Affinage

DCTN2

Dynactin subunit 2 · UniProt Q13561

Length
401 aa
Mass
44.2 kDa
Annotated
2026-06-09
31 papers in source corpus 12 papers cited in narrative 12 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

DCTN2 (dynactin subunit 2/dynamitin/p50) is a structural subunit of the dynactin complex whose function is central to dynein-mediated retrograde microtubule transport, and whose overexpression acts as a dominant-negative disruptor of the dynein-dynactin motor (PMID:16369996, PMID:23380587). Genetic interference with dynein activity through DCTN2 overexpression blocks pericentrosomal clustering and trafficking of diverse cargoes, including autophagosomes during hypertonic and oxidative stress, where it abolishes dynein ATPase activation and autophagolysosome formation, as well as Golgi positioning and centrosome organization (PMID:16369996, PMID:23380587, PMID:24912985). DCTN2 serves as a required host factor for retrograde transport of viral cargoes toward the nucleus, physically associating with the murine leukemia virus preintegration complex and supporting HSV-1 capsid transport (PMID:27194765, PMID:33472938). At centrosomes, DCTN2 is regulated by phosphorylation: FER tyrosine kinase phosphorylates DCTN2 at tyrosine 6 to drive formation of tubular recycling domains in early endosomes and promote triple-negative breast cancer cell invasion (PMID:35385742), while its physical interaction with ROCK1 mediates metabolic stress-induced centrosome amplification (PMID:34080666). In hepatocellular carcinoma, DCTN2 promotes G1/S cell cycle progression via CDK4/Cyclin D1/p21 and drives proliferation, invasion, and survival through activation of AKT signaling (PMID:39958200, PMID:38842133).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2006 Medium

    Established that DCTN2 overexpression acts as a dominant-negative perturbant of the dynein-dynactin motor, linking its dosage to centrosome, Golgi, and mitotic defects in cancer cells.

    Evidence Genomic amplification (QFMPCR), Western blot, and immunofluorescence in SJSA-1 osteosarcoma cells

    PMID:16369996

    Open questions at the time
    • Phenotypes derive from overexpression rather than loss of function
    • No direct structural mapping of which motor interactions are disrupted
  2. 2013 Medium

    Showed DCTN2 is required for microtubule-dependent autophagosome trafficking, connecting the dynein-dynactin complex to autophagic flux under stress.

    Evidence DCTN2 overexpression as genetic dynein inhibition with LC3/ATG12 imaging and flux assays under hypertonic stress

    PMID:23380587

    Open questions at the time
    • Relies on overexpression-based dynein inhibition
    • Does not define how DCTN2 couples autophagosomes to dynein
  3. 2014 Medium

    Tied DCTN2 disruption to loss of dynein ATPase activation, providing an enzymatic readout for impaired motor function during autophagosome transport.

    Evidence DCTN2 overexpression with dynein ATPase assay and live-cell autophagosome tracking in primary coronary arterial myocytes

    PMID:24912985

    Open questions at the time
    • Overexpression rather than endogenous perturbation
    • Mechanistic link between DCTN2 and ATPase regulation not resolved at molecular level
  4. 2016 Medium

    Identified DCTN2 as a required host factor that associates with the MLV preintegration complex for retrograde transport toward the nucleus.

    Evidence FLAG-integrase co-IP/mass spectrometry plus RNAi knockdown infection assay

    PMID:27194765

    Open questions at the time
    • Direct versus indirect binding to the PIC not distinguished
    • Does not address whether the interaction is via assembled dynactin
  5. 2021 Medium

    Generalized DCTN2's role in dynein-dependent viral transport to HSV-1 capsid movement and placed it in a dynein-dynactin neurodegeneration pathway.

    Evidence shRNA knockdown with capsid transport imaging in SK-N-SH cells; RNAi epistasis in a Drosophila Hsc70-5 loss model

    PMID:33404278 PMID:33472938

    Open questions at the time
    • Drosophila modifier evidence is genetic without DCTN2-specific molecular mechanism
    • Whether transport defects are direct consequences of dynactin disruption not isolated
  6. 2021 Medium

    Defined a centrosomal pool of DCTN2 that binds ROCK1 to drive metabolic stress-induced centrosome amplification.

    Evidence Co-IP/mass spectrometry, immunofluorescence, and combined siRNA knockdown with centrosome counting in colon cancer cells

    PMID:34080666

    Open questions at the time
    • Direct versus dynactin-mediated DCTN2-ROCK1 interaction unresolved
    • Mechanism connecting the interaction to centriole duplication not defined
  7. 2022 High

    Identified DCTN2 as a direct FER kinase substrate phosphorylated at tyrosine 6, linking this modification to endosomal recycling architecture and tumor cell invasion.

    Evidence Chemical-genetic substrate identification, Y6 phosphosite mutagenesis, endosomal recycling and 3D invasion assays in TNBC

    PMID:35385742

    Open questions at the time
    • How Y6 phosphorylation alters dynactin assembly or dynein engagement is unspecified
    • Structural consequence of the modification not determined
  8. 2022 Medium

    Placed DCTN2 as a positive regulator of G1/S transition through CDK4/Cyclin D1/p21 in hepatocellular carcinoma.

    Evidence siRNA knockdown with cell cycle protein Westerns and proliferation/invasion/apoptosis assays in Huh7 and Hep3B

    PMID:39958200

    Open questions at the time
    • Whether cell cycle effects depend on dynactin transport function is unknown
    • Direct targets linking DCTN2 to CDK4/Cyclin D1 not identified
  9. 2024 Medium

    Connected DCTN2's tumor-promoting activity to AKT pathway activation via epistatic rescue.

    Evidence siRNA knockdown with p-AKT Westerns and pharmacological AKT rescue in HCC cells

    PMID:38842133

    Open questions at the time
    • Mechanism by which DCTN2 modulates AKT phosphorylation not defined
    • Direct molecular link between dynactin function and AKT signaling missing
  10. 2025 Low

    Implicated DCTN2 in glial cell survival and stress responsiveness relevant to neurodegeneration.

    Evidence siRNA knockdown with viability/apoptosis assays in glial lines; bulk RNA-seq of AD patient fibroblasts

    PMID:40566894

    Open questions at the time
    • Single knockdown experiment without mechanistic pathway placement
    • Correlative biomarker associations do not establish causality

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DCTN2 phosphorylation, ROCK1 binding, and downstream signaling (AKT, cell cycle) are mechanistically integrated with its core dynactin/dynein transport role remains unresolved.
  • No structural model of how DCTN2 modifications alter dynactin assembly
  • Whether signaling and cell cycle roles are separable from motor transport function is unknown
  • No reconstituted system linking DCTN2 to dynein motility under these conditions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005815 microtubule organizing center 2 GO:0005768 endosome 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-9609507 Protein localization 2 R-HSA-9612973 Autophagy 2
Partners
DCTN3FERROCK1
Complex memberships
dynactin

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 DCTN2 (dynactin-2/dynamitin) overexpression disrupts the dynein-dynactin motor complex, causing alterations in microtubule-directed movement of molecular cargoes (e.g., TP53) and organelles (e.g., Golgi), centrosome biology, cellular movement, and mitosis, with predisposition to mitotic block and polyploidy. In SJSA-1 osteosarcoma cells with genomic DCTN2 amplification and sustained overexpression, diminished centrosome and Golgi marker focus was observed by immunofluorescence microscopy. QFMPCR for genomic amplification, Western blot, immunofluorescence microscopy, overexpression studies in cancer cell lines Molecular carcinogenesis Medium 16369996
2013 Overexpression of DCTN2 (dynamitin/p50) interferes with dynein activity, blocking autophagosome clustering at the pericentrosomal region during hypertonic stress. Genetic interference of dynein activity via DCTN2 overexpression reduced autophagosome trafficking and autophagic flux, demonstrating that DCTN2 functions as part of the dynein-dynactin complex required for microtubule-dependent autophagosome transport. DCTN2 overexpression (genetic dynein inhibition), LC3/ATG12 immunofluorescence, autophagy flux assays in cells under hypertonic stress Autophagy Medium 23380587
2014 DCTN2 (dynamitin) overexpression disrupts the dynein complex and blocks ROS-induced dynein ATPase activation, autophagosome movement, and autophagolysosome formation in coronary arterial myocytes (CAMs), establishing DCTN2 as a structural component whose disruption abolishes dynein-mediated autophagosome trafficking. DCTN2 overexpression, dynein ATPase activity assay, live-cell autophagosome movement tracking, autophagolysosome formation assay in primary CAMs Journal of cellular and molecular medicine Medium 24912985
2016 DCTN2/p50/dynamitin interacts with the murine leukemia virus (MLV) preintegration complex (PIC) early during infection, as determined by co-immunoprecipitation and mass spectrometry. RNAi-mediated silencing of DCTN2 profoundly reduced ecotropic MLV infection efficiency, establishing that DCTN2 is a required host factor for retrograde dynein-dependent transport of the MLV PIC toward the nucleus. FLAG-tagged integrase immunoprecipitation + mass spectrometry, RNAi knockdown with infection efficiency assay Journal of virology Medium 27194765
2021 Knockdown of DCTN2 (DCTN2-p50) in a Drosophila model of mitochondrial chaperone Hsc70-5 loss suppressed adult phenotypes including altered body posture and heat-induced paralysis, placing DCTN2 in the same pathway as dynactin-dynein function relevant to Parkinson's disease-related neurodegeneration. Genetic epistasis via RNAi knockdown in Drosophila; behavioral phenotype rescue assays Autophagy Low 33404278
2021 Inhibition of DCTN2 and DCTN3 expression using shRNA-expressing lentiviruses inhibited intracellular transport of HSV-1 virion capsids toward the nucleus of human neuroblastoma cells, establishing that dynactin subunits including DCTN2 are required for dynein-mediated retrograde capsid transport during HSV-1 infection. shRNA lentiviral knockdown, capsid transport tracking by fluorescence microscopy in SK-N-SH cells Journal of virology Medium 33472938
2021 DCTN2 is localized to centrosomes in colon cancer cells. ROCK1 physically binds DCTN2 as identified by immunoprecipitation and mass spectrometry. High glucose, insulin, and palmitic acid treatment increased ROCK1 and DCTN2 protein levels and promoted their binding, triggering centrosome amplification. Simultaneous siRNA knockdown of both ROCK1 and DCTN2 completely inhibited centrosome amplification, establishing DCTN2 as a centrosomal component whose interaction with ROCK1 mediates diabetes-associated centrosome amplification. Immunoprecipitation + mass spectrometry proteomics, immunofluorescence, siRNA knockdown of ROCK1 and/or DCTN2, centrosome counting Oncology reports Medium 34080666
2022 FER tyrosine kinase phosphorylates DCTN2 at tyrosine 6, identified using chemical genetics. DCTN2 tyrosine 6 phosphorylation is essential for the development of tubular recycling domains in early endosomes and for propagation of TNBC cell invasion in 3D culture. Chemical genetics to identify FER substrate, phosphorylation site mutagenesis (Y6), endosomal recycling assays, 3D invasion assays Cell reports High 35385742
2022 DCTN2 knockdown in hepatocellular carcinoma (HCC) cells (Huh7 and Hep3B) decreased proliferation, invasion, and migration, enhanced apoptosis, and reduced cell cycle progression through the G1/S phase by downregulating CDK4, Cyclin D1, and upregulating p21, establishing DCTN2 as a regulator of G1/S cell cycle progression. siRNA knockdown, Western blot for cell cycle proteins (CDK4, Cyclin D1, p21), cell proliferation/invasion/migration assays, apoptosis assay Liver research Medium 39958200
2024 DCTN2 knockdown in HCC cells inhibited AKT phosphorylation and downstream AKT pathway targets; rescue experiments with AKT pathway activation partially reversed the anti-tumor effects of DCTN2 knockdown, establishing that DCTN2 exerts tumor-promoting effects through modulation of the AKT signaling pathway. siRNA knockdown, Western blot for p-AKT and downstream targets, pharmacological AKT rescue experiments, proliferation and migration assays Journal of cellular and molecular medicine Medium 38842133
2018 DCTN2 (dynamitin) co-localizes with phosphorylated alpha-synuclein (p-SNCA) in both brainstem-type and cortical Lewy bodies and Lewy neurites in Parkinson's disease and dementia with Lewy bodies brains, but not in multiple system atrophy inclusions, as shown by immunohistochemistry. This establishes that the dynactin complex (including DCTN2) is specifically incorporated into Lewy body pathology. Immunohistochemistry on autopsied human brains from PD, DLB, and MSA patients with anti-DCTN2 antibodies Neuropathology Low 30215870
2025 DCTN2 knockdown in glial cell lines resulted in increased cell toxicity and apoptosis. In Alzheimer's disease patient-derived fibroblasts, DCTN2 expression was differentially responsive to ER stress compared to controls, with DCTN2 fold change positively correlating with cognitive function and negatively with AD blood biomarkers. siRNA knockdown in glial cell lines with cell viability and apoptosis assays; bulk RNA sequencing of AD patient-derived fibroblasts Psychiatry investigation Low 40566894

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 A polypyrimidine tract binding protein, pumpkin RBP50, forms the basis of a phloem-mobile ribonucleoprotein complex. The Plant cell 156 19122103
2012 Selection of novel reference genes for use in the human central nervous system: a BrainNet Europe Study. Acta neuropathologica 98 22864814
2013 Hypertonic stress promotes autophagy and microtubule-dependent autophagosomal clusters. Autophagy 55 23380587
2008 A different view on DNA amplifications indicates frequent, highly complex, and stable amplicons on 12q13-21 in glioma. Molecular cancer research : MCR 38 18403636
2024 Gender-specific effects of polystyrene nanoplastic exposure on triclosan-induced reproductive toxicity in zebrafish (Danio rerio). The Science of the total environment 33 38692326
2021 Cellular and Viral Determinants of HSV-1 Entry and Intracellular Transport towards Nucleus of Infected Cells. Journal of virology 26 33472938
2008 Low-dose photons modify liver response to simulated solar particle event protons. Radiation research 26 18302490
2014 Enhancement of dynein-mediated autophagosome trafficking and autophagy maturation by ROS in mouse coronary arterial myocytes. Journal of cellular and molecular medicine 20 24912985
2001 Blood glucose- and triglyceride-lowering effect of trans-dehydrocrotonin, a diterpene from Croton cajucara Benth., in rats. Diabetes, obesity & metabolism 19 11903418
2012 New insights into the brain protein metabolism of Gastrodia elata-treated rats by quantitative proteomics. Journal of proteomics 17 22402058
1996 The retinoblastoma gene product (Rb) induces binding of a conformationally inactive nuclear factor-kappaB. The Journal of biological chemistry 17 8798717
2016 Dynein Regulators Are Important for Ecotropic Murine Leukemia Virus Infection. Journal of virology 14 27194765
2015 Variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A are associated with intermediate Charcot-Marie-Tooth disease in a Norwegian family. Acta neurologica Scandinavica 13 26517670
2018 Dynactin is involved in Lewy body pathology. Neuropathology : official journal of the Japanese Society of Neuropathology 12 30215870
2006 Phenotypic changes associated with DYNACTIN-2 (DCTN2) over expression characterise SJSA-1 osteosarcoma cells. Molecular carcinogenesis 11 16369996
2021 Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperone Hsc70-5 in Drosophila. Autophagy 9 33404278
2021 Binding between ROCK1 and DCTN2 triggers diabetes‑associated centrosome amplification in colon cancer cells. Oncology reports 9 34080666
2021 The expression, localisation and interactome of pigeon CRY2. Scientific reports 9 34645873
2020 Role of Phosphorylated Gonadotropin-Regulated Testicular RNA Helicase (GRTH/DDX25) in the Regulation of Germ Cell Specific mRNAs in Chromatoid Bodies During Spermatogenesis. Frontiers in cell and developmental biology 9 33425888
2022 FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer. Cell reports 8 35385742
2022 Dynactin 2 acts as an oncogene in hepatocellular carcinoma through promoting cell cycle progression. Liver research (Beijing, China) 7 39958200
2017 Proteomic analysis of chicken embryo fibroblast cells infected with recombinant H5N1 avian influenza viruses with and without NS1 eIF4GI binding domain. Oncotarget 5 29492200
2014 The functional proteomics analysis of VEGF-treated human epithelial ovarian cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 5 25192722
2024 Pan-cancer analysis of DCTN2 and its tumour-promoting role in HCC by modulating the AKT pathway. Journal of cellular and molecular medicine 3 38842133
2024 Regulatory role of lncMD1 in goat skeletal muscle satellite cell differentiation via miR-133a-3p and miR-361-3p targeting. International journal of biological macromolecules 3 39306179
2022 AMFR and DCTN2 genes cause transplantation resistance of adipose-derived mesenchymal stem cells in type 1 diabetes mellitus. Frontiers in pharmacology 3 36267277
2020 Inherited motor-sensory neuropathy with upper limb predominance associated with the tropomyosin-receptor kinase fused gene. Neuromuscular disorders : NMD 3 32085962
2025 Serum inflammation-related proteins in a acute compartment syndrome rat model. Scientific reports 2 39747444
2025 Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer's Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts. Psychiatry investigation 2 40566894
2024 Neither alpha-synuclein fibril strain nor host murine genotype influences seeding efficacy. NPJ Parkinson's disease 1 38773124
2023 Neither alpha-synuclein-preformed fibrils derived from patients with GBA1 mutations nor the host murine genotype significantly influence seeding efficacy in the mouse olfactory bulb. bioRxiv : the preprint server for biology 1 37662402

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