Affinage

SHANK3

SH3 and multiple ankyrin repeat domains protein 3 · UniProt Q9BYB0

Length
1806 aa
Mass
191.3 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHANK3 (ProSAP2) is a master postsynaptic scaffold of excitatory glutamatergic synapses that physically links membrane receptors to the actin cytoskeleton and, through self-assembly, organizes the material properties of the postsynaptic density (PSD) (PMID:10527873, PMID:40848728). Its PDZ domain binds the SAPAP/GKAP family to bridge PSD-95-associated receptors to deeper scaffold and cytoskeletal layers (PMID:10527873), while SAM domain-mediated oligomerization drives the PSD to behave as a glass-like condensate whose stiffness is required for normal synaptic transmission and plasticity (PMID:40848728). Loss of SHANK3 reduces synaptic Homer1b/c, GKAP, GluA1, mGluR5 and NMDAR subunits and impairs LTP/LTD, AMPAR redistribution, and mGluR5-dependent signaling (PMID:21558424, PMID:21565394, PMID:21795692), in part by disrupting Rac1/PAK/cofilin-dependent actin dynamics and NMDAR surface expression (PMID:24089484); SHANK3 also binds actin directly through its SPN domain under conformational control by the adjacent ARR domain (PMID:34610274). Beyond passive scaffolding, SHANK3 couples synaptic activity to the nucleus, serving as a required adaptor for CaMKIIα- and L-type calcium channel-driven CREB phosphorylation and c-Fos induction (PMID:32019829), and it nucleates dynamic signaling complexes with Rich2, the ABI1/WAVE complex, HCN channels, and CTTNBP2 to control spine morphology, AMPAR exocytosis, Ih currents, and zinc-tuned condensate stability (PMID:23739967, PMID:30610205, PMID:26966193, PMID:35562389). SHANK3 abundance at synapses is tightly regulated by zinc binding (PMID:21939532, PMID:27144302), by ubiquitin-proteasome turnover controlled by ERK2-mediated phosphorylation and USP8-mediated deubiquitination (PMID:30696942, PMID:29735556), by PP2A-gated phosphorylation that bidirectionally controls homeostatic scaling (PMID:35471151), and by DNA methylation, miRNAs, and downstream chromatin-modifying pathways (β-catenin/HDAC2, EHMT1/2) (PMID:17419801, PMID:26572867, PMID:29531362, PMID:30659288). SHANK3 deficiency models Phelan-McDermid syndrome and autism-associated phenotypes, with synaptic and behavioral deficits reversible by re-expression of SHANK3 or pharmacological restoration of downstream pathways (PMID:24132240, PMID:26886798, PMID:31332372). Outside the CNS, SHANK3 performs analogous scaffolding roles, regulating TRPV1 in nociceptors (PMID:27916453), TRPM2 in vagal neurons (PMID:36845137), intestinal barrier and zinc transport (PMID:28345660, PMID:28906292), skeletal muscle Z-disc integrity via α-ACTININ (PMID:32522805), and cardiac mitophagy via CaMKII (PMID:36436456).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 1999 High

    Establishing how postsynaptic receptors couple to deeper scaffold and cytoskeleton, the discovery that SHANK3's PDZ domain binds SAPAP/GKAP positioned SHANK3 as the physical link between PSD-95-bound receptors and the cytoskeleton.

    Evidence Yeast two-hybrid, reciprocal Co-IP, and co-transfection in HEK cells

    PMID:10527873

    Open questions at the time
    • Did not define higher-order scaffold assembly
    • No in vivo functional consequence shown
  2. 2005 Medium

    To explain how SHANK3 is delivered to synapses, deletion mapping identified a C-terminal SAM-domain-containing targeting signal required for postsynaptic localization.

    Evidence GFP-tagged deletion constructs and live imaging in hippocampal neurons

    PMID:15659222

    Open questions at the time
    • Molecular partners mediating targeting not identified
    • Mechanism of SAM-dependent targeting not resolved
  3. 2007 High

    Addressing why SHANK3 is expressed tissue-specifically, CpG island methylation was shown to causally control SHANK3 (but not SHANK1/2) protein levels.

    Evidence Bisulfite sequencing with methionine and 5-Aza-2′-deoxycytidine pharmacology and western blot

    PMID:17419801

    Open questions at the time
    • Methyl-binding effectors not identified
    • Link to disease-relevant expression changes not established
  4. 2011 High

    Genetic loss-of-function mouse and knockdown studies established SHANK3 as essential for excitatory synapse composition, plasticity, and circuit function, defining its role in striatal/cortico-striatal connectivity and receptor-specific deficits (Homer1b/c, GKAP, GluA1, mGluR5, NMDAR).

    Evidence Multiple Shank3 deletion mouse models with electrophysiology, PSD fractionation, and RNAi rescue

    PMID:21423165 PMID:21558424 PMID:21565394 PMID:21795692

    Open questions at the time
    • Different exon deletions yield partially distinct phenotypes
    • Isoform-specific contributions not yet separated
  5. 2011 High

    To explain how SHANK3 mutations destabilize the scaffold, a C-terminal truncation was shown to drive polyubiquitination and proteasomal redistribution of wild-type SHANK3 and NMDAR NR1, linking mutation to dominant scaffold loss.

    Evidence Co-IP, polyubiquitination assays, and LTP/LTD electrophysiology in a Shank3ΔC mouse

    PMID:21565394

    Open questions at the time
    • E3 ligase not identified at this stage
    • Generalizability to other truncations unknown
  6. 2011 Medium

    Identifying an upstream regulator of scaffold assembly, zinc was shown to be required for SHANK3 PSD localization, with amyloid-beta-mediated zinc sequestration reducing synaptic SHANK3 and synapse density.

    Evidence Cell-based Zn2+ binding assays, hippocampal cultures, and APP-PS1 mice with zinc supplementation

    PMID:21939532

    Open questions at the time
    • Zinc-binding site on SHANK3 not mapped here
    • Stoichiometry of zinc effect unclear
  7. 2013 High

    Expanding the partner network, proteomic and binding studies identified Rich2 and clarified intramolecular autoinhibition (SPN–ARR) controlling Sharpin/α-fodrin access, linking SHANK3 conformation to spine plasticity and AMPAR exocytosis.

    Evidence Proteomic screen, BRET, interfering peptides, and binding assays with ASD mutants

    PMID:23739967 PMID:23897824

    Open questions at the time
    • Regulation of the conformational switch in vivo not defined
    • Cross-talk between ligand sets not resolved
  8. 2013 Medium

    Establishing transsynaptic and nuclear roles, SHANK3 was shown to modulate Neurexin-Neuroligin presynaptic function and to undergo activity-dependent synapse-to-nucleus shuttling that alters transcription, with a schizophrenia mutation causing constitutive nuclear accumulation.

    Evidence Overexpression/knockdown electrophysiology and nuclear/synaptic fractionation with transcriptional analysis

    PMID:23100419 PMID:24382453

    Open questions at the time
    • Nuclear interaction partners incompletely defined
    • Physiological significance of shuttling in vivo unclear
  9. 2013 High

    To resolve how SHANK3 controls NMDAR function, knockdown was shown to drive NMDAR hypofunction through Rac1/PAK/cofilin-mediated actin disruption and reduced NR1 surface expression.

    Evidence siRNA knockdown, surface biotinylation, and pharmacological epistasis on the Rac1/PAK/cofilin pathway

    PMID:24089484

    Open questions at the time
    • Direct biochemical link between SHANK3 and Rac1/PAK not shown
    • Whether actin effect is direct or scaffold-mediated unclear
  10. 2013 High

    Human-cell validation: SHANK3 re-expression restored excitatory transmission deficits in Phelan-McDermid syndrome iPSC neurons, and IGF1 provided a SHANK3-independent rescue, anchoring SHANK3 function in human disease neurons.

    Evidence PMDS patient iPSC neurons with lentiviral SHANK3 rescue, IGF1 treatment, and electrophysiology

    PMID:24132240

    Open questions at the time
    • Mechanism of IGF1 bypass not defined
    • Long-term/in vivo translatability unaddressed
  11. 2014 Medium

    Characterizing SHANK3 complexity, multiple intragenic promoters and splicing were shown to generate isoforms with distinct localization, regulation, and spine effects, explaining cell-type and activity specificity.

    Evidence RT-PCR, qPCR, western blot, and imaging of isoform-specific GFP constructs

    PMID:25071925

    Open questions at the time
    • Functional roles of individual isoforms incompletely mapped
    • Isoform-specific partner repertoires unknown
  12. 2015 Medium

    Post-transcriptional control of SHANK3 was established via direct miRNA targeting of its 3'UTR (miR-7, miR-34a, miR-504), affecting spine morphology in a SHANK3-dependent manner.

    Evidence Luciferase 3'UTR reporters and lentiviral miRNA manipulation in hippocampal neurons

    PMID:26572867

    Open questions at the time
    • Physiological contexts engaging each miRNA unclear
    • In vivo relevance not tested
  13. 2015 High

    Extending SHANK3 beyond the CNS, its proline-rich region was shown to bind TRPV1 and regulate TRPV1 surface expression in DRG neurons, defining a peripheral role in pain signaling.

    Evidence Co-IP, surface expression assays, conditional Nav1.8-Cre knockout, and behavioral pain assays

    PMID:27916453

    Open questions at the time
    • Whether scaffolding mechanism mirrors CNS PSD role unclear
    • Other peripheral TRPV1 contexts untested
  14. 2016 High

    SHANK3 was shown to bind HCN channel subunits and control Ih currents, identifying an Ih channelopathy as a downstream mediator of SHANK3 mutation phenotypes.

    Evidence Co-IP, Ih electrophysiology in engineered human and mouse neurons, and pharmacological Ih blockade phenocopy

    PMID:26966193 PMID:29327340

    Open questions at the time
    • Domain mediating HCN binding not fully mapped
    • Relative contribution of Ih vs glutamatergic deficits unclear
  15. 2016 High

    Mechanistic and therapeutic insight into reversibility came from Akt-mTORC1/PP2A-B56β/CLK2 signaling deficits and adult SHANK3 re-expression rescuing synaptic and select behavioral phenotypes.

    Evidence Phosphoproteomics with genetic/pharmacological CLK2-Akt manipulation, and inducible adult Shank3 re-expression mouse

    PMID:26847545 PMID:26886798

    Open questions at the time
    • Why some phenotypes (anxiety, motor) are irreversible unknown
    • Direct vs indirect link of SHANK3 to PP2A/CLK2 unresolved
  16. 2016 High

    Linking SHANK3 to chromatin, β-catenin/HDAC2 signaling was shown to mediate social deficits, with HDAC inhibition restoring NMDAR function and actin gene expression.

    Evidence Co-IP, nuclear fractionation, HDAC2 knockdown, romidepsin treatment, ChIP, and behavior

    PMID:29531362

    Open questions at the time
    • How synaptic SHANK3 loss elevates nuclear β-catenin not fully defined
    • Direct chromatin targets incompletely cataloged
  17. 2017 Medium

    Peripheral epithelial roles emerged: SHANK3 binds ZIP4 to control intestinal zinc transport and regulates barrier integrity through a PKCε-ZO-1 pathway.

    Evidence Co-IP, knockdown in Caco-2/iPSC enterocytes, and Shank3 KO mice with permeability assays

    PMID:28345660 PMID:28906292

    Open questions at the time
    • Mechanism connecting SHANK3 to PKCε not defined
    • Relationship between zinc transport and barrier roles unclear
  18. 2018 Medium

    USP8 was identified as a deubiquitinase stabilizing SHANK3, establishing reversible ubiquitination as a control point for activity-dependent SHANK3 levels and spine density.

    Evidence Co-IP, deubiquitination assays, and bidirectional USP8 manipulation in rat neurons

    PMID:29735556

    Open questions at the time
    • E3 ligase counterpart not jointly defined here
    • Activity signals driving USP8 engagement unclear
  19. 2019 High

    The kinase coupling SHANK3 degradation to signaling was identified as ERK2, which directly binds and phosphorylates SHANK3 to promote ubiquitin-dependent turnover, complementing modular roles defined by the S685/ABI1-WAVE axis.

    Evidence Kinome-wide screen, binding/phosphorylation/ubiquitination assays, in vivo ERK2 inhibition, and S685 knock-in mouse with Co-IP

    PMID:30610205 PMID:30696942

    Open questions at the time
    • Identity of the E3 ligase remains undefined
    • Interplay between ERK2 phosphosites and other regulatory sites unclear
  20. 2019 High

    Circuit- and chromatin-level mechanisms were refined: ACC-restricted SHANK3 loss is sufficient for social deficits rescuable by AMPAR potentiation, and EHMT1/2-driven H3K9me2 (via Arc) mediates NMDAR and behavioral deficits.

    Evidence Region-specific conditional KO with pharmacological rescue, and EHMT1/2 inhibition/knockdown with human postmortem confirmation and electrophysiology

    PMID:30659288 PMID:31332372

    Open questions at the time
    • How synaptic SHANK3 loss elevates EHMT1/2 not defined
    • Generalizability across brain regions partially open
  21. 2020 High

    SHANK3 was established as a required adaptor for activity-to-nucleus signaling through direct CaMKIIα binding (residues 829–1130; RRK949-951) coupling LTCCs to CREB/c-Fos, and direct SPN-domain actin binding under ARR-conformational and Rap1-competitive control.

    Evidence Direct binding with purified CaMKIIα, mutagenesis, shRNA/rescue, actin co-sedimentation, and molecular simulations

    PMID:32019829 PMID:34610274

    Open questions at the time
    • How conformational opening is triggered physiologically unclear
    • Integration of CaMKII and actin functions not unified
  22. 2020 High

    Non-neuronal scaffolding roles were defined in skeletal muscle, where SHANK3 binds α-ACTININ at Z-discs to maintain sarcomere and NMJ integrity, with pharmacological rescue of motor deficits.

    Evidence Co-IP, Z-disc immunofluorescence in myotubes, Shank3 mice, patient biopsies, and Tirasemtiv rescue

    PMID:32522805

    Open questions at the time
    • Whether muscle role uses same domains as PSD scaffolding unclear
    • Contribution to PMDS motor phenotype quantification incomplete
  23. 2020 Medium

    The transcriptional-repression mechanism of truncated SHANK3 was clarified: truncations expose an N-terminal NLS, and the PDZ domain binds β-catenin armadillo repeats to sequester both in nuclear bodies and repress β-catenin transcription.

    Evidence Fractionation, Co-IP, NLS mutagenesis, and luciferase reporter assays

    PMID:32202324

    Open questions at the time
    • In vivo relevance of nuclear sequestration not established
    • Target gene set repressed not defined
  24. 2021 Medium

    Biophysical analyses tied ASD missense mutations to altered protein structure, conformational flexibility, synaptic targeting, and turnover, connecting molecular destabilization to synaptic dysfunction.

    Evidence SAXS, biophysical structural analysis, and FRAP in rat hippocampal neurons

    PMID:33945465

    Open questions at the time
    • High-resolution structures not determined
    • Direct link from conformational change to specific binding losses unclear
  25. 2022 Medium

    Phase-separation principles entered SHANK3 biology: CTTNBP2 promotes SHANK3 co-condensation, and zinc drives a liquid-to-gel transition stabilizing synaptic condensates, mechanistically integrating zinc regulation with material-state control.

    Evidence Co-condensation/phase separation assays, FRAP, zinc supplementation, and mouse behavior

    PMID:35562389

    Open questions at the time
    • Relationship to SAM-domain oligomerization not unified here
    • Endogenous zinc dynamics governing transition unclear
  26. 2022 High

    Homeostatic plasticity control was assigned to PP2A-gated SHANK3 phosphorylation at S1586/S1615, which bidirectionally gates synaptic scaling and modifies SHANK3 synaptic localization.

    Evidence Deep-scale phosphoproteomics, phosphomimetic/phosphodeficient mutagenesis, PP2A inhibition, and scaling assays

    PMID:35471151

    Open questions at the time
    • Kinase(s) opposing PP2A at these sites not identified
    • How phosphorylation alters localization mechanistically unclear
  27. 2022 Medium

    Additional peripheral and signaling roles were defined: SHANK3 binds STIM1 to promote its degradation and engage Nrf2 antioxidant signaling, binds cardiac CaMKII to regulate mitophagy, and forms ADNP-actin complexes amenable to NAP rescue.

    Evidence Co-IP, conditional/double KO models, mitophagy/oxidative assays, and NAP behavioral rescue

    PMID:35538192 PMID:36436456 PMID:38064762

    Open questions at the time
    • Tissue-specific generality of these interactions unclear
    • Shared vs distinct domains used for each partner undefined
  28. 2023 Medium

    A vagal-neuron role was established whereby SHANK3 regulates TRPM2 expression to control body temperature and systemic inflammation, extending non-synaptic peripheral functions.

    Evidence Conditional KO, vagal knockdown, RNAscope, and LPS inflammation model

    PMID:36845137

    Open questions at the time
    • Mechanism linking SHANK3 to TRPM2 transcription unclear
    • Direct physical interaction not demonstrated
  29. 2024 Medium

    SHANK3 function was extended to oligodendrocyte lineage cells, where mutation impairs glutamatergic signaling, myelination transcripts, myelin ultrastructure, and axonal conductivity, broadening its role beyond neurons.

    Evidence InsG3680 mice, patient iPSC-derived oligodendrocytes, electrophysiology, and electron microscopy

    PMID:39392881

    Open questions at the time
    • Whether oligodendrocyte SHANK3 uses the same PSD machinery unclear
    • Contribution of myelin deficits to behavior not quantified
  30. 2025 High

    The unifying biophysical principle was established: SAM-domain oligomerization drives the PSD condensate into a glass-like material state via network percolation, and disrupting it softens the condensate, impairs plasticity, and causes autistic-like behavior.

    Evidence Reconstituted PSD condensate with rheology, SAM oligomerization mutagenesis, electrophysiology, and knock-in mouse behavior

    PMID:40848728

    Open questions at the time
    • How material state mechanistically tunes receptor signaling unclear
    • Regulators of glass-state transition in vivo undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SHANK3's many regulatory inputs (zinc, phosphorylation, ubiquitination, conformational state, phase separation) are integrated in real time to set PSD composition and material properties, and which E3 ligase executes ERK2/ubiquitin-dependent degradation, remain unresolved.
  • E3 ligase for SHANK3 degradation unidentified
  • Unified model linking condensate material state to receptor signaling missing
  • Domain logic distinguishing CNS scaffolding from peripheral roles undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 3 GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-4839726 Chromatin organization 3
Partners
ACTN2 (Α-ACTININ)CAMKIICTNNB1 (Β-CATENIN)CTTNBP2GKAP/SAPAPHCN2HOMER1TRPV1
Complex memberships
WAVE regulatory complex (ABI1/WAVE)postsynaptic density (PSD)

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 SHANK3 (ProSAP2) PDZ domain directly binds SAPAP/GKAP family proteins, as demonstrated by yeast two-hybrid, co-immunoprecipitation, and co-transfection in HEK cells, establishing SHANK3 as a link between SAP90/PSD-95-bound membrane receptors and the cytoskeleton at glutamatergic synapses. Yeast two-hybrid, co-immunoprecipitation, co-transfection in HEK cells Biochemical and biophysical research communications High 10527873
2005 Postsynaptic targeting of ProSAP2/SHANK3 in hippocampal neurons requires the integrity of the C-terminus, specifically a region encompassing the SAM domain; removal of 54 residues from the N-terminus of the minimal targeting construct resulted in diffuse cytoplasmic distribution, defining a novel C-terminal synaptic targeting signal. GFP-tagged deletion constructs expressed in hippocampal neurons, live imaging Journal of neurochemistry Medium 15659222
2006 ProSAPiP1 is a novel binding partner of ProSAP2/SHANK3 PDZ domain; the complex co-immunoprecipitates and co-localizes at excitatory spines/synapses, and ProSAPiP1 links SPAR to synapses via ProSAP2/SHANK3, adding a new node to the PSD scaffold network. Co-immunoprecipitation, co-localization by confocal microscopy, yeast two-hybrid The Journal of biological chemistry Medium 16522626
2007 Tissue-specific expression of SHANK3 (but not SHANK1 or SHANK2) is regulated by DNA methylation of its CpG islands: CpG islands are hypermethylated in tissues with low/absent SHANK3 protein and unmethylated in expressing tissues; SHANK3 protein is reduced in hippocampal neurons after methionine treatment and induced in HeLa cells after 5-Aza-2′-deoxycytidine treatment. Bisulfite sequencing, methionine treatment, 5-Aza-2′-deoxycytidine treatment, western blot Journal of neurochemistry High 17419801
2011 Shank3 deletion in mice causes defects at striatal synapses and cortico-striatal circuits, demonstrating a critical role for SHANK3 in neuronal connectivity; electrophysiological and biochemical analyses revealed reduced postsynaptic density proteins at striatal synapses. Genetic mouse model (Shank3 deletion), electrophysiology, biochemical PSD fractionation, behavioral analysis Nature High 21423165
2011 Loss of major Shank3 isoforms (exons 4-9 deletion) reduces synaptic levels of Homer1b/c, GKAP, and GluA1 at the PSD and attenuates activity-dependent redistribution of GluA1-containing AMPA receptors, impairing LTP in CA1 hippocampus. Genetic mouse model, PSD biochemical fractionation, western blot, electrophysiology (LTP recordings), immunofluorescence Human molecular genetics High 21558424
2011 A C-terminal deletion mutation of Shank3 (Shank3ΔC) causes the mutant protein to interact with wild-type Shank3 and promote its polyubiquitination and redistribution to proteasomes, resulting in >90% reduction of Shank3 at synapses; similarly, the NR1 subunit of NMDA receptor shows increased polyubiquitination and reduced synaptic levels, leading to reduced NMDAR-dependent LTP and LTD and enhanced mGluR-dependent LTD. Genetic mouse model, co-immunoprecipitation, polyubiquitination assay, electrophysiology (LTP/LTD recordings), proteasome fractionation Cell High 21565394
2011 SHANK3 knockdown in neuronal cultures specifically reduces synaptic expression of mGluR5 (but not other major synaptic proteins), impairs mGluR5-dependent ERK1/2 and CREB phosphorylation, impairs mGluR5-dependent LTD, and reduces mEPSC frequency; these effects are rescued by a positive allosteric modulator of mGluR5. RNAi knockdown in neuronal cultures, western blot, immunofluorescence, electrophysiology (mEPSC recording, LTD), ERK/CREB phosphorylation assays The Journal of biological chemistry High 21795692
2011 Zinc sequestration by amyloid-beta prevents association of Zn2+ ions with ProSAP2/SHANK3, leading to reduced ProSAP2/Shank3 at the PSD and decreased synapse density; zinc supplementation or pre-saturation of Aβ with zinc countered these effects, demonstrating zinc-dependent regulation of SHANK3 scaffold assembly. Cell-based Zn2+ binding assay, rat hippocampal cultures, zinc supplementation, immunofluorescence, synapse density quantification, APP-PS1 mouse model Molecular neurodegeneration Medium 21939532
2012 Synaptic levels of ProSAP2/SHANK3 regulate AMPA and NMDA receptor-mediated synaptic transmission and modulate presynaptic structure/function through Neurexin-Neuroligin transsynaptic signaling; ASD-associated mutations in SHANK3 disrupt both postsynaptic receptor signaling and transsynaptic signaling. Overexpression and knockdown in rat hippocampal neurons, electrophysiology (AMPAR/NMDAR EPSCs), immunofluorescence of pre/postsynaptic proteins The Journal of neuroscience Medium 23100419
2013 SHANK3 expression restores excitatory synaptic transmission deficits in iPSC-derived neurons from Phelan-McDermid syndrome patients; IGF1 treatment promotes formation of mature excitatory synapses lacking SHANK3 but containing PSD95 and NMDA receptors, demonstrating SHANK3's role in excitatory synapse function in human neurons. iPSC-derived neurons from PMDS patients, lentiviral SHANK3 re-expression, IGF1 treatment, electrophysiology (synaptic transmission recordings), immunofluorescence Nature High 24132240
2013 Shank3 deficiency induces NMDA receptor hypofunction via actin cytoskeleton disruption through the Rac1/PAK/cofilin signaling pathway; Shank3 siRNA reduces NR1 surface expression and NMDAR currents, effects blocked by actin stabilizers and constitutively active Rac1 or PAK, and occluded by Rac1/PAK inhibitors or cofilin activation. siRNA knockdown in rat cortical cultures, whole-cell patch clamp (NMDAR currents), surface biotinylation, immunocytochemistry (F-actin), pharmacological manipulation of Rac1/PAK/cofilin pathway The Journal of neuroscience High 24089484
2013 Rich2 (Rho-GAP interacting CIP4 homolog 2) is a new Shank3 binding partner identified by proteomics; Rich2-Shank3 interaction increases in dendritic spines during LTP; Rich2 controls AMPA receptor GluA1 exocytosis; disruption of the Rich2-Shank3 complex inhibits spine enlargement and GluA1 exocytosis during LTP. Proteomic screen, BRET microscopy, siRNA knockdown, interfering mimetic peptide, AMPA receptor exocytosis assay, spine morphology analysis The Journal of neuroscience High 23739967
2013 ProSAP2/Shank3 undergoes activity-dependent synapse-to-nucleus shuttling in hippocampal neurons; a schizophrenia-associated de novo mutation (R1117X) causes constitutive nuclear accumulation independent of synaptic activity and alters transcription of schizophrenia risk genes (Synaptotagmin 1, LRRTM1), identifying novel nuclear interaction partners. Immunofluorescence, live imaging, activity manipulation (TTX/bicuculline), nuclear/synaptic fractionation, transcriptional analysis Experimental neurology Medium 24382453
2013 The Shank3 ankyrin repeat region is regulated by an intramolecular interaction with the adjacent SPN (Shank/ProSAP N-terminal) domain, which restricts access of ligands Sharpin and α-fodrin; ASD-associated L68P mutation disrupts this intramolecular blockade, resulting in a gain-of-function with enhanced binding to these ligands. Binding assays in heterologous cells, expression of wild-type and mutant Shank3 in neurons, electrophysiology (rescue experiments after knockdown) The Journal of biological chemistry Medium 23897824
2014 Shank3 gene displays extensive mRNA and protein isoforms from multiple intragenic promoters and alternative splicing; isoform expression is brain-region/cell-type specific, developmentally regulated, activity-dependent, and epigenetically controlled; different Shank3 isoforms show distinct subcellular distributions and differential effects on dendritic spine morphology in hippocampal neurons. RT-PCR, quantitative real-time RT-PCR, western blot, cellular imaging of isoform-specific GFP constructs in hippocampal neurons Molecular autism Medium 25071925
2015 SHANK3 interacts with TRPV1 via its proline-rich region in dorsal root ganglion sensory neurons and regulates TRPV1 surface expression; Shank3 haploinsufficiency reduces capsaicin-induced spontaneous pain, DRG neuron inward currents, and spinal cord synaptic currents, establishing a peripheral mechanistic role for SHANK3 in pain signaling. Co-immunoprecipitation (SHANK3-TRPV1), surface expression assay, patch clamp electrophysiology, conditional knockout (Nav1.8-Cre), behavioral pain assays Neuron High 27916453
2016 SHANK3 mutations severely and specifically impair hyperpolarization-activated cation (Ih) channels; SHANK3 protein interacts with HCN channel proteins (HCN1, HCN2, HCN4); chronic pharmacological blockage of Ih channels reproduces SHANK3 mutation phenotypes (altered neuronal morphology and synaptic connectivity), suggesting Ih channelopathy mediates downstream effects. Engineered conditional mutations in human neurons, electrophysiology (Ih current recording), co-immunoprecipitation (SHANK3-HCN), pharmacological Ih blockade, mouse Shank3-deficient neurons Science High 26966193
2016 Shank3 deficiency causes down-regulation of Akt-mTORC1 signaling through enhanced phosphorylation and activation of PP2A regulatory subunit B56β due to increased steady-state levels of its kinase CLK2; pharmacological/genetic Akt activation or CLK2 inhibition relieves synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. Quantitative phosphoproteomics, pharmacological and genetic manipulation (CLK2 inhibition, Akt activation), electrophysiology in patient iPSC-derived neurons, behavioral assays in Shank3-deficient mice Science High 26847545
2016 Re-expression of Shank3 in adult mice (after developmental absence) improves synaptic protein composition, spine density, and neural function in the striatum, and rescues social interaction deficits and repetitive grooming, but not anxiety or motor coordination deficits, demonstrating partial reversibility of Shank3-dependent phenotypes. Conditional knock-in mouse model (inducible Shank3 re-expression), western blot, spine density analysis, electrophysiology, behavioral assays Nature High 26886798
2016 Shank3 deficiency increases nuclear localization of β-catenin (a Shank3-binding protein), which induces HDAC2 upregulation and social deficits; HDAC2 knockdown in PFC rescues social deficits; romidepsin (HDAC inhibitor) treatment elevates expression and histone acetylation of Grin2a and actin-regulatory genes, restoring NMDA-receptor function and actin filaments. Co-immunoprecipitation (Shank3-β-catenin), nuclear fractionation, HDAC2 knockdown, HDAC inhibitor treatment, NMDA receptor electrophysiology, ChIP (histone acetylation), behavioral assays Nature neuroscience High 29531362
2016 Zinc stabilizes Shank3 at the postsynaptic density; zinc supplementation increases Shank3 labeling intensity at PSD and prevents reversal of NMDA-induced Shank3 accumulation, demonstrated by pre-embedding immunogold electron microscopy. Pre-embedding immunogold electron microscopy, depolarization (high K+) and NMDA treatment, zinc supplementation in dissociated rat hippocampal cultures PloS one Medium 27144302
2017 Shank3 protein interaction with ZIP4 (zinc uptake transporter) was demonstrated by co-immunoprecipitation; SHANK3-deficient enterocytes show decreased expression of ZIP2 and ZIP4 correlating with SHANK3 levels, and reduced ZIP4 co-localizes with SHANK3 at the plasma membrane, identifying a role for SHANK3 in intestinal zinc homeostasis. Co-immunoprecipitation (ZIP4-SHANK3), SHANK3 knockdown in Caco-2 cells, iPSC-derived enterocytes from PMDS patients, immunohistochemistry in Shank3αβ KO mice Scientific reports Medium 28345660
2017 SHANK3 regulates intestinal barrier function by modulating ZO-1 expression through a PKCε-dependent pathway; SHANK3 overexpression enhances ZO-1 expression while knockdown reduces it; SHANK3 KO mice show leaky epithelial barrier. SHANK3 overexpression/knockdown in intestinal epithelial cells, SHANK3 KO mouse model, TEER/paracellular permeability assays, western blot (ZO-1, PKCε), immunoblotting Inflammatory bowel diseases Medium 28906292
2018 USP8 is a deubiquitinating enzyme that regulates SHANK3 ubiquitination and protein levels; USP8 enhances SHANK3 and SHANK1 protein levels via deubiquitination, increases dendritic spine density, and is essential for activity-dependent changes in SHANK3 protein levels. Co-immunoprecipitation (USP8-SHANK3), ubiquitination assay, USP8 overexpression/knockdown in primary rat neurons, western blot, dendritic spine analysis The Journal of neuroscience Medium 29735556
2019 An ASD-linked missense variant at Shank3 S685 disrupts recruitment of ABI1 and the WAVE complex to the PSD, impairing synapse and dendritic spine development; this function is independent of Shank3's binding to GKAP and Homer, demonstrating modular independent functions of Shank3. In vivo phosphorylation profiling, co-immunoprecipitation (Shank3-ABI1/WAVE complex), knock-in mouse model with S685 mutation, dendritic spine analysis, behavioral assays Molecular psychiatry Medium 30610205
2019 Conditional knockout of Shank3 in the anterior cingulate cortex (ACC) is sufficient to cause excitatory synaptic dysfunction and social interaction deficits; selective enhancement of ACC activity, SHANK3 restoration in ACC, or systemic AMPA receptor-positive modulator administration improved social behavior in Shank3 mutant mice. Conditional knockout (region-specific Cre), electrophysiology (excitatory synaptic transmission), behavioral assays, pharmacological rescue Nature neuroscience High 31332372
2019 ERK2 binds Shank3 directly and phosphorylates it at three residues to promote poly-ubiquitination-dependent degradation; genetic deletion or pharmacological inhibition of ERK2 increases Shank3 protein abundance in vivo. Kinome-wide siRNA screen, ERK2-Shank3 co-immunoprecipitation/binding, phosphorylation assay, ubiquitination assay, in vivo pharmacological/genetic ERK2 inhibition, western blot Molecular psychiatry High 30696942
2019 SHANK3 mutations increase histone methyltransferases EHMT1/2 and H3K9me2 in prefrontal cortex; EHMT1/2 inhibition or knockdown rescues autism-like social deficits and restores NMDAR-mediated synaptic function; Arc was identified as a causal downstream factor for NMDAR function rescue. Western blot (EHMT1/2, H3K9me2 in Shank3 KD mice and human postmortem brains), EHMT1/2 inhibitor (UNC0642) treatment, EHMT knockdown in PFC, electrophysiology (NMDAR currents), behavioral assays Molecular psychiatry High 30659288
2020 SHANK3 localizes to Z-discs in skeletal muscle sarcomeres and co-immunoprecipitates with α-ACTININ; SHANK3 deficiency leads to shortened Z-discs, impaired acetylcholine receptor clustering at neuromuscular junctions, and motor deficits rescued by troponin activator Tirasemtiv. Co-immunoprecipitation (SHANK3-α-ACTININ), immunofluorescence (Z-disc localization), hiPSC-derived myotubes, Shank3Δ11-/- mice, PMDS patient muscle biopsies, behavioral rescue with Tirasemtiv Science translational medicine High 32522805
2020 CaMKIIα directly binds Shank3 between residues 829–1130; mutation of Shank3 residues 949Arg-Arg-Lys951 to alanines disrupts CaMKII binding; both Shank3 binding to CaMKII and to LTCCs is required for depolarization-induced CREB phosphorylation and c-Fos expression, establishing Shank3 as a required scaffold for LTCC-to-nucleus signaling. Co-immunoprecipitation from mouse forebrain, direct binding assay with purified CaMKIIα, site-directed mutagenesis, shRNA/rescue in hippocampal neurons, CREB phosphorylation and c-Fos expression assays The Journal of neuroscience High 32019829
2020 Truncating mutations in SHANK3 that remove postsynaptic targeting sequences expose a nuclear localization signal in the N-terminal part of the protein; truncated SHANK3 interacts with β-catenin via the PDZ domain of SHANK3 and armadillo repeats of β-catenin, sequestering both in nuclear bodies and strongly repressing β-catenin-dependent transcriptional activation. Subcellular localization analysis (immunofluorescence, fractionation), co-immunoprecipitation (truncated Shank3-β-catenin), luciferase transcriptional reporter assays, NLS identification and mutagenesis Journal of neurochemistry Medium 32202324
2021 Two ASD-associated missense mutations in SHANK3 cause distinct changes in secondary and tertiary protein structure, increased conformational fluctuations (by SAXS and biophysical analysis), and result in altered synaptic targeting and changes in protein turnover at synaptic sites in rat primary hippocampal neurons. SAXS, biophysical structural analysis, FRAP in rat hippocampal neurons, synaptic localization analysis eLife Medium 33945465
2021 SHANK3 directly interacts with actin through its SPN domain; this interaction is inhibited by an intramolecular closed conformation where the adjacent ARR domain covers the actin-binding interface; actin and Rap1 compete for binding to SHANK3; SHANK3-actin interaction regulates dendritic spine morphology in neurons. Molecular simulations, targeted mutagenesis, actin co-sedimentation assay, co-immunoprecipitation, dendritic spine morphology analysis in neurons, integrin activity assay in cancer cells Current biology High 34610274
2022 Phosphorylation of Shank3 at S1586 and S1615 bidirectionally gates homeostatic synaptic scaling: sites are hypophosphorylated during scaling up (via PP2A activity) and hyperphosphorylated during scaling down; phosphomimetic mutations prevent scaling up while phosphodeficient mutations prevent scaling down; these phosphorylation states modify Shank3 synaptic localization. Deep-scale quantitative phosphoproteomics, immunoaffinity isolation, phosphomimetic/phosphodeficient mutagenesis, PP2A pharmacological inhibition, synaptic scaling assay, Shank3 synaptic localization analysis in neocortical neurons eLife High 35471151
2022 SHANK3 interacts with STIM1 via direct binding and promotes proteasome-mediated degradation of STIM1; STIM1 downregulation via SHANK3 induces Nrf2 Ser40 phosphorylation, Nrf2 nuclear translocation, and upregulation of antioxidant genes (NQO1, HO-1), protecting against ischemia/reperfusion-induced oxidative stress and inflammation. Co-immunoprecipitation (Shank3-STIM1), Shank3 conditional KO and double KO (Shank3+Stim1), western blot (Nrf2, NQO1, HO-1), in vitro HT22 cell assays, in vivo I/R mouse model Redox biology Medium 38064762
2022 CTTNBP2 facilitates SHANK3 co-condensation at dendritic spines through liquid-liquid phase separation; zinc binding to CTTNBP2 promotes liquid-to-gel phase transition, reducing CTTNBP2 mobility and enhancing stability/synaptic retention of CTTNBP2-SHANK3 condensates. Co-condensation assays, FRAP, phase separation assays, zinc supplementation, ASD mutation analysis, behavioral assays in mice Nature communications Medium 35562389
2022 ADNP interacts with SHANK3 and actin in mouse brain extracts; NAP (ADNP-derived peptide) normalizes Shank3-Adnp-actin interactions as shown by actin co-immunoprecipitation, and NAP treatment ameliorates behavior in Shank3 InsG3680 mutant mice. Co-immunoprecipitation (Shank3-Adnp-actin) from mouse brain, NAP treatment, behavioral assays in Shank3 InsG3680 mice Molecular psychiatry Medium 35538192
2022 Cardiac Shank3 directly binds CaMKII (demonstrated by IP assay), and this interaction increases in the aged heart; enhanced Shank3/CaMKII binding impedes mitochondrial translocation of CaMKII, inhibiting Parkin-mediated mitophagy and causing mitochondrial dysfunction and cardiac damage. Co-immunoprecipitation (cardiac Shank3-CaMKII), cardiac-specific Shank3 conditional KO, mitophagy assays, mitochondrial function assays Redox biology Medium 36436456
2023 Shank3 in vagal sensory neurons (nodose ganglion) regulates TRPM2 expression; Shank3 deficiency in Nav1.8-expressing sensory neurons or selective Shank3 knockdown in vagal neurons impairs body temperature regulation and increases LPS-induced systemic inflammation (IL-6), identifying a peripheral, non-synaptic role for SHANK3. Conditional Shank3 KO (Nav1.8-Cre), Shank3/Trpm2 knockdown in nodose ganglion, RNAscope in situ hybridization, LPS inflammation model, body temperature measurement Frontiers in immunology Medium 36845137
2009 ProSAPiP2 is a novel binding partner of ProSAP2/SHANK3 PDZ domain, expressed in neurons, localized to dendrites and spines and enriched in the PSD; it interacts with actin, potentially linking PSD components to the cytoskeleton. Co-immunoprecipitation, immunofluorescence, PSD fractionation, actin binding assay Biochemical and biophysical research communications Low 19481056
2015 miR-7, miR-34a, and miR-504 post-transcriptionally regulate SHANK3 expression through direct binding sites in the 3' UTR; overexpression or inhibition of miR-7 and miR-504 affected dendritic spines in hippocampal neurons in a Shank3-dependent manner. Luciferase reporter assay (miRNA 3' UTR binding), lentiviral miRNA overexpression in hippocampal neurons, western blot, spine morphology analysis Molecular brain Medium 26572867
2018 Shank3 deficiency causes Ih channelopathy in thalamocortical neurons; Shank3 increases HCN channel surface expression in heterologous systems; Shank3Δ13-16 deficiency causes reduction in HCN2 expression and Ih current amplitude, altered resting membrane potential, increased input resistance, and abnormal spike firing—phenotypes resembling HCN2-/- TC neurons. Heterologous expression of Shank3 isoforms with HCN channels (surface expression assay), electrophysiology (Ih current recording) in thalamocortical neurons from Shank3 KO mice, comparison with HCN2-/- mice The Journal of physiology High 29327340
2024 Shank3 mutation (InsG3680) impairs glutamatergic signaling in oligodendrocytes and reduces expression of myelination-related transcripts and proteins in vivo; SHANK3 has a postsynaptic role in oligodendrocyte precursor cells similar to its role in neurons, and SHANK3 deficiency impairs myelin ultrastructure and axonal conductivity. InsG3680 mouse model, iPSC-derived OLs from patient with InsG3680 mutation, electrophysiology (OPC glutamatergic responses), western blot, electron microscopy (myelin ultrastructure), axonal conductivity measurement Science advances Medium 39392881
2025 Shank3 SAM domain-mediated oligomerization is essential for the PSD condensate to form a glass-like material state through network percolation; disruption of Shank3 SAM oligomerization softens the PSD condensate, impairs synaptic transmission and plasticity, and causes autistic-like behavior in mice; reconstituted PSD condensate forms a soft glass material without irreversible amyloid structure. Reconstituted PSD condensate (in vitro phase separation), rheology (material property measurement), SAM domain oligomerization mutagenesis, electrophysiology (synaptic transmission/plasticity), behavioral assays in knock-in mice Cell High 40848728

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 1223 21423165
2006 Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature genetics 1168 17173049
2011 Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Human molecular genetics 448 21558424
2013 SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 358 24132240
2016 Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature 316 26886798
2003 Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. Journal of medical genetics 293 12920066
2015 Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects. Neuron 266 26687841
2016 Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science (New York, N.Y.) 263 26966193
2013 Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Molecular autism 263 23758760
2009 Novel de novo SHANK3 mutation in autistic patients. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 257 18615476
2001 Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. American journal of human genetics 236 11431708
2019 Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice. Nature neuroscience 229 31332372
2018 Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nature neuroscience 190 29531362
2019 Atypical behaviour and connectivity in SHANK3-mutant macaques. Nature 186 31189958
2011 Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses. The Journal of biological chemistry 160 21795692
1999 Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family. Biochemical and biophysical research communications 154 10527873
2012 Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 148 23100419
2017 Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. eLife 130 28139198
2014 Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice. Molecular autism 130 25071925
2016 CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency. Science (New York, N.Y.) 127 26847545
2016 SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons. Neuron 125 27916453
2012 SHANK3 as an autism spectrum disorder-associated gene. Brain & development 120 22749736
2015 Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits. The Journal of neuroscience : the official journal of the Society for Neuroscience 119 26134648
2016 Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice. Molecular psychiatry 105 27021819
2005 C-terminal synaptic targeting elements for postsynaptic density proteins ProSAP1/Shank2 and ProSAP2/Shank3. Journal of neurochemistry 99 15659222
2013 Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 98 24089484
2011 Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism. Cell 97 21565394
2019 Deletion of Autism Risk Gene Shank3 Disrupts Prefrontal Connectivity. The Journal of neuroscience : the official journal of the Society for Neuroscience 93 31061091
2015 Phelan-McDermid Syndrome and SHANK3: Implications for Treatment. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 87 25894671
2022 Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes. Nature communications 81 36202854
2017 Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development. Molecular psychiatry 81 28948968
2021 Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications. Journal of neurodevelopmental disorders 72 34784886
2019 Shank3 modulates sleep and expression of circadian transcription factors. eLife 71 30973326
2019 Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Molecular psychiatry 68 30659288
2016 The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations. Epilepsia 61 27554343
2015 Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. Molecular autism 60 26045941
2015 Post-transcriptional regulation of SHANK3 expression by microRNAs related to multiple neuropsychiatric disorders. Molecular brain 58 26572867
2011 Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold. Molecular neurodegeneration 55 21939532
2007 DNA methylation regulates tissue-specific expression of Shank3. Journal of neurochemistry 55 17419801
2013 Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 23739967
2019 An autism-linked missense mutation in SHANK3 reveals the modularity of Shank3 function. Molecular psychiatry 51 30610205
2013 The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation. Experimental neurology 51 24382453
2014 Interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome. American journal of medical genetics. Part A 50 24700646
2017 Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3. Scientific reports 49 28345660
2006 ProSAP-interacting protein 1 (ProSAPiP1), a novel protein of the postsynaptic density that links the spine-associated Rap-Gap (SPAR) to the scaffolding protein ProSAP2/Shank3. The Journal of biological chemistry 49 16522626
2021 Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model. Molecular autism 44 33468258
2020 Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles. Science translational medicine 42 32522805
2013 SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region. The Journal of biological chemistry 42 23897824
2023 Shank3 ameliorates neuronal injury after cerebral ischemia/reperfusion via inhibiting oxidative stress and inflammation. Redox biology 41 38064762
2015 PsAP2 an AP2/ERF family transcription factor from Papaver somniferum enhances abiotic and biotic stress tolerance in transgenic tobacco. Plant molecular biology 39 26319514
2022 SH3- and actin-binding domains connect ADNP and SHANK3, revealing a fundamental shared mechanism underlying autism. Molecular psychiatry 38 35538192
2022 Neural circuit pathology driven by Shank3 mutation disrupts social behaviors. Cell reports 38 35675770
2020 Early Restoration of Shank3 Expression in Shank3 Knock-Out Mice Prevents Core ASD-Like Behavioral Phenotypes. eNeuro 38 32327468
2020 Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 32019829
2020 Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice. Molecular autism 36 33126897
2023 Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice. Brain, behavior, and immunity 35 37657643
2022 SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system. Cellular and molecular life sciences : CMLS 34 35726031
2022 Ablation of Shank3 alleviates cardiac dysfunction in aging mice by promoting CaMKII activation and Parkin-mediated mitophagy. Redox biology 34 36436456
2022 Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3. Nature communications 33 35562389
2018 USP8 Deubiquitinates SHANK3 to Control Synapse Density and SHANK3 Activity-Dependent Protein Levels. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 29735556
2017 Investigation of SHANK3 in schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 33 28371232
2017 SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCε-dependent Pathway. Inflammatory bowel diseases 33 28906292
2020 Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats. Molecular autism 32 33203459
2018 Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders. American journal of medical genetics. Part A 30 30537371
2020 Subacute Neuropsychiatric Syndrome in Girls With SHANK3 Mutations Responds to Immunomodulation. Pediatrics 29 32015180
2015 MicroRNA-7/Shank3 axis involved in schizophrenia pathogenesis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 29 25882257
2018 Shank3-deficient thalamocortical neurons show HCN channelopathy and alterations in intrinsic electrical properties. The Journal of physiology 28 29327340
2016 Zinc Stabilizes Shank3 at the Postsynaptic Density of Hippocampal Synapses. PloS one 27 27144302
2021 Rescue of histone hypoacetylation and social deficits by ketogenic diet in a Shank3 mouse model of autism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 26 34703011
2022 A bidirectional switch in the Shank3 phosphorylation state biases synapses toward up- or downscaling. eLife 25 35471151
2022 A cross-talk between nitric oxide and the glutamatergic system in a Shank3 mouse model of autism. Free radical biology & medicine 25 35716826
2023 Shank3 deletion in PV neurons is associated with abnormal behaviors and neuronal functions that are rescued by increasing GABAergic signaling. Molecular autism 24 37528484
2022 Deletion of the Autism-Associated Protein SHANK3 Abolishes Structural Synaptic Plasticity after Brain Trauma. International journal of molecular sciences 24 35682760
2020 Autism-associated miR-873 regulates ARID1B, SHANK3 and NRXN2 involved in neurodevelopment. Translational psychiatry 24 33262327
2019 Autism-associated Shank3 mutations alter mGluR expression and mGluR-dependent but not NMDA receptor-dependent long-term depression. Synapse (New York, N.Y.) 24 30868621
2019 Severe white matter damage in SHANK3 deficiency: a human and translational study. Annals of clinical and translational neurology 24 31788990
2009 Association study of SHANK3 gene polymorphisms with autism in Chinese Han population. BMC medical genetics 24 19566951
2023 Modeling SHANK3-associated autism spectrum disorder in Beagle dogs via CRISPR/Cas9 gene editing. Molecular psychiatry 23 37848710
2022 Dormant state of quiescent neural stem cells links Shank3 mutation to autism development. Molecular psychiatry 23 35444258
2022 Shank3 influences mammalian sleep development. Journal of neuroscience research 23 36056598
2019 A kinome-wide RNAi screen identifies ERK2 as a druggable regulator of Shank3 stability. Molecular psychiatry 23 30696942
2010 Proline-rich synapse-associated protein-1 and 2 (ProSAP1/Shank2 and ProSAP2/Shank3)-scaffolding proteins are also present in postsynaptic specializations of the peripheral nervous system. Neuroscience 23 20800661
2017 Shank3-deficient rats exhibit degraded cortical responses to sound. Autism research : official journal of the International Society for Autism Research 22 29052348
2016 Activity and circadian rhythm influence synaptic Shank3 protein levels in mice. Journal of neurochemistry 22 27329942
2021 Autism-associated SHANK3 missense point mutations impact conformational fluctuations and protein turnover at synapses. eLife 21 33945465
2021 Shank3 Deficiency is Associated With Altered Profile of Neurotransmission Markers in Pups and Adult Mice. Neurochemical research 21 34453663
2020 Truncating mutations in SHANK3 associated with global developmental delay interfere with nuclear β-catenin signaling. Journal of neurochemistry 21 32202324
2019 Neural Stem Cells from Shank3-ko Mouse Model Autism Spectrum Disorders. Molecular neurobiology 21 31773410
2013 Identification of two novel Shank3 transcripts in the developing mouse neocortex. Journal of neurochemistry 20 24164323
2021 SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling. Current biology : CB 19 34610274
2024 Shank3 mutation impairs glutamate signaling and myelination in ASD mouse model and human iPSC-derived OPCs. Science advances 18 39392881
2015 Novel Therapeutic Approach for Autism Spectrum Disorder: Focus on SHANK3. Current neuropharmacology 17 26511836
2009 ProSAPiP2, a novel postsynaptic density protein that interacts with ProSAP2/Shank3. Biochemical and biophysical research communications 17 19481056
2025 Shank3 oligomerization governs material properties of the postsynaptic density condensate and synaptic plasticity. Cell 16 40848728
2023 Excessive self-grooming, gene dysregulation and imbalance between the striosome and matrix compartments in the striatum of Shank3 mutant mice. Frontiers in molecular neuroscience 16 37008785
2022 Age, brain region, and gene dosage-differential transcriptomic changes in Shank3-mutant mice. Frontiers in molecular neuroscience 16 36311023
2021 Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer's Disease. Frontiers in aging neuroscience 16 34504419
2021 Restoring Shank3 in the rostral brainstem of shank3ab-/- zebrafish autism models rescues sensory deficits. Communications biology 16 34921227
2023 SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis. Frontiers in immunology 15 36845137
2016 The association of SHANK3 gene polymorphism and autism. Minerva pediatrics 15 27271042

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