Affinage

ARPC5L

Actin-related protein 2/3 complex subunit 5-like protein · UniProt Q9BPX5

Length
153 aa
Mass
16.9 kDa
Annotated
2026-06-09
11 papers in source corpus 10 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARPC5L is an alternative isoform subunit of the Arp2/3 actin-nucleating complex whose incorporation confers branch-specific properties distinct from its paralog ARPC5, allowing the same machinery to drive different actin-dependent processes depending on stimulus and context (PMID:36662867). At the structural level, ARPC5L versus ARPC5 incorporation defines the stability of ARPC1 within branch junctions and tunes actin network ultrastructure and protrusion characteristics, and the two isoforms differentially position Ena/VASP family elongators to produce isoform-specific effects on migration (PMID:36662867). ARPC5L confers stimulus selectivity in the nucleus: in CD4 T cells it drives TCR-induced nuclear actin polymerization downstream of nuclear calcium-calmodulin and N-WASP signaling, whereas replication-stress-induced nuclear actin requires ARPC5 instead (PMID:37162507). ARPC5L also acts as a force-dependent partner of the focal-adhesion protein talin 1, binding a cryptic mechanosensitive site exposed between talin rod helix bundles R1 and R2 under tension to mediate ECM stiffness sensing and substrate-dependent cell spreading (PMID:39167642, PMID:38328095, PMID:39344156, PMID:38895381). Functionally, ARPC5L-containing Arp2/3 complex is required for the enhanced single-cell migration persistence driven by combined PI3K activation and KMT2D loss in mammary epithelial cells (PMID:38786098), while it is dispensable for macrophage phagocytosis and host-microbiota homeostasis, a role specific to ARPC5 [PMID:bio_10.1101_2024.07.18.604111].

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2023 High

    Established that ARPC5L and ARPC5 are not redundant Arp2/3 subunits but partition actin-dependent functions by stimulus and subcellular compartment.

    Evidence Isoform-specific knockdown/knockout with live-cell imaging of nuclear and cytoplasmic actin and calcium-calmodulin/N-WASP epistasis in CD4 T cells

    PMID:37162507

    Open questions at the time
    • Molecular basis for why ARPC5L versus ARPC5 is recruited to specific stimuli is unresolved
    • How nuclear N-WASP selectively activates ARPC5L-containing complexes is not defined
  2. 2023 High

    Resolved how isoform identity changes the Arp2/3 complex physically, linking ARPC5L incorporation to branch-junction stability, network ultrastructure, and Ena/VASP positioning.

    Evidence Isoform-specific knockouts combined with cryo-electron tomography of branch junctions and FRAP protein-dynamics measurements

    PMID:36662867

    Open questions at the time
    • Structural determinants within ARPC5L responsible for differential ARPC1 stabilization not pinpointed
    • Mechanism coupling branch-junction stability to Ena/VASP recruitment unknown
  3. 2024 High

    Identified ARPC5L as a force-gated binding partner of talin 1, connecting the Arp2/3 subunit directly to mechanosensing at adhesions.

    Evidence Site-directed mutagenesis of the talin R1-R2 cryptic site, pull-down assays, cellular spreading/traction rescue on compliant substrates, and an aortic-mechanics mouse model

    PMID:38328095 PMID:39167642

    Open questions at the time
    • Whether talin binds intact Arp2/3 complex or free ARPC5L is not established
    • Functional consequence of talin-ARPC5L binding for actin nucleation itself is undefined
  4. 2024 Medium

    Demonstrated directly that the talin-ARPC5L interaction is tension-dependent, confirming force as the trigger for cryptic-site exposure.

    Evidence DNA-based molecular clamp applying defined tension to a talin fragment, with pull-down assays and negative-stain EM

    PMID:38895381 PMID:39344156

    Open questions at the time
    • Single-lab in vitro reconstitution; physiological force thresholds in cells not measured
    • Binding affinity and stoichiometry not quantified
  5. 2024 Medium

    Placed ARPC5L downstream of oncogenic PI3K/KMT2D signaling as an effector of migration persistence in epithelial cells.

    Evidence Genetic reconstitution of PI3K H1047R plus KMT2D knockout in MCF10A, ARPC5L siRNA depletion, single-cell migration assays

    PMID:38786098

    Open questions at the time
    • Transcriptional route from KMT2D loss to ARPC5L induction not mapped
    • Single method per epistasis step
  6. 2024 Medium

    Defined the boundary of ARPC5L function by showing it is dispensable for phagocyte function, sharpening the division of labor with ARPC5 in vivo.

    Evidence Conditional hematopoietic Arpc5 and Arpc5l knockout mice with intestinal inflammation phenotyping and macrophage phagocytosis/killing assays (preprint)

    PMID:bio_10.1101_2024.07.18.604111

    Open questions at the time
    • Preprint, single lab, not yet peer-reviewed
    • Does not test ARPC5L roles in other immune lineages

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the cell selects ARPC5L- versus ARPC5-containing Arp2/3 complexes at specific stimuli, locations, and force regimes remains the central open question.
  • No mechanism for isoform-selective assembly or recruitment
  • Functional significance of reported PKD2 association and Src-dependent phosphorylation not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0140299 molecular sensor activity 2 GO:0005198 structural molecule activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
GO:0005856 cytoskeleton 1
Partners
ARPC1PKD2TLN1WASL
Complex memberships
Arp2/3 complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 ARPC5L specifically drives nuclear actin polymerization upon TCR activation in CD4 T cells, while ARPC5 is required for cytoplasmic actin dynamics. TCR-induced nuclear actin polymerization requires nuclear calcium-calmodulin signaling and N-WASP upstream of ARPC5L. In contrast, DNA replication stress-induced nuclear actin polymerization specifically requires ARPC5 but not ARPC5L. Reverse genetics (isoform-specific knockdown/knockout), live-cell imaging of nuclear and cytoplasmic actin polymerization in CD4 T cells, stimulus-specific perturbation experiments eLife High 37162507
2023 ArpC5L and ArpC5 differentially regulate Arp2/3 complex-dependent cell migration by defining structural stability of ArpC1 in branch junctions, determining protrusion characteristics, and affecting actin network ultrastructure. ArpC5 isoforms also differentially position Ena/VASP family actin elongators, which mediate isoform-specific effects on actin assembly, placing ArpC5/ArpC5L and Ena/VASP in a shared signaling pathway enhancing cell migration. Reverse genetics (isoform-specific knockouts), cellular structural biology (cryo-electron tomography of branch junctions), FRAP/protein dynamics measurements, fluorescence microscopy of actin network ultrastructure Science advances High 36662867
2024 Mutation of a mechanosensitive site between talin 1 rod-domain helix bundles R1 and R2 promotes binding of the Arp2/3 complex subunit ARPC5L to a cryptic site in talin, and this interaction mediates altered ECM stiffness sensing in cells. Cells bearing these talin mutations spread and exert tension on compliant substrates in an ARPC5L-dependent manner. Site-directed mutagenesis of talin 1, pull-down assays, cellular phenotype rescue experiments on compliant substrates, mouse genetic model (ascending aorta mechanics) Science advances High 38328095 39167642
2024 Tension applied to the talin rod domain via a DNA-based molecular clamp induces binding of ARPC5L to a cryptic site within the talin structure, as shown by pull-down assays, demonstrating that ARPC5L binding to talin is force-dependent. DNA-based molecular clamp device applying defined tension to talin fragment, pull-down assays, negative-stain electron microscopy ACS nano Medium 38895381 39344156
2024 In mammary epithelial cells (MCF10A), combined PI 3-kinase activation (H1047R) and KMT2D inactivation induces ARPC5L gene expression, and ARPC5L depletion fully abolishes the enhanced single-cell migration persistence exhibited by these double-mutant cells, placing ARPC5L-containing Arp2/3 complex downstream of these oncogenic signals in mediating migration. Genetic reconstitution (PI3K mutation + KMT2D knockout), ARPC5L siRNA depletion, single-cell migration assays Cells Medium 38786098
2024 Loss of Arpc5l (but not Arpc5) in the murine hematopoietic system does NOT cause intestinal inflammation or impair macrophage phagocytosis and bacterial killing, establishing that Arpc5l-containing Arp2/3 complexes are dispensable for mononuclear phagocyte function and host-microbiota homeostasis, in contrast to Arpc5. Conditional hematopoietic knockout mouse models for Arpc5 and Arpc5l, intestinal inflammation phenotyping, macrophage phagocytosis and bacterial killing assays bioRxivpreprint Medium bio_10.1101_2024.07.18.604111
2016 ARPC5L was identified as a component of PKD2 protein complexes in cytosolic and Golgi-enriched fractions, alongside the canonical Arp2/3 complex subunits, suggesting ARPC5L-containing Arp2/3 complexes interact with PKD2. Affinity enrichment combined with chemical cross-linking/mass spectrometry from cytosolic and Golgi subcellular fractions Journal of proteome research Low 27559607
2014 ARPC5L was found to be dephosphorylated in osteosarcoma SaOS-2 cells treated with the Src inhibitor SI-83, concomitant with impaired cell migration and adhesion, suggesting that phosphorylation of ARPC5L may contribute to Src-driven cytoskeletal dynamics and metastatic behavior. Gel-based phosphoproteomics of SI-83-treated osteosarcoma cells, cell migration and adhesion assays Molecular bioSystems Low 24615350

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 'Conceptualizing' the Endometrium: Identification of Conceptus-Derived Proteins During Early Pregnancy in Cattle. Biology of reproduction 82 25947061
2014 Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency. EMBO molecular medicine 78 24480542
2023 ArpC5 isoforms regulate Arp2/3 complex-dependent protrusion through differential Ena/VASP positioning. Science advances 22 36662867
2023 ARPC5 isoforms and their regulation by calcium-calmodulin-N-WASP drive distinct Arp2/3-dependent actin remodeling events in CD4 T cells. eLife 19 37162507
2014 Proteomics and phosphoproteomics provide insights into the mechanism of action of a novel pyrazolo[3,4-d]pyrimidine Src inhibitor in human osteosarcoma. Molecular bioSystems 18 24615350
2024 Cellular stiffness sensing through talin 1 in tissue mechanical homeostasis. Science advances 12 39167642
2016 Protein Interaction Network of Human Protein Kinase D2 Revealed by Chemical Cross-Linking/Mass Spectrometry. Journal of proteome research 11 27559607
2024 DNA-Based Molecular Clamp for Probing Protein Interactions and Structure under Force. ACS nano 7 39344156
2024 Mechanosensing through talin 1 contributes to tissue mechanical homeostasis. bioRxiv : the preprint server for biology 2 38328095
2024 A DNA-based molecular clamp for probing protein interactions and structure under force. bioRxiv : the preprint server for biology 2 38895381
2024 PI 3-Kinase and the Histone Methyl-Transferase KMT2D Collaborate to Induce Arp2/3-Dependent Migration of Mammary Epithelial Cells. Cells 0 38786098

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