Affinage

PFN2

Profilin-2 · UniProt P35080

Length
140 aa
Mass
15.0 kDa
Annotated
2026-06-10
17 papers in source corpus 9 papers cited in narrative 9 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

PFN2 is an actin-binding protein that couples actin homeostasis to cytoskeletal remodeling and intracellular signaling (PMID:32978259, PMID:32788350). Biochemically, it serves as a stable activating cofactor of the actin N-terminal acetyltransferase NAA80: PFN2 binds NAA80's proline-rich loop, forms a ternary complex with G-actin, and stimulates NAA80 catalytic activity, positioning the PFN2–NAA80 complex to acetylate G-actin before its incorporation into filaments (PMID:32978259). Through an actin/dynamin-dependent role in endocytosis, PFN2 modulates ERK and FGF signaling, cell cycle progression, and differentiation in embryonic stem cells; its level is tightly controlled by the miR-290 microRNA family acting on a conserved 3'UTR site [PMID:32788350, PMID:bio_10.1101_2024.10.02.616359]. PFN2 abundance is further set post-transcriptionally by an Iron Response Element in its 3'UTR that gates Wnt/β-catenin signaling during germ-layer specification [PMID:bio_10.1101_2024.10.02.616359], by hnRNPA2B1-mediated m6A stabilization of its mRNA (PMID:40010516), and post-translationally by cIAP1-directed ubiquitin-proteasome degradation, which in turn influences reactive oxygen species (PMID:30352681). Transcriptionally, PFN2 is driven by ETS1 together with KMT5A-deposited H4K20me1, by OCT1, and by SIX2, and these inputs feed into context-dependent disease programs including endothelial- and epithelial-to-mesenchymal transition via TGF-β/Smad signaling, ferroptosis, and cancer cell stemness through a SIX2/YBX-1/JNK feedback loop (PMID:34238215, PMID:40010516, PMID:39256760, PMID:35413990).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2018 Medium

    Established that PFN2 abundance is set post-translationally by targeted degradation, linking it to redox state.

    Evidence Ubiquitination assays, proteasome inhibition, and E3 ligase identification with ROS measurement

    PMID:30352681

    Open questions at the time
    • Ubiquitin linkage specificity (degradative vs regulatory) not fully resolved
    • Mechanistic connection between PFN2 level and ROS not defined
    • Limited orthogonal validation
  2. 2020 High

    Defined PFN2's direct biochemical activity: it is a stable activator of the actin N-terminal acetyltransferase NAA80, resolving how a profilin family member contributes to actin acetylation.

    Evidence Interaction proteomics, in vitro enzyme assays, SAXS, analytical ultracentrifugation, and NAA80 proline-rich loop mutagenesis

    PMID:32978259

    Open questions at the time
    • High-resolution structure of the ternary complex not determined
    • Cellular consequences of PFN2-dependent actin acetylation not directly tested
    • Whether PFN2 has NAA80-independent actin roles unresolved
  3. 2020 High

    Showed PFN2 is a functional miR-290 target whose overexpression suppresses endocytosis and ERK signaling, placing it in a microRNA circuit controlling stem cell differentiation.

    Evidence miRNA-KO and Pfn2-KO ESCs, miR-290 re-introduction, 3'UTR mutagenesis, endocytosis/ERK/cell-cycle readouts

    PMID:32788350

    Open questions at the time
    • Molecular basis of PFN2–dynamin interaction in endocytosis not structurally defined
    • How endocytic defect connects to ERK signaling not fully mapped
  4. 2020 Low

    Linked PFN2 to pro-tumorigenic EMT via TGF-β/Smad signaling in triple-negative breast cancer.

    Evidence Gain-of-function with proliferation/migration/invasion assays, Smad2/3 and EMT marker Western blots, and xenografts

    PMID:33047272

    Open questions at the time
    • Single lab gain-of-function without mechanistic placement of PFN2 in the Smad cascade
    • Direct interaction with Smad machinery not shown
    • Not independently confirmed
  5. 2021 Medium

    Identified transcriptional and epigenetic control of PFN2 (ETS1 + KMT5A/H4K20me1) driving endothelial-to-mesenchymal transition under high glucose.

    Evidence ChIP, dual-luciferase reporter, epistasis knockdown/overexpression, and in vivo diabetic nephropathy model

    PMID:34238215

    Open questions at the time
    • Mechanism by which KMT5A represses while ETS1 activates the same promoter not reconciled
    • Downstream effectors of PFN2 in EndMT not defined
  6. 2022 Medium

    Established OCT1 as a direct transcriptional driver of PFN2 supporting migration and tumor growth in AR-negative castration-resistant prostate cancer.

    Evidence ChIP-seq, siRNA knockdown, migration assays, and in vivo tumor growth

    PMID:35413990

    Open questions at the time
    • Downstream PFN2 effectors in prostate cancer migration not identified
    • Single-lab study
  7. 2024 Medium

    Revealed a SIX2/PFN2/YBX-1/JNK positive feedback loop sustaining gastric cancer stemness, showing PFN2 acts reciprocally on its own transcriptional activator.

    Evidence ChIP, Co-IP, IP-MS, RNA stability assay, RNA-seq, and JNK inhibition with gain/loss-of-function

    PMID:39256760

    Open questions at the time
    • How PFN2 recruits YBX-1 to stabilize SIX2 mRNA mechanistically unclear
    • Link between PFN2 and JNK activation not biochemically defined
  8. 2024 Medium

    Demonstrated that a dual miR-290/IRE 3'UTR module on the Pfn2 transcript coordinates two sequential signaling steps (FGF then Wnt/β-catenin) during germ-layer formation.

    Evidence 3'UTR element deletions (IRE, miRNA site), ESC differentiation, Wnt/FGF readouts, nuclear β-catenin (preprint)

    PMID:bio_10.1101_2024.10.02.616359

    Open questions at the time
    • Iron-dependent regulation via the IRE not biochemically confirmed
    • Preprint, not peer-reviewed
    • How PFN2 level changes translate to Wnt/FGF output not mechanistically resolved
  9. 2025 Medium

    Connected m6A regulation to PFN2 function, showing hnRNPA2B1-mediated mRNA stabilization promotes cardiomyocyte ferroptosis in ischemia-reperfusion injury.

    Evidence m6A reader interaction, RNA stability assays, ferroptosis marker quantification, OGD/R and in vivo MIRI models

    PMID:40010516

    Open questions at the time
    • How PFN2 protein mechanistically drives lipid ROS/ferroptosis not defined
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PFN2's core actin-acetylation cofactor activity mechanistically connects to its diverse signaling and disease roles (endocytosis, EMT, ferroptosis, stemness) remains unresolved.
  • No study links PFN2-dependent actin acetylation to its cancer or ferroptosis phenotypes
  • Structural basis of the ternary actin–NAA80–PFN2 complex unresolved
  • Whether disease functions are actin-dependent or independent is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0098772 molecular function regulator activity 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 1
Complex memberships
actin–NAA80–PFN2 ternary complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 PFN2 is a stable interaction partner of the actin N-terminal acetyltransferase NAA80. PFN2 binding to NAA80 via NAA80's proline-rich loop specifically increases NAA80's intrinsic catalytic activity. NAA80, actin, and PFN2 form a ternary complex (shown by SAXS), and PFN2 binding promotes interaction between the globular domains of actin and NAA80, facilitating actin N-terminal acetylation. The majority of cellular NAA80 is stably bound to PFN2 rather than actin, suggesting the PFN2-NAA80 complex acetylates G-actin before filament incorporation. Interaction proteomics, analytical ultracentrifugation, in vitro enzyme assays, small-angle X-ray scattering (SAXS), deletion mutagenesis of NAA80 proline-rich loop The Journal of biological chemistry High 32978259
2020 PFN2 is a target of the miR-290 family of microRNAs in embryonic stem cells (ESCs). In the absence of miRNAs, PFN2 is upregulated in ESCs, causing decreased endocytosis, impaired ERK signaling, delayed cell cycle progression, and repressed differentiation. Knockout of Pfn2, reintroduction of miR-290, or disruption of the PFN2-dynamin interaction domain all reversed the endocytosis defect. Mutagenesis of the single canonical conserved 3' UTR miR-290-binding site of Pfn2 or overexpression of Pfn2 ORF alone in wild-type cells largely recapitulated these phenotypes. miRNA knockout ESCs, Pfn2 knockout, miR-290 re-introduction, Pfn2 3'UTR mutagenesis, endocytosis assays, ERK signaling assays, cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America High 32788350
2018 PFN2 is ubiquitinated via differential ubiquitin-linkages (for either degradation or as a regulatory signal) by the E3 ligase cIAP1 (cellular inhibitor of apoptosis 1), targeting PFN2 for proteasomal degradation. PFN2 levels regulated by cIAP1 affect intracellular levels of reactive oxygen species. Ubiquitination assays, proteasome inhibition, E3 ligase identification, ROS measurement Biochemical and biophysical research communications Medium 30352681
2021 In high-glucose conditions, the transcription factor ETS1 cooperates with KMT5A (which mediates H4K20 monomethylation) to regulate PFN2 promoter activity and transcription, driving endothelial-to-mesenchymal transition (EndMT) in glomerular endothelial cells. ChIP assays showed H4K20me1 and ETS1 occupy the PFN2 promoter region. Knockdown of ETS1 suppressed high glucose-induced PFN2 expression and EndMT, while ETS1 overexpression-mediated EndMT was reversed by PFN2 knockdown. KMT5A upregulation suppressed PFN2 and EndMT, while sh-KMT5A-mediated EndMT was counteracted by PFN2 knockdown. ChIP assay, dual luciferase reporter assay, siRNA knockdown, overexpression, Western blot, immunofluorescence, in vivo DN model Molecular medicine (Cambridge, Mass.) Medium 34238215
2025 The m6A reader hnRNPA2B1 binds to the m6A site ('AGACU') of PFN2 mRNA and enhances its stability. This hnRNPA2B1-PFN2 axis promotes ferroptosis in cardiomyocytes during myocardial ischemia-reperfusion injury, as evidenced by increased lipid ROS, MDA, and Fe2+. PFN2 knockdown attenuated ferroptosis in hnRNPA2B1-overexpressing cardiomyocytes. m6A reader interaction studies, RNA stability assay, siRNA knockdown, overexpression, ferroptosis marker measurement (lipid ROS, MDA, Fe2+, GSH, FTH1), in vitro OGD/R model and in vivo MIRI model Free radical biology & medicine Medium 40010516
2024 Transcription factor SIX2 directly binds to the PFN2 promoter and promotes PFN2 transcription. In turn, PFN2 promotes mRNA stability of SIX2 by recruiting RNA-binding protein YBX-1, and subsequently activates the downstream MAPK/JNK pathway, forming a SIX2/PFN2 positive feedback loop that enhances gastric cancer cell stemness. ChIP, Co-immunoprecipitation, IP-MS, RNA stability assay, RNA-sequencing, JNK pathway inhibition, gain- and loss-of-function experiments Journal of translational medicine Medium 39256760
2024 The Pfn2 3'UTR contains both a miR-290 binding site and an Iron Response Element (IRE). Deletion of the IRE leads to decreased PFN2 protein, a Wnt signaling defect, reduced nuclear beta-catenin, and a block in mesendodermal lineage differentiation. Deletion of the miR-290 site leads to increased PFN2 and reduced FGF signaling during pluripotency transition. This coordinated miRNA-IRE axis on the Pfn2 transcript controls two sequential signal transduction steps during ESC differentiation into primary germ layers. 3'UTR mutagenesis (IRE deletion, miRNA site deletion), ESC differentiation assays, Wnt/FGF signaling readouts, nuclear beta-catenin measurement bioRxivpreprint Medium bio_10.1101_2024.10.02.616359
2020 PFN2 promotes proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells. PFN2 overexpression upregulates Smad2 and Smad3, further inducing EMT. PFN2-overexpressing cells exhibit stronger tumorigenicity in vivo. CCK-8 assay, transwell migration/invasion assay, Western blot (Smad2/3, EMT markers), xenograft tumor model Breast cancer (Tokyo, Japan) Low 33047272
2022 OCT1 transcription factor directly regulates PFN2 expression in AR-negative castration-resistant prostate cancer cells, as identified by ChIP-seq. PFN2 knockdown by siRNA significantly inhibited migration of AR-negative prostate cancer cells and showed a marked inhibitory effect on tumor growth in vivo. ChIP-seq, siRNA knockdown, cell migration assay, in vivo tumor growth assay, immunohistochemistry Scientific reports Medium 35413990

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Circle RNA circABCB10 Modulates PFN2 to Promote Breast Cancer Progression, as Well as Aggravate Radioresistance Through Facilitating Glycolytic Metabolism Via miR-223-3p. Cancer biotherapy & radiopharmaceuticals 38 32522014
2019 Long non‑coding RNA FOXD2‑AS1/miR‑150‑5p/PFN2 axis regulates breast cancer malignancy and tumorigenesis. International journal of oncology 30 30628646
2021 ets1 associates with KMT5A to participate in high glucose-mediated EndMT via upregulation of PFN2 expression in diabetic nephropathy. Molecular medicine (Cambridge, Mass.) 29 34238215
2020 PFN2 and NAA80 cooperate to efficiently acetylate the N-terminus of actin. The Journal of biological chemistry 26 32978259
2020 Profilin 2 (PFN2) promotes the proliferation, migration, invasion and epithelial-to-mesenchymal transition of triple negative breast cancer cells. Breast cancer (Tokyo, Japan) 20 33047272
2018 PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease. Journal of neurology, neurosurgery, and psychiatry 16 29449460
2022 OCT1-target neural gene PFN2 promotes tumor growth in androgen receptor-negative prostate cancer. Scientific reports 14 35413990
2019 Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy. Neurology. Genetics 14 32042914
2020 MicroRNA-dependent inhibition of PFN2 orchestrates ERK activation and pluripotent state transitions by regulating endocytosis. Proceedings of the National Academy of Sciences of the United States of America 13 32788350
2019 Long non-coding RNA TUG1 regulates the progression and metastasis of osteosarcoma cells via miR-140-5p/PFN2 axis. European review for medical and pharmacological sciences 13 31799645
2023 Hsa_circ_0020134 promotes liver metastasis of colorectal cancer through the miR-183-5p-PFN2-TGF-β/Smad axis. Translational oncology 11 37925795
2022 Circ_0008500 Knockdown Improves Radiosensitivity and Inhibits Tumorigenesis in Breast Cancer Through the miR-758-3p/PFN2 Axis. Journal of mammary gland biology and neoplasia 10 35239064
2022 Impact of miR-1/miR-133 Clustered miRNAs: PFN2 Facilitates Malignant Phenotypes in Head and Neck Squamous Cell Carcinoma. Biomedicines 9 35327465
2018 Ubiquitin-proteasome dependent regulation of Profilin2 (Pfn2) by a cellular inhibitor of apoptotic protein 1 (cIAP1). Biochemical and biophysical research communications 6 30352681
2025 HnRNPA2B1 promotes cardiac ferroptosis via m6A-dependent stabilization of PFN2 mRNA in myocardial ischemia-reperfusion injury. Free radical biology & medicine 5 40010516
2024 The SIX2/PFN2 feedback loop promotes the stemness of gastric cancer cells. Journal of translational medicine 4 39256760
2023 Urinary extracellular vesicles prevent di-(2-ethylhexyl) phthalate-induced hypospadias by facilitating epithelial-mesenchymal transition via PFN2 delivery. Cell biology and toxicology 4 37953354

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