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PACSIN3

Protein kinase C and casein kinase substrate in neurons protein 3 · UniProt Q9UKS6

Round 2 corrected
Length
424 aa
Mass
48.5 kDa
Annotated
2026-04-29
48 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PACSIN3 is an F-BAR/SH3 domain scaffold protein that couples membrane remodeling with endocytic trafficking and cytoskeletal regulation in muscle, epithelial, and dividing cells. Its C-terminal SH3 domain binds proline-rich motifs in dynamin, N-WASP, synaptojanin-1, Sos, TRPV4, and ADAM12, thereby coordinating vesicle fission, actin polymerization, ion channel gating, and ectodomain shedding (PMID:11082044, PMID:16627472, PMID:12952982). The N-terminal F-BAR domain dimerizes, binds phosphoinositides, and drives membrane tubulation required for caveolar biogenesis in muscle, notochord morphogenesis in zebrafish, and correct positioning of Piezo1 and Rab11-FIP3 endosomes at the cytokinetic bridge during abscission (PMID:19997509, PMID:34714681, PMID:34990060). PACSIN3 also inhibits TRPV4 channel activation by restricting PIP2 access to the channel's gating domain, as demonstrated by FRET, electrophysiology, and NMR structural studies of the SH3–TRPV4 complex (PMID:23690576, PMID:30244966).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 High

    Cloning of PACSIN3 established it as a ubiquitous SH3-domain adaptor linking dynamin, N-WASP, and synaptojanin-1 to endocytic membrane trafficking, resolving the question of whether a non-neuronal PACSIN family member existed with conserved SH3-mediated endocytic functions.

    Evidence cDNA cloning, GST pull-down, co-immunoprecipitation, transferrin endocytosis assay with SH3 mutagenesis in cultured cells

    PMID:11082044

    Open questions at the time
    • Tissue-specific functions not addressed
    • No in vivo loss-of-function data
    • F-BAR domain function unexplored
  2. 2003 High

    Identification of ADAM12 and Sos as PACSIN3 SH3-domain partners expanded its interactome beyond core endocytic machinery, revealing roles in EGFR transactivation via proHB-EGF shedding and in Ras/actin signaling.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, siRNA knockdown with proHB-EGF shedding assay (ADAM12); SILAC peptide pull-down with IP confirmation (Sos)

    PMID:12952982 PMID:14679214

    Open questions at the time
    • In vivo relevance of ADAM12–PACSIN3 axis unknown
    • Whether Sos interaction modulates Ras signaling directly untested
  3. 2006 High

    Discovery that PACSIN3 specifically shifts TRPV4 to the plasma membrane by inhibiting its endocytosis answered how an SH3-domain scaffold could selectively regulate an ion channel's subcellular distribution, distinguishing PACSIN3 from the other isoforms.

    Evidence Yeast two-hybrid, co-IP, co-expression/localization, dynamin inhibition, domain mutational analysis in heterologous cells

    PMID:16627472

    Open questions at the time
    • Mechanism of channel gating modulation not yet resolved
    • Endogenous tissue context not examined
  4. 2007 Medium

    PACSIN3 was shown to be upregulated during adipocyte differentiation and to increase plasma membrane GLUT1 (but not GLUT4) levels, establishing a cargo-selective vesicle trafficking role in metabolic cells.

    Evidence Overexpression in 3T3-L1 adipocytes, subcellular fractionation, photoaffinity labeling, glucose uptake assay

    PMID:17320047

    Open questions at the time
    • No loss-of-function confirmation
    • Mechanism of GLUT1 selectivity over GLUT4 unknown
    • In vivo metabolic consequence not tested
  5. 2009 High

    Zebrafish pacsin3 morphant phenotypes and structural analysis of the F-BAR/EFC domain resolved the question of whether PACSIN3's membrane-remodeling activity is essential in vivo, linking phosphoinositide-dependent membrane tubulation to notochord cell polarization and migration during embryogenesis.

    Evidence Morpholino knockdown in zebrafish with rescue by Drosophila Syndapin, crystal structure of EFC domain, phosphoinositide binding assays, domain mutagenesis

    PMID:19997509

    Open questions at the time
    • Mammalian in vivo knockout data still lacking at this stage
    • Specific phosphoinositide species preference in mammalian cells not mapped
  6. 2013 High

    Electrophysiology and FRET experiments revealed that PACSIN3 inhibits TRPV4 activation by cell swelling and heat through its F-BAR domain, which restricts PIP2 access to the channel's gating region — answering how PACSIN3 modulates channel function beyond trafficking.

    Evidence Patch-clamp electrophysiology, FRET analysis of TRPV4 tail proximity, translocatable phosphatase PIP2 depletion, F-BAR deletion mutagenesis

    PMID:23690576

    Open questions at the time
    • Whether F-BAR-mediated membrane curvature or direct lipid sequestration underlies PIP2 restriction unresolved
    • In vivo physiological consequences of TRPV4 inhibition by PACSIN3 not tested
  7. 2018 High

    The NMR structure of the PACSIN3 SH3 domain bound to TRPV4's proline-rich region provided atomic-resolution insight into how SH3 binding rigidifies the adjacent PIP2-binding site, establishing a hierarchical allosteric mechanism for channel inhibition.

    Evidence NMR structure determination, isothermal titration calorimetry, domain mutagenesis

    PMID:30244966

    Open questions at the time
    • Full-length PACSIN3–TRPV4 complex structure not available
    • Whether allosteric rigidification mechanism generalizes to other PACSIN3 targets unknown
  8. 2021 Medium

    PACSIN3 was shown to position Piezo1 and Rab11-FIP3/ESCRT-III endosomes at the intercellular bridge during cytokinesis, revealing an unexpected role for an F-BAR scaffold in abscission and demonstrating that loss causes multinucleation.

    Evidence siRNA knockdown, live-cell imaging, immunofluorescence, multinucleation assays in vitro and in vivo

    PMID:34714681

    Open questions at the time
    • Whether PACSIN3 recruits Piezo1 directly or via an intermediate adaptor is unclear
    • Mechanism linking Piezo1 mechanosensing to abscission completion not defined
    • Single-lab finding awaiting independent replication
  9. 2022 Medium

    Synthesis of in vivo data established PACSIN3 as essential for caveolar biogenesis in muscle, creating membrane reservoirs critical for muscle function and linking PACSIN3 loss to muscular disorders.

    Evidence Review consolidating in vivo model data and caveolae biogenesis assays across studies

    PMID:34990060

    Open questions at the time
    • Specific muscular disorder genetics involving PACSIN3 mutations in humans not demonstrated by primary studies in this timeline
    • Direct caveolin-PACSIN3 structural interaction not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PACSIN3's F-BAR-mediated membrane remodeling is coordinated with its SH3-mediated protein interactions in a cargo- and tissue-specific manner, and whether PACSIN3 mutations cause human Mendelian disease, remain unresolved.
  • No human PACSIN3 disease-causing mutations reported in the timeline
  • No full-length structural model of PACSIN3 in complex with a membrane
  • Cargo selectivity mechanism (e.g., GLUT1 vs GLUT4) not explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0008092 cytoskeletal protein binding 2 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 3 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 1
Partners
ADAM12DNM1NWASPPIEZO1SOS1SYNJ1TRPV4

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PACSIN3 was cloned and found to differ from PACSIN1/2 by having a short proline-rich region and lacking NPF motifs; it is mainly expressed in lung and muscle tissues. All three PACSIN isoforms bind dynamin, synaptojanin 1, and N-WASP via their SH3 domains, co-localize with dynamin (but not clathrin), and overexpression inhibits transferrin endocytosis in a dose-dependent, SH3-domain-dependent manner. cDNA cloning, GST pull-down, co-immunoprecipitation, co-localization microscopy, transferrin endocytosis assay, SH3-domain mutagenesis Journal of cell science High 11082044
2003 PACSIN3 SH3 domain specifically binds a proline-rich sequence of the Sos protein, linking PACSIN3 to actin remodeling/endocytic signaling downstream of Sos. Synthetic peptide affinity pull-down with SILAC-based quantitative mass spectrometry, confirmed by immunoprecipitation The Journal of biological chemistry Medium 14679214
2003 PACSIN3 binds the cytoplasmic domain of ADAM12/meltrin alpha via a proline-rich region (residues 829–840) of ADAM12; overexpression of PACSIN3 enhances TPA-induced proHB-EGF ectodomain shedding, while siRNA knockdown of PACSIN3 significantly attenuates shedding induced by TPA and angiotensin II, establishing PACSIN3 as an up-regulator of ADAM12-mediated proHB-EGF shedding and EGFR transactivation. Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, co-localization, siRNA knockdown, proHB-EGF shedding assay The Journal of biological chemistry High 12952982
2004 PACSIN/Syndapin proteins, including PACSIN3, link membrane trafficking with the cytoskeleton through SH3-domain-mediated interactions with dynamin (vesicle fission) and N-WASP (Arp2/3-dependent actin polymerization), and can oligomerize to couple actin polymerization bursts with vesicle fission. Review/synthesis of biochemical interaction data (pull-down, Co-IP, domain mapping) from multiple studies Journal of cell science Medium 15226389
2006 All three PACSIN isoforms bind the N-terminus of TRPV4 via their SH3 domains; PACSIN3 specifically shifts TRPV4 localization toward the plasma membrane (away from cytosol), an effect mimicked by blocking dynamin-mediated endocytosis, indicating PACSIN3 modulates TRPV4 subcellular distribution by inhibiting its endocytosis. Interaction requires both the proline-rich domain of TRPV4 upstream of its ankyrin repeats and the C-terminal SH3 domain of PACSIN3. PACSIN1/2 do not affect TRPV4 localization despite binding. Yeast two-hybrid screen, biochemical co-immunoprecipitation, co-expression/localization assays, dynamin inhibition, domain mutational analysis The Journal of biological chemistry High 16627472
2007 PACSIN3 is the only PACSIN isoform upregulated during 3T3-L1 adipocyte differentiation; overexpression of PACSIN3 increases glucose uptake by elevating plasma membrane localization of GLUT1 (but not GLUT4), as shown by subcellular fractionation and photoaffinity labeling, establishing a role for PACSIN3 in GLUT1 vesicle trafficking. Adipocyte differentiation assay, overexpression, subcellular fractionation, photoaffinity labeling of GLUT1/GLUT4, glucose uptake assay Biochemical and biophysical research communications Medium 17320047
2007 PACSIN3 is identified as an interacting partner of FasL in Schwann cells via a proteomics approach, consistent with its role in endocytosis and trafficking of FasL to regulate its cell surface expression. Proteomic pull-down / affinity purification from Schwann cell lysates FEBS letters Low 17761170
2009 Zebrafish Pacsin3 (Syndapin ortholog) is required for notochord formation: pacsin3 morphants fail to polarize, migrate, and differentiate axial mesodermal cells, causing stunted body axis. The phenotype is rescued by Drosophila Syndapin expression and depends critically on the membrane-inserting prong of the EFC/F-BAR domain and high-affinity phosphoinositide binding by the antiparallel EFC dimer, linking directional cell migration and endocytosis during embryonic morphogenesis. Morpholino knockdown (zebrafish), rescue by ectopic Drosophila Syndapin expression, crystal structure of Drosophila EFC domain, domain mutagenesis, biochemical phosphoinositide binding assays PloS one High 19997509
2013 PACSIN3 (co-expressed with TRPV4) abrogates TRPV4 activation by cell swelling and heat. This inhibition requires the F-BAR domain; a PACSIN3 mutant lacking F-BAR still binds TRPV4 N-tails without affecting channel activation or PIP2-dependent tail rearrangement. PACSIN3 binding restricts TRPV4 access to PIP2 and prevents PIP2-induced tail rearrangement required for channel gating by physiological stimuli. FRET analysis of TRPV4 tail proximity, electrophysiology (patch-clamp), translocatable phosphatase PIP2 depletion, domain deletion mutagenesis, heterologous expression Proceedings of the National Academy of Sciences of the United States of America High 23690576
2018 NMR structure of the PACSIN3 SH3 domain in complex with the TRPV4 N-terminal proline-rich region (PRR) was determined; the PRR binds as a class I polyproline II (PPII) helix with a conserved cis-proline breaking the PPII conformation. SH3 binding rigidifies both the PRR and the adjacent PIP2-binding site. PACSIN1, 2, and 3 SH3 domains all bind TRPV4 N-terminus, with Syndapin/PACSIN binding influencing the PIP2 site but not vice versa, establishing a hierarchical interaction network. NMR structure determination, isothermal titration calorimetry (ITC) affinity measurements, domain mutagenesis Structure High 30244966
2019 IL-6 post-transcriptionally downregulates Pacsin3 protein in differentiating rat primary skeletal myoblasts (via miR-154-3p and/or miR-338-3p induction), while IGF-I does not affect Pacsin3 expression, suggesting cytokine-specific regulation of Pacsin3 during muscle differentiation. miRNA microarray, qRT-PCR, Western blot, wound healing migration assay in primary rat skeletal myoblasts Cell and tissue research Low 31820147
2021 PACSIN3 positions the mechanosensitive Piezo1 channel at the intercellular bridge (ICB) during cytokinesis; genetic or pharmacological inhibition of Pacsin3 causes mislocation of Rab11-FIP3 endosomes, ALIX, and ESCRT-III at the ICB, impairs abscission, and leads to multinucleation, establishing PACSIN3 as required for Piezo1 positioning and proper endosome trafficking during cytokinetic abscission. siRNA knockdown, live-cell imaging, immunofluorescence, in vitro and in vivo multinucleation assays Science advances Medium 34714681
2022 PACSIN3 is abundant in muscle tissue and necessary for caveolar biogenesis, creating membrane reservoirs that control muscle function; loss of PACSIN3 function is linked to muscular disorders. Review summarizing experimental data from multiple studies (in vivo models, caveolae biogenesis assays) Acta physiologica Medium 34990060

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
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
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
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
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2003 A novel proteomic screen for peptide-protein interactions. The Journal of biological chemistry 243 14679214
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2000 All three PACSIN isoforms bind to endocytic proteins and inhibit endocytosis. Journal of cell science 169 11082044
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
1999 Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1. The Journal of biological chemistry 149 10531379
2006 PACSINs bind to the TRPV4 cation channel. PACSIN 3 modulates the subcellular localization of TRPV4. The Journal of biological chemistry 144 16627472
2005 Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities. The EMBO journal 142 15719014
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2004 The syndapin protein family: linking membrane trafficking with the cytoskeleton. Journal of cell science 130 15226389
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
2019 The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2. Molecular cell 124 30639242
2013 Phosphatidylinositol-4,5-biphosphate-dependent rearrangement of TRPV4 cytosolic tails enables channel activation by physiological stimuli. Proceedings of the National Academy of Sciences of the United States of America 123 23690576
2023 The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation. Science (New York, N.Y.) 117 37616343
2003 PACSIN3 binds ADAM12/meltrin alpha and up-regulates ectodomain shedding of heparin-binding epidermal growth factor-like growth factor. The Journal of biological chemistry 73 12952982
2009 Structural requirements for PACSIN/Syndapin operation during zebrafish embryonic notochord development. PloS one 39 19997509
2018 Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2. Structure (London, England : 1993) 34 30244966
2022 PACSIN proteins in vivo: Roles in development and physiology. Acta physiologica (Oxford, England) 33 34990060
2008 Identification and transcript analysis of a novel wallaby (Macropus eugenii) basal-like breast cancer cell line. Molecular cancer 29 18179684
2021 The mechanosensitive Piezo1 channel controls endosome trafficking for an efficient cytokinetic abscission. Science advances 25 34714681
2019 Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis. Neurology. Genetics 19 31041394
2007 A proteomic screen reveals novel Fas ligand interacting proteins within nervous system Schwann cells. FEBS letters 18 17761170
2007 PACSIN3 overexpression increases adipocyte glucose transport through GLUT1. Biochemical and biophysical research communications 17 17320047
2020 Amyotrophy Induced by a High-Fat Diet Is Closely Related to Inflammation and Protein Degradation Determined by Quantitative Phosphoproteomic Analysis in Skeletal Muscle of C57BL/6 J Mice. The Journal of nutrition 15 31618431
2020 Association of Cholinergic Muscarinic M4 Receptor Gene Polymorphism with Schizophrenia. The application of clinical genetics 11 32368127
2023 Hypomethylation in MTNR1B: a novel epigenetic marker for atherosclerosis profiling using stenosis radiophenotype and blood inflammatory cells. Clinical epigenetics 9 36658621
2019 Interleukin-6 affects pacsin3, ephrinA4 expression and cytoskeletal proteins in differentiating primary skeletal myoblasts through transcriptional and post-transcriptional mechanisms. Cell and tissue research 6 31820147
2024 Transcriptome analysis of mRNA and miRNA in the development of LeiZhou goat muscles. Scientific reports 5 38684760
2024 Identification and role of differentially expressed genes/proteins between pulmonary tuberculosis patients and controls across lung tissues and blood samples. Immunity, inflammation and disease 3 39023413
2021 Molecular Expression of Some Oncogenes and Predisposing Behaviors Contributing to the Aggressiveness of Prostate Cancer. Reports of biochemistry & molecular biology 3 34277869
2025 Identification of candidate cardiomyopathy modifier genes through genome sequencing and RNA profiling. Frontiers in cardiovascular medicine 0 40791945