Affinage

DYNLL2

Dynein light chain 2, cytoplasmic · UniProt Q96FJ2

Round 2 corrected
Length
89 aa
Mass
10.3 kDa
Annotated
2026-04-28
51 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DYNLL2 is a conserved homodimeric hub protein of the LC8 dynein light chain family that functions as a dimerization engine and cytoskeletal anchor, sequestering diverse partners through paired binding grooves until signal-dependent phosphorylation triggers their release. It sequesters the pro-apoptotic BH3-only protein Bmf on myosin V motor complexes; JNK phosphorylation or anoikis releases Bmf to activate Bax/Bak-dependent apoptosis (PMID:11546872, PMID:12591950). DYNLL2 similarly tethers the AMBRA1–Beclin 1–VPS34 autophagy initiation complex to the cytoskeleton, with ULK1 phosphorylation of AMBRA1 liberating the complex for autophagosome nucleation (PMID:20921139), and recruits PAK1 downstream of CDK11p58 phosphorylation to promote mitotic progression and, in macrophages, OMV endocytosis leading to Caspase-11 inflammasome activation (PMID:19520772, PMID:41360226). At excitatory synapses, DYNLL2 dimerization drives large-scale hetero-oligomerization of GKAP at the postsynaptic density, stabilizing the PSD-95 scaffold and enhancing NMDA receptor-mediated currents in an activity-dependent manner (PMID:22328512, PMID:24938595).

Mechanistic history

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

    Identification of DYNLL2 as a postsynaptic density component that directly binds GKAP established its first known scaffolding interaction and linked it to the PSD-95–myosin V trafficking complex in dendritic spines.

    Evidence Yeast two-hybrid, co-IP from rat brain, immunogold EM

    PMID:10844022

    Open questions at the time
    • Whether DYNLL2-GKAP binding is functionally required for synaptic transmission was untested
    • Stoichiometry and oligomeric state of the complex unknown
    • No distinction from DYNLL1 function at synapses
  2. 2001 High

    Discovery that DYNLL2 sequesters the pro-apoptotic BH3-only protein Bmf on the actin cytoskeleton revealed a general mechanism — cytoskeletal anchoring of a death sensor — and showed that anoikis releases Bmf to trigger apoptosis.

    Evidence Co-IP, subcellular fractionation, anoikis and apoptosis assays in multiple cell types

    PMID:11546872

    Open questions at the time
    • Phosphorylation-based mechanism of Bmf release was not yet defined
    • Whether DYNLL1 and DYNLL2 are redundant in Bmf sequestration was unclear
  3. 2003 High

    Demonstration that JNK phosphorylates Bmf to cause its release from DYNLL2-containing motor complexes provided the upstream kinase signal linking stress-activated MAPK signaling to the cytoskeletal sequestration/release mechanism.

    Evidence In vitro JNK kinase assay, JNK knockout cells, Bax/Bak-dependent apoptosis readout

    PMID:12591950

    Open questions at the time
    • Precise phospho-site(s) on Bmf that disrupt DYNLL2 binding not structurally mapped
    • In vivo physiological contexts for JNK-Bmf-DYNLL2 axis beyond UV damage not explored
  4. 2009 Medium

    CDK11p58-mediated phosphorylation of PAK1 at Ser174 was shown to promote PAK1 recruitment to DYNLL2, linking DYNLL2 to mitotic kinase signaling and cell-cycle progression.

    Evidence Co-IP with phosphomimetic/non-phosphorylatable PAK1 mutants, nocodazole cell-cycle block

    PMID:19520772

    Open questions at the time
    • Single-lab study; independent replication pending
    • Whether DYNLL2 binding activates PAK1 catalytically or simply relocates it was not resolved
    • In vivo mitotic phenotype of DYNLL2 depletion not tested
  5. 2010 High

    DYNLL2 was found to anchor the AMBRA1–Beclin 1–VPS34 autophagy initiation complex to dynein/cytoskeleton; ULK1-mediated phosphorylation of AMBRA1 releases the complex for ER-localized autophagosome nucleation, extending the sequestration-and-release paradigm to autophagy.

    Evidence Co-IP, ULK1 kinase assay, autophagy induction, subcellular fractionation, fluorescence microscopy

    PMID:20921139

    Open questions at the time
    • Relative contributions of DYNLL1 vs DYNLL2 to AMBRA1 tethering not separated
    • Structural basis of AMBRA1–DYNLL2 interaction unknown
  6. 2012 High

    BRET imaging and electrophysiology in living neurons demonstrated that the DYNLL2-GKAP interaction stabilizes the PSD and enhances NMDA receptor-mediated currents, with synaptic activity further promoting the interaction — establishing DYNLL2 as an activity-dependent regulator of excitatory synaptic strength.

    Evidence BRET in cultured neurons, NMDA-EPSC recording, immunostaining

    PMID:22328512

    Open questions at the time
    • Quantitative stoichiometry of complexes in spines vs shafts not determined
    • Upstream signals regulating activity-dependent DYNLL2-GKAP association unidentified
  7. 2014 High

    Quantitative fluorescence fluctuation microscopy revealed that DYNLL2 dimerization drives formation of large hetero-oligomeric GKAP–DYNLL2 assemblies preferentially in dendritic spines (~16 DYNLL2 + ~13 GKAP monomers), while shaft complexes are smaller tetramers — defining DYNLL2 as a dimerization engine for postsynaptic scaffold organization.

    Evidence Two-photon sN&B microscopy in living neurons, electrophysiology, disruption of GKAP-DYNLL2 binding

    PMID:24938595

    Open questions at the time
    • Mechanism driving spine-specific oligomer growth vs shaft tetramer is unknown
    • Contribution of other PSD components to the large complex not assessed
  8. 2014 High

    Atomic-resolution structures of DYNLL2 bound to the myosin 5a tail revealed that intrinsically disordered partner segments fold into β-strands within the DYNLL2 binding groove, with extended flanking contacts modifying quaternary organization — providing the structural basis for DYNLL2's role as a hub that orders disordered partners.

    Evidence NMR spectroscopy, X-ray crystallography, molecular dynamics simulation

    PMID:25312846

    Open questions at the time
    • Structures with other partners (Bmf, AMBRA1, GKAP) not yet solved
    • How flanking contacts influence selectivity among the many DYNLL2 partners is not clear
  9. 2025 Medium

    DYNLL2–PAK1 interaction was shown to regulate OMV endocytosis in macrophages, enabling cytosolic LPS release and Caspase-11/GSDMD-dependent pyroptosis, expanding DYNLL2's roles to innate immune signaling and identifying Oroxylin A as a pharmacological disruptor of this interaction.

    Evidence Co-IP, DYNLL2/PAK1 knockdown, Caspase-11/GSDMD cleavage assay, murine endotoxemia model, virtual screening and Oroxylin A treatment

    PMID:41360226

    Open questions at the time
    • Single-lab finding; independent replication and structural validation of Oroxylin A binding site needed
    • Whether DYNLL2 directly controls vesicle trafficking machinery or acts solely through PAK1 kinase activity is unresolved
    • Specificity of DYNLL2 vs DYNLL1 in this innate immune pathway not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying structural and selectivity model explaining how DYNLL2 discriminates among its many disordered partners and how phosphorylation at partner sites allosterically disrupts binding remains to be established, as does the degree of functional redundancy with the 93%-identical paralog DYNLL1 across its diverse cellular roles.
  • No systematic comparison of DYNLL1 vs DYNLL2 partner selectivity or knockout phenotypes
  • Structural basis of phosphorylation-induced partner release not determined for any partner
  • In vivo phenotype of DYNLL2-specific loss in mammalian systems not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005856 cytoskeleton 4 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1 R-HSA-9612973 Autophagy 1
Partners
AMBRA1BECN1BMFDLG4GKAPMYO5APAK1
Complex memberships
Dynein complex (LC8 light chain)Myosin V motor complexPSD-95–GKAP–DYNLL2 postsynaptic scaffold

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 DYNLL2 (DLC2, 93% identical to DLC1) was identified as a direct binding partner of GKAP (guanylate kinase domain-associated protein) via yeast two-hybrid screen. A complex containing PSD-95, GKAP, DYNLL2, and myosin-V was co-immunoprecipitated from rat brain extracts. DYNLL2 co-localizes with PSD-95 and F-actin in dendritic spines and is enriched in biochemical purifications of the postsynaptic density (PSD), suggesting a role in trafficking of the PSD-95 scaffold complex via motor proteins. Yeast two-hybrid screen, co-immunoprecipitation from rat brain, immunofluorescence co-localization, immunogold electron microscopy The Journal of Neuroscience High 10844022
2001 In healthy cells, the pro-apoptotic BH3-only protein Bmf is sequestered to myosin V motor complexes through direct association with dynein light chain 2 (DYNLL2). Certain damage signals such as loss of cell attachment (anoikis) release Bmf from DYNLL2, allowing it to translocate and bind pro-survival Bcl-2 proteins, thereby triggering apoptosis. This positions DYNLL2 as a cytoskeletal anchor that sequesters a pro-apoptotic sensor. Co-immunoprecipitation, subcellular fractionation, anoikis assay, functional apoptosis readout Science High 11546872
2003 JNK phosphorylates Bmf, which is normally sequestered by binding to dynein (via DYNLL2) and myosin V motor complexes. JNK-mediated phosphorylation of Bmf causes its release from the motor complexes, providing a mechanistic link between the JNK stress signaling pathway and mitochondrial (Bax/Bak-dependent) apoptosis. In vitro kinase assay, co-immunoprecipitation, Bax/Bak-dependent apoptosis readout, JNK gene disruption Proceedings of the National Academy of Sciences High 12591950
2009 CDK11p58 phosphorylates PAK1 at Ser174, and this phosphorylation event promotes the recruitment of PAK1 into a myosin V motor complex through binding to dynein light chain 2 (DYNLL2). The phosphomimetic PAK1(S174E) bound DYNLL2 and accelerated mitotic progression in a nocodazole-blocked cell model, whereas the non-phosphorylatable PAK1(S174A) had the opposite effect, indicating DYNLL2 mediates PAK1's role in mitosis downstream of CDK11p58. Co-immunoprecipitation, site-directed mutagenesis (S174A/S174E), nocodazole cell-cycle block assay, kinase substrate mapping Journal of Biochemistry Medium 19520772
2010 AMBRA1 tethers the BECLIN1-VPS34 autophagy core complex to the cytoskeleton through interaction with dynein light chains 1 and 2 (including DYNLL2). Upon autophagy induction, ULK1 phosphorylates AMBRA1, releasing the complex from dynein. This releases the autophagy complex to the endoplasmic reticulum, enabling autophagosome nucleation. Thus DYNLL2 participates in cytoskeletal anchoring of the autophagy initiation machinery. Co-immunoprecipitation, ULK1 kinase assay, autophagy induction assays, subcellular fractionation, fluorescence microscopy The Journal of Cell Biology High 20921139
2012 DYNLL2 interacts with GKAP in dendritic spines and this interaction stabilizes scaffolding protein expression at the postsynaptic density (PSD) and enhances synaptic NMDA receptor activity. BRET imaging showed the interaction occurs in spines; electrophysiological recording confirmed that disrupting the GKAP-DYNLL2 interaction reduces NMDA receptor-mediated currents. Sustained synaptic activity further promotes GKAP-DYNLL2 interaction, revealing an activity-dependent regulatory pathway. BRET imaging in living neurons, immunostaining, electrophysiological recording of NMDA receptor currents Journal of Cell Science High 22328512
2014 Using two-photon scanning number and brightness (sN&B) fluorescence fluctuation microscopy in living neurons, DYNLL2 dimerization was found to be required for its interaction with GKAP, which in turn potentiates GKAP self-association. In dendritic shafts, DYNLL2-GKAP complexes consist mainly of two DLC2 and two GKAP monomers, while in spines the hetero-complexes are much larger (~16 DYNLL2 and ~13 GKAP monomers). Disrupting the GKAP-DYNLL2 interaction decreased spine-preferential GKAP localization and inhibited NMDA receptor activity, demonstrating DYNLL2 functions as a dimerization engine organizing the postsynaptic scaffold. Two-photon scanning number and brightness (sN&B) fluorescence fluctuation microscopy, electrophysiology, fluorescence imaging in living neurons Journal of Cell Science High 24938595
2014 NMR spectroscopy, X-ray crystallography, and molecular dynamics simulations characterized DYNLL2 binding to the myosin 5a (myo5a) tail. The DYNLL2-binding region of myo5a resides in an intrinsically disordered domain with nascent helical character in the free form, which folds into a β-strand upon DYNLL2 binding. One peptide is accommodated in each parallel DYNLL2 binding groove. The myo5a motif has extended flanking contacts beyond the core consensus: N-terminal extension folds back partially blocking the β-sheet edge, while C-terminal extension contacts the dimer interface and interacts with symmetry-related residues of the second myo5a peptide. NMR spectroscopy, X-ray crystallography, molecular dynamics simulations Biochemistry High 25312846
2015 DYNLL2 protein levels in oxytocin neurons of the hypothalamic paraventricular nucleus (PVN) are regulated by fasted/fed states, being higher in the fed condition. In fed animals, NMDA receptor-mediated EPSCs on oxytocin neurons were increased. DYNLL2 upregulation correlated with increased NMDA receptor-mediated synaptic input, consistent with a role for DYNLL2 in NMDA receptor trafficking to the postsynaptic site in the context of metabolic state-dependent synaptic plasticity. Whole-cell electrophysiology (mEPSC and NMDA-EPSC recording), western blot for DYNLL2 protein, immunostaining Neuropeptides Medium 26344333
2022 In chicken primary myoblasts, DYNLL2 was identified as a hub gene controlling myoblast differentiation. miR-148a-3p was found to directly target DYNLL2 mRNA; overexpression of miR-148a-3p suppressed DYNLL2 and promoted myosin heavy chain (MYHC) expression and myoblast differentiation. This defines a miR-148a-3p → DYNLL2 regulatory axis in skeletal muscle fiber development. WGCNA on transcriptome data, miRNA transfection in chicken primary myoblasts, western blot for MYHC protein BMC Genomics Medium 35379193
2025 DYNLL2 interacts directly with PAK1 to regulate endocytosis of Gram-negative bacterial outer membrane vesicles (OMVs) in macrophages/monocytes. The DYNLL2-PAK1 complex facilitates cytosolic LPS release and subsequent Caspase-11 inflammasome activation, triggering pyroptosis via Gasdermin D (GSDMD) cleavage. Depletion of either DYNLL2 or PAK1 suppressed OMV internalization, Caspase-11/GSDMD cleavage, and proinflammatory cytokine release. The flavonoid Oroxylin A was identified as an inhibitor of the DYNLL2-PAK1 interaction that blocks Caspase-11-dependent pyroptosis in vitro and improves survival in murine endotoxemia models. Co-immunoprecipitation, DYNLL2/PAK1 knockdown, endotoxemia mouse model, Caspase-11/GSDMD cleavage assay, virtual screening, Oroxylin A pharmacological inhibition Biochemical Pharmacology Medium 41360226

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
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
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
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
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2003 JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America 881 12591950
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
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
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2001 Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis. Science (New York, N.Y.) 501 11546872
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
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
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2010 The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. The Journal of cell biology 395 20921139
2004 Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nature biotechnology 266 15146197
2011 Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. The EMBO journal 265 21399614
2012 Viral immune modulators perturb the human molecular network by common and unique strategies. Nature 219 22810585
2016 A High-Density Map for Navigating the Human Polycomb Complexome. Cell reports 216 27705803
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2000 Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein. The Journal of neuroscience : the official journal of the Society for Neuroscience 196 10844022
2005 Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. Proceedings of the National Academy of Sciences of the United States of America 96 16217026
2010 DLC2 modulates angiogenic responses in vascular endothelial cells by regulating cell attachment and migration. Oncogene 33 20208559
2009 Deleted in liver cancer 2 (DLC2) was dispensable for development and its deficiency did not aggravate hepatocarcinogenesis. PloS one 24 19668331
2005 Mitochondrial targeting of growth suppressor protein DLC2 through the START domain. FEBS letters 24 16364308
2014 The tumour suppressor DLC2 ensures mitotic fidelity by coordinating spindle positioning and cell-cell adhesion. Nature communications 20 25518808
2012 DLC2/StarD13 plays a role of a tumor suppressor in astrocytoma. Oncology reports 20 22614672
2009 START-GAP2/DLC2 is localized in focal adhesions via its N-terminal region. Biochemical and biophysical research communications 20 19250640
2012 GKAP-DLC2 interaction organizes the postsynaptic scaffold complex to enhance synaptic NMDA receptor activity. Journal of cell science 19 22328512
2015 Fasted/fed states regulate postsynaptic hub protein DYNLL2 and glutamatergic transmission in oxytocin neurons in the hypothalamic paraventricular nucleus. Neuropeptides 18 26344333
2014 DYNLL2 dynein light chain binds to an extended linear motif of myosin 5a tail that has structural plasticity. Biochemistry 16 25312846
2007 The NMR structure of the murine DLC2 SAM domain reveals a variant fold that is similar to a four-helix bundle. BMC structural biology 15 17519008
2017 In vivo evidence supporting a metastasis suppressor role for Stard13 (Dlc2) in ErbB2 (Neu) oncogene induced mouse mammary tumors. Genes, chromosomes & cancer 14 29218825
2022 Weighted gene co-expression network indicates that the DYNLL2 is an important regulator of chicken breast muscle development and is regulated by miR-148a-3p. BMC genomics 13 35379193
2009 CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression. Journal of biochemistry 11 19520772
2019 Role of DLC2 and RhoA/ROCK pathway in formalin induced inflammatory pain in mice. Neuroscience letters 10 31323253
2014 The stoichiometry of scaffold complexes in living neurons - DLC2 functions as a dimerization engine for GKAP. Journal of cell science 9 24938595
2011 The RhoA GTPase-activating protein DLC2 modulates RhoA activity and hyperalgesia to noxious thermal and inflammatory stimuli. Neuro-Signals 9 22204965
2018 DLC2 inhibits development of glioma through regulating the expression ratio of TAp73α/TAp73β. American journal of cancer research 8 30094094
2018 DLC2 operates as a tumor suppressor gene in breast cancer via the RhoGTPase pathway. Oncology letters 8 30719106
2012 Comparative next-generation mapping of the Phytophthora infestans resistance gene Rpi-dlc2 in a European accession of Solanum dulcamara. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 7 22907632
2025 Targeting the DYNLL2-PAK1 axis inhibits caspase-11-dependent pyroptosis to alleviate sepsis. Biochemical pharmacology 1 41360226