression/knockdown), MRTFA nuclear localization imaging, MRTFA/G-actin complex assay, transcriptomic analysis of ARPC2/ACTR2/MRTFA-depleted cells International journal of molecular sciences Medium 41898590
2023 Inhibition of ARPC2 with benproperine (BPP) disrupts intestinal stem cell (ISC) homeostasis: at lower doses it promotes and at higher doses it inhibits intestinal organoid growth and crypt cell proliferation; it decreases Lgr5 ISC feature gene expression and reduces Paneth cell differentiation. Mechanistically, ARPC2 inhibition activates the YAP1 (Yes1-associated transcriptional regulator) pathway, linking actin polymerization to ISC regulation. Organoid culture, BrdU/EdU incorporation, flow cytometry, IHC, phalloidin staining for F-actin, in vivo mouse experiments with BPP Burns & trauma Medium 37849945
2025 KLF7-IT1 (a lncRNA) stabilizes ARPC2 protein in macrophages, thereby facilitating intracellular LPS internalization and downstream caspase-4 activation; ARPC2 silencing attenuates caspase-4 activation, gasdermin-D-mediated pyroptosis, phosphatidylserine exposure, and tissue factor activity, placing ARPC2 as a cytoskeletal mediator connecting LPS sensing to pyroptosis and hypercoagulation in sepsis. siRNA knockdown of ARPC2, caspase-4 activity assay, gasdermin-D cleavage measurement, phosphatidylserine exposure assay, tissue factor activity assay, LPS internalization imaging Biochemical and biophysical research communications Low 41275797
2024 Overexpression of Palladin in ArpC2-knockout cells rescues EPEC pedestal length, demonstrating that Palladin can substitute for Arp2/3 complex function in actin pedestal elongation during EPEC infection. ArpC2-/- cell lines, Palladin overexpression rescue experiment, EPEC pedestal length quantification, Palladin actin-binding domain and VASP-binding domain mutants Cytoskeleton (Hoboken, N.J.) Medium 39692253

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nature genetics 485 18836448
2019 Benproperine, an ARPC2 inhibitor, suppresses cancer cell migration and tumor metastasis. Biochemical pharmacology 43 30710516
2019 Pimozide suppresses cancer cell migration and tumor metastasis through binding to ARPC2, a subunit of the Arp2/3 complex. Cancer science 38 31571309
2019 ARPC2 promotes breast cancer proliferation and metastasis. Oncology reports 29 31002363
2014 Forkhead Box F1 represses cell growth and inhibits COL1 and ARPC2 expression in lung fibroblasts in vitro. American journal of physiology. Lung cellular and molecular physiology 29 25260753
2015 Arp2/3 complex subunit ARPC2 binds to microtubules. Plant science : an international journal of experimental plant biology 26 26706062
2008 Functional surfaces on the p35/ARPC2 subunit of Arp2/3 complex required for cell growth, actin nucleation, and endocytosis. The Journal of biological chemistry 25 18381280
2017 Role of ARPC2 in Human Gastric Cancer. Mediators of inflammation 23 28694563
2019 RBM3 upregulates ARPC2 by binding the 3'UTR and contributes to breast cancer progression. International journal of oncology 22 30720048
2019 Alternatively spliced variants of the 5'-UTR of the ARPC2 mRNA regulate translation by an internal ribosome entry site (IRES) harboring a guanine-quadruplex motif. RNA biology 15 31387452
2013 Proteomic analysis identifies an NADPH oxidase 1 (Nox1)-mediated role for actin-related protein 2/3 complex subunit 2 (ARPC2) in promoting smooth muscle cell migration. International journal of molecular sciences 15 24152438
2023 Intelectin enhances the phagocytosis of macrophages via CDC42-WASF2-ARPC2 signaling axis in Megalobrama amblycephala. International journal of biological macromolecules 10 36907302
2023 Actin polymerization inhibition by targeting ARPC2 affects intestinal stem cell homeostasis. Burns & trauma 6 37849945
2022 Gibberellic acid sensitive dwarf encodes an ARPC2 subunit that mediates gibberellic acid biosynthesis, effects to grain yield in rice. Frontiers in plant science 6 36618614
2022 S-Benproperine, an Active Stereoisomer of Benproperine, Suppresses Cancer Migration and Tumor Metastasis by Targeting ARPC2. Pharmaceuticals (Basel, Switzerland) 3 36558913
2024 Arpc2 integrates ecdysone and juvenile hormone metabolism to influence metamorphosis and reproduction in Tribolium castaneum. Pest management science 2 38477435
2024 Overexpressed Palladin Rescues Enteropathogenic E. coli (EPEC) Pedestal Lengths in ArpC2 Depleted Cells. Cytoskeleton (Hoboken, N.J.) 2 39692253
2025 KLF7-IT1-ARPC2 axis in macrophages orchestrates caspase-4-driven hypercoagulation in sepsis. Biochemical and biophysical research communications 1 41275797
2026 ARPC2 Promotes Pulmonary Fibrosis by Regulating MRTFA Activity Independent of the Canonical ARP2/3 Complex. International journal of molecular sciences 0 41898590
2004 [Construction and expression of the fusion vector of His-tagged human ARPC2 gene]. Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA 0 15201074

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