Affinage

ARPC5

Actin-related protein 2/3 complex subunit 5 · UniProt O15511

Length
151 aa
Mass
16.3 kDa
Annotated
2026-06-09
17 papers in source corpus 14 papers cited in narrative 14 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

ARPC5 (p16-Arc) is the smallest subunit of the Arp2/3 actin-nucleation complex, and within that complex its N-terminal tail functions as an autoinhibitory element whose release upon nucleation-promoting-factor binding to Arp2 is allosterically coupled to complex activation, with closure of the Arp2 ATP-binding cleft and rotation toward the active conformation (PMID:40042350). Mammalian cells contain two compositionally distinct Arp2/3 complexes built around the ARPC5 and ARPC5L isoforms, both incorporated into native complexes purified from neutrophils (PMID:12451597), and these isoforms carry out divergent cellular functions: ARPC5-containing complexes stabilize ArpC1 at actin branch junctions, position Ena/VASP proteins at the leading edge, and shape protrusion dynamics during migration (PMID:36662867), drive cytoplasmic actin dynamics after TCR stimulation while ARPC5L specifically mediates nuclear actin polymerization through a calcium-calmodulin-N-WASP pathway (PMID:37162507). ARPC5 activity is set post-translationally by phosphorylation: MAPKAPK2 phosphorylates the A isoform at Ser-77 (PMID:12829704), and PKC phosphorylation is required for rear MTOC polarization and directional migration (PMID:21281821). Biallelic null mutations in ARPC5 disrupt Arp2/3 complex conformation and selectively impair IL-6 classical signaling, with re-expression rescuing complex function, defining ARPC5 deficiency as a cause of human disease (PMID:37349293). Beyond its structural role in actin nucleation, ARPC5 has an unconventional function as a translational suppressor in male germ cells, where it blocks 80S ribosome formation and routes mRNAs into chromatoid/P bodies, a microRNA-controlled activity required for normal spermatid differentiation and fertility (PMID:22447776).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 High

    Establishing that ARPC5 exists as two distinct isoforms both built into native Arp2/3 complexes revealed that mammalian cells assemble compositionally heterogeneous nucleation machines rather than a single uniform complex.

    Evidence Affinity purification of Arp2/3 from neutrophils, isoform-specific antibodies, and immunofluorescence co-localization in C2C12 cells

    PMID:12451597

    Open questions at the time
    • Did not assign distinct functions to the two isoforms
    • Tissue-specific isoform expression ratios not resolved
  2. 2003 High

    Identification of MAPKAPK2 phosphorylation of ARPC5A at Ser-77, but not the B isoform, showed that the two isoforms are differentially regulated by signaling kinases even within intact complexes.

    Evidence In vitro kinase assays with recombinant MAPKAPK2, MALDI-MS, S77A mutagenesis, and Co-IP of native Arp2/3 from neutrophils

    PMID:12829704

    Open questions at the time
    • Functional consequence of Ser-77 phosphorylation for actin nucleation not defined
    • Upstream stimulus driving MK2-ARPC5 phosphorylation in vivo not established
  3. 2011 High

    Linking PKC phosphorylation of ARPC5 to rear MTOC polarization connected a post-translational modification of this subunit to directional cell migration.

    Evidence Phosphoproteomics, ARPC5 RNAi, phospho-dead mutant rescue, and PKC inhibition in neointimal smooth muscle cells

    PMID:21281821

    Open questions at the time
    • PKC phospho-site on ARPC5 not mapped here
    • Mechanistic link between ARPC5 phosphorylation and MTOC positioning unresolved
  4. 2012 High

    Discovery that ARPC5 acts as a translational suppressor in spermatids established a non-canonical, actin-independent role distinct from its Arp2/3 function.

    Evidence Mouse loss-of-function genetics, polysome profiling, RNA immunoprecipitation, and P-body imaging with fertility assays

    PMID:22447776

    Open questions at the time
    • Molecular mechanism by which ARPC5 blocks 80S assembly unknown
    • Whether this role requires Arp2/3 incorporation not addressed
  5. 2012 Medium

    Validation of ARPC5 as a direct miR-133a target with migration/invasion phenotypes placed it within a cancer-relevant cytoskeletal regulatory axis.

    Evidence 3'UTR luciferase reporter, siRNA knockdown, and migration/invasion plus actin morphology assays in HNSCC lines

    PMID:22378351

    Open questions at the time
    • Single-lab correlative cancer context
    • Did not connect actin phenotype to a specific Arp2/3 mechanism
  6. 2023 High

    Cryo-ET combined with reverse genetics defined how the ARPC5 and ARPC5L isoforms differentially set branch-junction stability and Ena/VASP positioning, giving isoform identity a structural and mechanistic basis in migration.

    Evidence CRISPR/siRNA depletion, cellular cryo-electron tomography, FRAP, and live-cell migration imaging

    PMID:36662867

    Open questions at the time
    • Atomic basis for how isoforms alter ArpC1 stability not resolved
    • How Ena/VASP is recruited isoform-specifically unclear
  7. 2023 High

    Dissection in CD4 T cells showed ARPC5 and ARPC5L drive distinct cytoplasmic versus nuclear actin programs downstream of separable signaling inputs, demonstrating spatial division of labor between the isoforms.

    Evidence Isoform-specific siRNA, compartment-resolved live actin imaging, and calcium-calmodulin/N-WASP pathway perturbation

    PMID:37162507

    Open questions at the time
    • How isoform composition is selected for nuclear vs cytoplasmic pools unknown
    • Downstream transcriptional consequences of nuclear actin not detailed
  8. 2023 High

    Human biallelic null mutations with in vitro rescue established ARPC5 as essential for proper Arp2/3 conformation and as a determinant of IL-6 classical signaling, defining a human disease connection.

    Evidence Patient genetics, ARPC5 re-expression complementation, Arp2/3 functional assays, and IL-6 signaling dissection

    PMID:37349293

    Open questions at the time
    • Mechanism linking Arp2/3 to IL-6 classical vs trans-signaling not fully resolved
    • Full clinical spectrum of deficiency not mapped
  9. 2023 Medium

    Identification of KLF4 as a direct transcriptional activator and ADAM17 as a downstream effector placed ARPC5 in a defined transcription-to-invasion axis in prostate cancer.

    Evidence ChIP, promoter luciferase assays, shRNA knockdown, ADAM17 rescue, and xenografts

    PMID:36881291

    Open questions at the time
    • Single-lab cancer context
    • Whether ADAM17 effect depends on Arp2/3 actin function unclear
  10. 2023 Medium

    Demonstration that CPEB2 binds and stabilizes ARPC5 mRNA added a post-transcriptional layer controlling ARPC5 abundance.

    Evidence RNA immunoprecipitation, FISH co-localization, and actinomycin D mRNA stability chase with knockdown/overexpression rescue

    PMID:37231521

    Open questions at the time
    • Single-lab finding
    • Physiological context where CPEB2 controls ARPC5 not established
  11. 2024 Medium

    TAGLN2 was shown to physically interact with ARPC5 and drive MEK/ERK-dependent tumor progression, linking ARPC5 to a proliferation/invasion signaling pathway.

    Evidence Co-IP, immunofluorescence, shRNA knockdown, MEK inhibition, and xenografts in pancreatic cancer

    PMID:38744388

    Open questions at the time
    • Single Co-IP-based interaction without structural mapping
    • Direct vs indirect coupling of ARPC5 to MEK/ERK unresolved
  12. 2024 Medium

    Isoform-resolved conditional knockouts defined ARPC5-specific (not ARPC5L) roles in macrophage phagocytosis/bacterial killing and in t-tubule membrane homeostasis, extending isoform specialization to innate immunity and muscle physiology.

    Evidence Hematopoietic- and myofiber-specific conditional Arpc5 deletion, phagocytosis/killing assays, t-tubule EM, and calcium/fatigue measurements (preprints)

    PMID:bio_10.1101_2024.07.18.604111 PMID:bio_10.1101_2024.08.13.607563

    Open questions at the time
    • Both findings are preprints not yet peer-reviewed
    • Molecular basis for ARPC5 over ARPC5L preference in these tissues unknown
  13. 2025 High

    High-resolution cryo-EM structures resolved how NPF binding to Arp2 triggers release of the ARPC5 N-terminal tail, defining it as an inhibitory element released during allosteric activation of the complex.

    Evidence 2.9-Å cryo-EM structures comparing NPF-bound and unbound Arp2 states

    PMID:40042350

    Open questions at the time
    • Whether ARPC5 vs ARPC5L tails differ in this inhibitory mechanism not addressed
    • Kinetics of tail release during nucleation not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a cell selects ARPC5 versus ARPC5L for incorporation into Arp2/3 complexes, and how this choice is coordinated with the kinase, microRNA, and transcriptional inputs that regulate ARPC5, remains unresolved.
  • No mechanism for isoform selection during complex assembly
  • Integration of phospho-regulation with isoform-specific functions not established
  • Relationship between the actin-nucleation and translational-suppressor roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0045182 translation regulator activity 1
Localization
GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
ARPC1CPEB2TAGLN2
Complex memberships
Arp2/3 complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 MAPKAPK2 (MK2) directly phosphorylates the A isoform (ARPC5A/p16-Arc) but not the B isoform of ARPC5 at serine-77; mutation of Ser-77 to alanine abolishes phosphorylation. MAPKAPK2 also phosphorylates ARPC5 within intact Arp2/3 complexes precipitated from neutrophil lysates. In vitro kinase assay with recombinant MAPKAPK2, 2D electrophoresis, MALDI-MS peptide fingerprinting, site-directed mutagenesis (S77A), Co-IP of Arp2/3 complex from neutrophil lysates The Journal of biological chemistry High 12829704
2003 ARPC5 exists as two isoforms (ARPC5A and ARPC5B) that are both incorporated into the Arp2/3 complex purified from human neutrophils, demonstrating that mammalian cells contain multiple compositionally distinct Arp2/3 complexes. Both isoforms co-localize with Arp2/3 complex in C2C12 cells when myc-tagged. Arp2/3 complex affinity purification from neutrophil extract, isoform-specific antibody generation, Western blot tissue distribution analysis, immunofluorescence co-localization in C2C12 cells Cell motility and the cytoskeleton High 12451597
2011 PKC phosphorylates ARPC5 in neointimal smooth muscle cells, and this phosphorylation is required for rear polarization of the MTOC. A non-phosphorylatable ARPC5 mutant abolishes rear MTOC polarization and directional migration of neointimal SMCs, linking ARPC5 phosphorylation to cytoskeletal organization underlying cell polarity. Phosphoproteomic screening, mass spectrometry, RNA silencing of ARPC5, transfection with non-phosphorylatable ARPC5 mutant, PKC inhibition, immunofluorescence of MTOC orientation The American journal of pathology High 21281821
2012 ARPC5 is a direct target of miR-133a; luciferase reporter assay confirmed direct binding. Silencing ARPC5 inhibits cell migration and invasion in HNSCC lines and causes reorganization of the actin cytoskeleton to a round, bleb-like morphology. Genome-wide gene expression analysis, bioinformatics, luciferase reporter assay (3'UTR), siRNA knockdown, migration/invasion assays, actin cytoskeleton imaging International journal of oncology Medium 22378351
2012 ARPC5 functions as a broadly acting translational suppressor in male germ cells: it inhibits translation initiation by blocking 80S ribosome formation and facilitates transport of mRNAs to chromatoid/P bodies. Loss of microRNA-dependent regulation of Arpc5 disrupts sequestration of germ cell mRNAs into translationally inert ribonucleoprotein particles, resulting in abnormal round spermatid differentiation and impaired fertility. Mouse genetics (loss-of-function), polysome profiling (80S formation assay), RNA immunoprecipitation, fluorescence imaging of chromatoid/P bodies, fertility assays Proceedings of the National Academy of Sciences of the United States of America High 22447776
2023 ARPC5 and ARPC5L isoforms differentially regulate Arp2/3 complex-dependent cell migration: both isoforms determine the structural stability of ArpC1 in actin branch junctions and influence protrusion characteristics and actin network ultrastructure. Additionally, ArpC5 isoforms differentially position Ena/VASP family proteins at the leading edge, and Ena/VASP mediates isoform-specific effects on actin assembly levels. Reverse genetics (CRISPR/siRNA), cellular cryo-electron tomography (cryo-ET), live-cell imaging, FRAP, immunofluorescence, migration assays Science advances High 36662867
2023 ARPC5 and ARPC5L isoforms play distinct roles in CD4 T cells: ARPC5 drives cytoplasmic actin dynamics after TCR stimulation and mediates nuclear actin polymerization triggered by DNA replication stress, while ARPC5L specifically drives nuclear actin polymerization upon TCR stimulation via a calcium-calmodulin-N-WASP signaling pathway. Isoform-specific siRNA knockdown, live-cell fluorescence imaging of actin (nuclear vs cytoplasmic), calcium-calmodulin pathway inhibitors, N-WASP inhibition/knockdown, cytokine expression assays eLife High 37162507
2023 Germline biallelic null mutations in ARPC5 disrupt Arp2/3 complex conformation and function; reestablishment of ARPC5 expression in vitro rescues Arp2/3 complex conformation and functions. ARPC5 deficiency also selectively impairs IL-6 classical signaling but not IL-6 trans-signaling. Human genetics (biallelic null patients), in vitro complementation (ARPC5 re-expression), Arp2/3 complex functional assays, IL-6 signaling pathway dissection Nature communications High 37349293
2025 Cryo-EM structures at 2.9-Å resolution reveal that NPF binding to Arp2 is allosterically linked to the release of ArpC5's N-terminal tail from Arp2 and induces conformational changes in Arp2 including closure of its ATP-binding cleft and partial rotation/translation toward the active-complex position. This defines ArpC5's N-terminal tail as an inhibitory element whose release is part of the allosteric activation mechanism of Arp2/3 complex. Cryo-electron microscopy (cryo-EM) at 2.9-Å resolution, structural comparison of two states (with and without NPF bound to Arp2) Proceedings of the National Academy of Sciences of the United States of America High 40042350
2023 KLF4 transcriptionally activates ARPC5 by binding to its promoter region, as demonstrated by chromatin immunoprecipitation and luciferase reporter assay. ARPC5 in turn upregulates ADAM17 as a downstream effector to promote prostate cancer cell migration and invasion. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, shRNA knockdown, ADAM17 overexpression rescue, xenograft mouse model Apoptosis Medium 36881291
2023 CPEB2 promotes ARPC5 mRNA stability through direct interaction, as shown by RNA immunoprecipitation and co-localization in the cytoplasm, and actinomycin D chase experiments demonstrating increased ARPC5 mRNA half-life when CPEB2 is expressed. RNA immunoprecipitation (RIP), FISH co-localization, actinomycin D mRNA stability assay, cycloheximide chase, shRNA knockdown/overexpression rescue Journal of orthopaedic surgery and research Medium 37231521
2024 TAGLN2 (transgelin-2) physically interacts with ARPC5 and promotes its expression, activating the MEK/ERK signaling pathway to drive pancreatic cancer cell proliferation, invasion, and metastasis. Silencing ARPC5 reverses TAGLN2 overexpression-induced effects. Co-immunoprecipitation (Co-IP), immunofluorescence, protein profiling, shRNA knockdown, MEK inhibitor (U0126), lentiviral overexpression, in vivo xenograft Cellular signalling Medium 38744388
2024 Arp2/3 complexes containing Arpc5 (but not the Arpc5l isoform) are required for macrophage phagocytosis and killing of intracellular bacteria; loss of Arpc5 in the murine hematopoietic system leads to failure of macrophages to restrict microbial invasion, causing intestinal inflammation and demonstrating an isoform-specific role for ARPC5-containing Arp2/3 complexes in innate immune defense. Conditional knockout (hematopoietic-specific Arpc5 vs Arpc5l deletion in mice), phagocytosis assays, intracellular bacterial killing assays, histopathology, in vivo mouse model bioRxivpreprint Medium bio_10.1101_2024.07.18.604111
2024 Arpc5-containing Arp2/3 complexes in the actomyosin cortex act as a gatekeeper for membrane availability required for t-tubule growth in muscle cells; disruption of Arpc5 leads to enlarged t-tubules and impaired synchronization between plasma membrane depolarization and calcium release, causing muscle fatigue. Conditional postnatal knockout of Arpc5 in myofibers (mice), electron microscopy of t-tubules, calcium imaging, muscle fatigue/force measurements bioRxivpreprint Medium bio_10.1101_2024.08.13.607563

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Actin-related protein 2/3 complex subunit 5 (ARPC5) contributes to cell migration and invasion and is directly regulated by tumor-suppressive microRNA-133a in head and neck squamous cell carcinoma. International journal of oncology 74 22378351
2003 Identification of the p16-Arc subunit of the Arp 2/3 complex as a substrate of MAPK-activated protein kinase 2 by proteomic analysis. The Journal of biological chemistry 47 12829704
2003 Identification and characterisation of a novel human isoform of Arp2/3 complex subunit p16-ARC/ARPC5. Cell motility and the cytoskeleton 35 12451597
2011 Rear polarization of the microtubule-organizing center in neointimal smooth muscle cells depends on PKCα, ARPC5, and RHAMM. The American journal of pathology 30 21281821
2012 Interaction between microRNAs and actin-associated protein Arpc5 regulates translational suppression during male germ cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 28 22447776
2023 ArpC5 isoforms regulate Arp2/3 complex-dependent protrusion through differential Ena/VASP positioning. Science advances 22 36662867
2021 YAP facilitates melanoma migration through regulation of actin-related protein 2/3 complex subunit 5 (ARPC5). Pigment cell & melanoma research 22 34468072
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
2023 Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling. Nature communications 13 37349293
2023 ARPC5 is transcriptionally activated by KLF4, and promotes cell migration and invasion in prostate cancer via up-regulating ADAM17 : ARPC5 serves as an oncogene in prostate cancer. Apoptosis : an international journal on programmed cell death 8 36881291
2023 CPEB2 enhances cell growth and angiogenesis by upregulating ARPC5 mRNA stability in multiple myeloma. Journal of orthopaedic surgery and research 8 37231521
2013 Effects of hypothyroidism on expression of CRMP2B and ARPC5 during development of the rat frontal cortex. International journal of biological sciences 8 23459330
2024 TAGLN2 targeted control of ARPC5-mediated activation of the MEK/ERK signaling pathway influences the proliferation, invasion, and metastasis of pancreatic cancer cells. Cellular signalling 6 38744388
2023 Long noncoding RNA DSCR8 promotes the proliferation of liver cancer cells and inhibits apoptosis via the miR-22-3p/ARPC5 Axis. Journal of Cancer 6 36605483
2025 NPF binding to Arp2 is allosterically linked to the release of ArpC5's N-terminal tail and conformational changes in Arp2/3 complex. Proceedings of the National Academy of Sciences of the United States of America 4 40042350
2023 MiR-145 regulates steroidogenesis in mouse primary granulosa cells by targeting Arpc5 and subsequent cytoskeleton remodeling. The Journal of reproduction and development 2 37081667
2024 LncRNA NEAT1 contributes to multiple myeloma progression via upregulating ARPC5 by sponging miR-133a. Archives of medical science : AMS 0 41403630

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