Affinage

Showing SHANK2 — SHANK is a alias.

SHANK2

SH3 and multiple ankyrin repeat domains protein 2 · UniProt Q9UPX8

Length
1849 aa
Mass
201.3 kDa
Annotated
2026-06-10
100 papers in source corpus 49 papers cited in narrative 50 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHANK2 (ProSAP1) is a multidomain postsynaptic scaffolding protein that nucleates the excitatory postsynaptic density (PSD), organizing glutamate receptor complexes, the actin cytoskeleton, and calcium-signaling machinery into a functional supercomplex (PMID:10433268, PMID:10527873, PMID:10414979). Its PDZ domain binds the GKAP/SAPAP family — an interaction amplified several-hundred-fold by a pre-PDZ binding site and an elongated BC loop that is itself required for synaptic targeting — physically linking SHANK2 to the NMDAR/PSD-95 complex, while a Homer-binding site cross-bridges it to mGluR5 to assemble a coclustered receptor scaffold (PMID:10433268, PMID:10527873, PMID:10433269, PMID:27185935). Through its proline-rich region and SH3 domain SHANK2 couples this scaffold to the actin cytoskeleton via cortactin, Abp1, IRSp53, betaPIX/PAK and Densin-180, an arrangement essential for spine actin maintenance and synapse remodeling, and recruits CaV1.3 L-type calcium channels to drive synaptic pCREB signaling (PMID:12421375, PMID:12626503, PMID:15014124, PMID:15689539, PMID:15689540, PMID:15647492, PMID:26547831). SHANK2 promotes dendritic spine maturation and enlargement and maintains glutamatergic transmission in a SAM-domain-dependent manner (PMID:11498055, PMID:29250591). By coupling the PSD to its endocytic zone, SHANK2 governs agonist-induced mGluR5 internalization and, together with SHANK3, drives zinc-dependent AMPAR subunit switching (PMID:30524232, PMID:31597090). Its N-terminal SPN domain is a Ras-association domain that sequesters active Rap1 and R-Ras to restrain integrin activation, and in epithelia SHANK2 binds aPKC and active Rap1 to control tight-junction formation and modulates NHE3 and CFTR transport (PMID:14679199, PMID:16293618, PMID:28263956, PMID:32268103). SHANK2 is regulated post-transcriptionally by miR-137 and post-translationally by PRMT7-mediated arginine methylation at R240, which exposes the ANK domain to drive endosomal FAK/cortactin signaling, and it acts as a Hippo pathway regulator in cancer cells (PMID:32844749, PMID:32661924, PMID:29665782). Loss-of-function SHANK2 variants are linked to autism spectrum disorder: knockout mice exhibit reduced spines, NMDAR dysfunction, and ASD-like behaviors rescued by NMDAR or mGluR5 modulators, and human ASD-associated mutations impair synaptic density, clustering, and connectivity (PMID:22699620, PMID:22346768, PMID:21994763, PMID:30911184).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1999 High

    Established SHANK2's foundational identity as a PSD scaffold by showing its PDZ domain binds GKAP/SAPAP to bridge the NMDAR/PSD-95 complex while its proline-rich region binds cortactin and its SAM domain mediates multimerization.

    Evidence Yeast two-hybrid, reciprocal Co-IP from rat brain, heterologous ternary-complex reconstitution, and domain mapping

    PMID:10433268 PMID:10527873

    Open questions at the time
    • Stoichiometry and higher-order architecture of the scaffold in situ not defined
    • Did not establish how the scaffold is dynamically regulated by activity
  2. 1999 High

    Showed SHANK cross-links Homer/mGluR5 complexes to the PSD-95/GKAP complex, extending the scaffold to metabotropic glutamate signaling.

    Evidence Co-IP from brain, heterologous cell clustering assay, and colocalization

    PMID:10433269

    Open questions at the time
    • Functional consequence of mGluR5 coclustering for downstream signaling not resolved at this stage
  3. 1999 High

    Localized SHANK2 to the PSD of excitatory synapses and defined its developmental accumulation, fixing its subcellular site of action.

    Evidence Subcellular fractionation, immunoelectron microscopy, and confocal microscopy of hippocampal neurons

    PMID:10414979

    Open questions at the time
    • Mechanism of targeting to the PSD not yet defined
  4. 2001 High

    Demonstrated SHANK is functionally instructive, driving spine head maturation/enlargement and IP3R accumulation through Homer recruitment rather than acting as a passive scaffold.

    Evidence Overexpression and dominant-negative constructs in hippocampal neurons with morphology, mEPSC electrophysiology, and FM4-64 uptake

    PMID:11498055

    Open questions at the time
    • Endogenous loss-of-function consequence not tested
    • Presynaptic enhancement mechanism (trans-synaptic signal) unidentified
  5. 2000 Medium

    Expanded the SHANK2 interactome to additional PDZ ligands (CIRL1, GluRdelta2, PLC-beta3, CFTR) and SH3/proline-rich partners (IRSp53, Densin-180, betaPIX, Abp1, alpha-fodrin, Sharpin), defining the multidomain partner spectrum.

    Evidence Yeast two-hybrid, Co-IP from brain and transfected cells, pull-down/affinity chromatography, and domain mapping across multiple papers

    PMID:10964907 PMID:11178875 PMID:11509555 PMID:12421375 PMID:12626503 PMID:15014124 PMID:15207857 PMID:15255944 PMID:15632121 PMID:15647492

    Open questions at the time
    • Many interactions rest on single-lab Co-IP without reciprocal in vivo validation
    • Quantitative contribution of each partner to scaffold assembly unranked
  6. 2003 High

    Revealed a non-neuronal role for SHANK2 in epithelial ion transport, negatively regulating CFTR and positively regulating NHE3.

    Evidence Yeast two-hybrid, Co-IP, SPR, heterologous expression, RNAi knockdown, and ion-current/transport functional assays

    PMID:14679199 PMID:16293618

    Open questions at the time
    • In vivo physiological relevance in intact epithelia not established
    • Did not connect epithelial and synaptic functions mechanistically
  7. 2005 High

    Identified SHANK2 as the scaffold coupling GPCR modulation to CaV1.3 L-type calcium channels and downstream pCREB signaling at synapses.

    Evidence Yeast two-hybrid, in vitro binding, dominant-negative peptides, dihydropyridine-resistant mutants, electrophysiology in medium spiny neurons, and CaV1.3 genetic deletion

    PMID:15689539 PMID:15689540

    Open questions at the time
    • Whether SHANK2 specifically (versus SHANK1/3) mediates this coupling not isolated
  8. 2016 High

    Solved the structural basis for high-affinity SHANK/SAPAP binding, showing a pre-PDZ site and elongated BC loop are required for synaptic targeting and SHANK-induced activity.

    Evidence Binding affinity measurements, deletion/point mutants, neuronal targeting assay, and electrophysiology

    PMID:27185935

    Open questions at the time
    • Structural regulation of this interface by phosphorylation/PTM not addressed
  9. 2011 High

    Connected SHANK2 to autism spectrum disorder by demonstrating that patient-derived ASD mutations reduce synaptic density, spine volume, clustering, and AMPAR currents.

    Evidence Neuronal transfection with patient versus control variants, knockdown-rescue, rAAV in vivo expression, morphology, mEPSC, and behavioral testing

    PMID:21994763 PMID:22346768

    Open questions at the time
    • Some readouts rely on overexpression/dominant-negative rather than endogenous variant context
  10. 2012 High

    Established reduced NMDAR function as a causal synaptic mechanism of ASD-like behavior in Shank2 knockout mice, pharmacologically reversible.

    Evidence Shank2-/- mouse electrophysiology, biochemical/morphological analysis, and pharmacological rescue with D-cycloserine and an mGluR5 PAM with behavioral readouts

    PMID:22699619 PMID:22699620

    Open questions at the time
    • Circuit and cell-type origin of the deficit not yet resolved in these global KOs
  11. 2014 High

    Placed SHANK2 downstream of syndapin I, identifying an upstream coordinator whose loss phenocopies Shank2 KO.

    Evidence Gene knockout, single-neuron RNAi, direct SH3-domain interaction assays, super-resolution imaging, and mEPSC electrophysiology

    PMID:24751538

    Open questions at the time
    • Molecular mechanism by which syndapin I positions SHANK2 not fully defined
  12. 2015 High

    Defined the SHANK-cortactin interaction as required for spine actin maintenance and activity-dependent synapse remodeling.

    Evidence miRNA pan-Shank knockdown, Latrunculin sensitivity, cortactin single-molecule PALM tracking, and rescue with a proline-rich deletion mutant

    PMID:26547831

    Open questions at the time
    • Isoform-specific contribution of SHANK2 versus SHANK1/3 to actin maintenance not separated
  13. 2017 High

    Reframed the SHANK N-terminal SPN domain as a Ras-association domain that sequesters active Rap1/R-Ras to inhibit integrin activation, linking SHANK to cell adhesion and migration.

    Evidence Crystal structure, GTPase binding assays, silencing with spreading/migration/invasion assays, and ASD SPN-domain mutation functional analysis

    PMID:28263956

    Open questions at the time
    • Demonstrated for SHANK1/3; direct SHANK2 SPN-Rap1 sequestration shown later in epithelia (#43)
  14. 2016 High

    Dissected SHANK2's cell-autonomous and circuit-specific roles, showing distinct cerebellar Purkinje-cell, excitatory-neuron, and inhibitory-neuron contributions to synaptic and behavioral phenotypes.

    Evidence Conditional/cell-type-specific KO mice with electron microscopy, in vivo and ex vivo electrophysiology, and behavioral batteries

    PMID:27581745 PMID:27903723 PMID:29572432

    Open questions at the time
    • How distinct cell-type circuits integrate to produce composite behavioral phenotype unresolved
  15. 2018 High

    Resolved a developmental sequence in which early NMDAR hyperfunction drives later hypofunction, demonstrating a critical-period intervention window.

    Evidence Longitudinal Shank2-/- electrophysiology with chronic memantine treatment and later behavioral outcome

    PMID:30466882

    Open questions at the time
    • Molecular trigger linking SHANK2 loss to early hyperfunction not identified
  16. 2018 High

    Showed human SHANK2 loss-of-function produces a hyperconnectivity phenotype in iPSC-derived neurons reversible by gene correction, complementing mouse hypoconnectivity findings.

    Evidence ASD patient and isogenic CRISPR-edited iPSC cortical neurons with connectivity assays, morphology, patch-clamp, and transcriptomics

    PMID:30911184

    Open questions at the time
    • Reconciliation of human hyperconnectivity with mouse synapse loss not mechanistically resolved
  17. 2019 High

    Defined SHANK2's role in coupling the PSD to its endocytic zone to control agonist-induced mGluR5 internalization, requiring Homer-, Dynamin2-, and cortactin-binding motifs.

    Evidence Knockdown with domain-specific rescue mutants, mGluR5 internalization imaging, and ASD-variant functional testing

    PMID:31597090

    Open questions at the time
    • In vivo relevance of endocytic-zone coupling for behavior not tested
  18. 2020 High

    Identified PRMT7-mediated arginine methylation at R240 as a switch exposing the ANK domain to drive endosomal FAK/cortactin signaling and cancer metastasis, plus a Hippo-regulatory role.

    Evidence Co-IP, in vitro methylation, structural domain analysis, endosomal imaging, phosphorylation assays, xenografts, and Hippo reporter/tumor assays

    PMID:32661924 PMID:32844749

    Open questions at the time
    • Whether R240 methylation regulates SHANK2 in neurons unaddressed
    • Hippo-regulatory mechanism (LATS1 activator identity) at medium confidence
  19. 2020 High

    Demonstrated an epithelial junctional function in which SHANK2 binds aPKC and active Rap1 via its SPN domain to control tight-junction formation.

    Evidence Co-IP, SPN-Rap1 binding assay, shRNA knockdown, and tight-junction immunofluorescence in epithelial cells

    PMID:32268103

    Open questions at the time
    • Integration with the SHANK2 ion-transport role in epithelia not addressed
  20. 2021 High

    Identified additional scaffold organizers (POSH) and downstream signaling outputs (mGluR5-ERK1/2, Ca2+-permeable AMPAR redistribution, PV-interneuron NMDAR-gap-junction burst firing) clarifying how SHANK2 loss disrupts circuits.

    Evidence Conditional KO mice, Co-IP, electrophysiology, in vivo cortical imaging, optogenetic rescue, hiPSC neurons, and RNA-seq

    PMID:34021263 PMID:34433814 PMID:34899182 PMID:35385725

    Open questions at the time
    • Causal hierarchy among these downstream pathways not fully ordered
    • Some readouts rely on overexpression rather than loss-of-function
  21. 2018 Medium

    Established translational control of SHANK2 by miR-137, linking a regulatory microRNA to SHANK2 protein dosage.

    Evidence Luciferase 3'UTR reporter assays, miR-137 overexpression/inhibition in hippocampal neurons, western blot, and qRT-PCR

    PMID:29665782

    Open questions at the time
    • In vivo and disease relevance of miR-137-SHANK2 regulation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SHANK2's diverse functions — synaptic scaffolding, epithelial junction/transport regulation, integrin/Rap1 sequestration, and cancer signaling — are integrated within a single cell, and whether PTM-driven domain rearrangements switch between these states, remains unresolved.
  • No unifying model reconciles neuronal and non-neuronal roles
  • Tissue-specific isoform usage governing function not mapped
  • Whether R240 methylation operates in neurons unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 4 GO:0140313 molecular sequestering activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-382551 Transport of small molecules 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ARHGEF7BAIAP2CACNA1DCTTNDLGAPGKAP/SAPAPHOMER1PRMT7
Complex memberships
NMDAR/PSD-95/GKAP/SHANK postsynaptic density supercomplexSHANK/betaPIX/PAK signaling complexSHANK2/Homer/PLC-beta3 complex

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Shank2 (ProSAP1) PDZ domain directly binds the C terminus of GKAP/SAPAP, forming a ternary Shank/GKAP/PSD-95 complex that can be coimmunoprecipitated from rat brain; the proline-rich region of Shank binds cortactin; and the SAM domain mediates Shank multimerization. Shank functions as a scaffold protein in the PSD linking NMDA receptor/PSD-95 complexes to regulators of the actin cytoskeleton. Yeast two-hybrid, coimmunoprecipitation from rat brain, heterologous cell assembly of ternary complex, domain mapping Neuron High 10433268 10527873
1999 Shank proteins bind Homer via a single Homer-binding site in Shank; Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. In heterologous cells, Shank clusters mGluR5 in the presence of Homer and mediates coclustering of Homer with PSD-95/GKAP, indicating that Shank cross-links Homer and PSD-95 complexes in the PSD. Coimmunoprecipitation from brain, heterologous cell clustering assay, colocalization Neuron High 10433269
1999 ProSAP1/Shank2 (CortBP1) is highly enriched in the postsynaptic density fraction of rat brain and localizes at PSDs of hippocampal excitatory synapses by immunoelectron microscopy; it accumulates at developing PSDs starting from postnatal day 8. Subcellular fractionation (PSD fraction), immunoelectron microscopy, confocal microscopy of hippocampal neurons The Journal of neuroscience High 10414979
1999 The PDZ domains of ProSAP1 (Shank2) and ProSAP2 (Shank3) interact with SAPAP/GKAP family proteins as determined by yeast two-hybrid screening and verified by coimmunoprecipitation and cotransfection in HEK cells. Yeast two-hybrid, coimmunoprecipitation, cotransfection in HEK cells Biochemical and biophysical research communications High 10527873
1999 Shank1, Shank2, and Shank3 are alternatively spliced at multiple sites, some of which delete specific protein-protein interaction domains including ankyrin repeats and SH3 domain, suggesting alternative splicing regulates the spectrum of Shank-interacting proteins. cDNA cloning, RT-PCR characterization of splice variants, immunoblot analysis with multiple antibodies The Journal of biological chemistry Medium 10506216
2001 Shank promotes maturation and enlargement of dendritic spine heads via its ability to recruit Homer to postsynaptic sites; this requires a PDZ-dependent targeting mechanism. Shank and Homer cooperate to induce accumulation of IP3 receptors in dendritic spines. Expression of Shank enhances presynaptic function (increased mEPSC frequency and FM4-64 uptake). Overexpression and dominant-negative constructs in hippocampal neurons, morphological analysis, electrophysiology (mEPSC), FM4-64 uptake assay Neuron High 11498055
2001 Sharpin directly interacts with the ankyrin repeats of Shank via its C-terminal half; Sharpin forms a complex with Shank in heterologous cells and brain (coimmunoprecipitation), colocalizes with Shank at excitatory synapses, and self-multimerizes via its N-terminal half. Coimmunoprecipitation from brain and heterologous cells, immunostaining colocalization, domain mapping Molecular and cellular neurosciences Medium 11178875
2001 The ankyrin repeats of Shank1 and Shank3 interact with the cytoskeletal protein alpha-fodrin (spectrin repeat 21 is sufficient); this interaction was verified by pull-down assays and coimmunoprecipitation from transfected cells and brain extracts, and both proteins colocalize in hippocampal synapses. Yeast two-hybrid screening, affinity chromatography, pull-down assays, coimmunoprecipitation from brain and transfected cells The Journal of biological chemistry Medium 11509555
2000 Shank PDZ domain specifically binds the C termini of the G-protein-coupled alpha-latrotoxin receptors CIRL1 and CIRL2 (yeast two-hybrid); in vivo, CIRL1 but not CIRL2 was coimmunoprecipitated with ProSAP1 (Shank2) from solubilized rat brain membranes. Shank1 induces clustering of CL1 in transfected cells. Yeast two-hybrid, coimmunoprecipitation from rat brain membranes, heterologous cell clustering assay The Journal of biological chemistry Medium 10964907
2002 ProSAP/Shank proline-rich domain interacts with IRSp53 (insulin receptor substrate) via the C-terminal SH3 domain of IRSp53 binding a novel proline-rich consensus sequence in ProSAP/Shank; the interaction was confirmed by coimmunoprecipitation from rat brain membranes, and IRSp53 can be recruited to the PSD via this interaction. Yeast two-hybrid, cotransfection in COS cells, coimmunoprecipitation from rat brain, mutational analysis Journal of neurochemistry Medium 12421375
2003 Shank2 interacts with CFTR via its PDZ domain (confirmed by yeast two-hybrid and coimmunoprecipitation in mammalian cells); Shank2 expression suppresses cAMP-induced phosphorylation and activation of CFTR, and stable knockdown of Shank2 in T84 colonic cells increases CFTR currents, demonstrating negative regulation of CFTR by Shank2. Yeast two-hybrid, coimmunoprecipitation, heterologous expression, antisense knockdown, electrophysiology (Cl⁻ current measurement) The Journal of biological chemistry High 14679199
2003 Shank interacts with betaPIX (a GEF for Rac1 and Cdc42) via the Shank PDZ domain binding the C-terminal leucine zipper domain and PDZ-binding motif of betaPIX; Shank forms a complex with betaPIX, PAK, and other signaling molecules in brain (coimmunoprecipitation); overexpression of Shank in neurons promotes synaptic accumulation of betaPIX and PAK. Yeast two-hybrid, coimmunoprecipitation from brain, domain mapping, overexpression in cultured neurons with immunostaining The Journal of biological chemistry Medium 12626503
2004 Shank2 directly interacts with GluRdelta2 (glutamate receptor delta2) via the Shank PDZ domain binding an internal motif in the GluRdelta2 C-terminal cytoplasmic domain; anti-GluRdelta2 antibodies immunoprecipitate Shank1, Shank2, Homer, and mGluR1alpha from cerebellar synaptosomal fractions. Shank2 also interacts with GRIP1 in cerebellum. Yeast two-hybrid, immunoprecipitation from cerebellar synaptosomal membrane fractions, immunolocalization in Purkinje cell dendrites Molecular and cellular neurosciences Medium 15207857
2004 F-actin binding protein Abp1 SH3 domain associates with a conserved proline-rich motif in the C-terminal parts of ProSAP1/Shank2 and ProSAP2/Shank3; endogenous Abp1 and ProSAP2 coimmunoprecipitate; neuronal stimulation induces redistribution of Abp1 to ProSAP-containing synapses, linking synaptic stimulation to cytoskeletal rearrangements. Affinity-purification, coimmunoprecipitation of endogenous proteins, in vivo recruitment assays, stimulation experiments The Journal of neuroscience High 15014124
2004 GKAP forms insoluble aggregates with Shank that colocalize with aggresome markers when GKAP cannot bind PSD-95; when both are overexpressed with palmitoylated PSD-95, they form synaptic clusters. Shank, when not associated with GKAP, forms filamentous structures through intramolecular SH3–ankyrin repeat interaction enabling multimerization. Synaptic activity induces Shank and GKAP intracellular aggregation and degradation. Overexpression in COS-7 cells and hippocampal neurons, dominant-negative PSD-95 constructs, activity-dependent degradation assays The Journal of neuroscience Medium 15496675
2004 Shank2E, an epithelial isoform of Shank2 containing six N-terminal ankyrin repeats, is concentrated at the apical membrane of liver epithelial cells (immunofluorescence and membrane fractionation), and coimmunoprecipitates with actin and co-distributes with actin in detergent-insoluble lipid rafts. Bioinformatics/cDNA sequencing, immunofluorescence, membrane fractionation, coimmunoprecipitation, detergent solubility The Biochemical journal Medium 14977424
2005 The PDZ domain of Shank2 specifically interacts with PLC-beta3 (but not other PLC-beta isotypes) via the C terminus of PLC-beta3; Homer 1b forms a ternary complex with Shank2 and PLC-beta3; microinjection of a peptide mimicking the PLC-beta3 C terminus markedly reduces mGluR-mediated intracellular calcium responses. Yeast two-hybrid, GST pulldown, coimmunoprecipitation, microinjection of competing peptide, intracellular calcium measurement The Journal of biological chemistry High 15632121
2005 CaV1.3a L-type Ca2+ channel C terminus specifically binds the Shank PDZ domain (not CaV1.2); the CaV1.3a proline-rich region also binds the Shank SH3 domain. The Shank-binding motifs in CaV1.3a are both necessary and sufficient for synaptic clustering of CaV1.3 channels in hippocampal neurons. Disruption of the CaV1.3–Shank interaction impairs pCREB signaling. Yeast two-hybrid, in vitro binding assay, recombinant expression in hippocampal neuronal cultures, dominant-negative peptides, dihydropyridine-resistant mutants, pCREB immunostaining The Journal of neuroscience High 15689539 15689540
2005 D2 dopaminergic and M1 muscarinic receptor modulation of striatal CaV1.3 channels depends on the Shank-binding domain of CaV1.3 and is disrupted by a peptide competing for the CaV1.3 PDZ domain; modulation is also disrupted by peptides targeting the Shank–Homer interaction, placing Shank as a scaffold coupling GPCRs to L-type Ca2+ channels at corticostriatal synapses. Intracellular dialysis of competing peptides, electrophysiology in medium spiny neurons, genetic deletion of CaV1.3 The Journal of neuroscience High 15689540
2005 Postsynaptic targeting of ProSAP1/Shank2 and ProSAP2/Shank3 (but not Shank1) relies on the integrity of C-terminal sequences including the SAM domain; the shortest construct maintaining full synaptic targeting comprised the last 417 amino acids of ProSAP1/Shank2, defining a novel C-terminal synaptic targeting signal. GFP-tagged deletion constructs expressed in hippocampal neurons, fluorescence microscopy Journal of neurochemistry Medium 15659222
2005 Shank2 associates with and positively regulates Na+/H+ exchanger 3 (NHE3): Shank2 interaction with NHE3 was confirmed by coimmunoprecipitation and surface plasmon resonance; Shank2 increases NHE3 membrane expression and basal activity and attenuates cAMP-dependent inhibition of NHE3. Knockdown of native Shank2 in Caco-2 cells decreases NHE3 expression, activity, and amplifies cAMP inhibition. Yeast two-hybrid, coimmunoprecipitation, surface plasmon resonance, heterologous expression, RNAi knockdown, functional NHE3 activity assays The Journal of biological chemistry High 16293618
2005 Densin-180 interacts with Shank (Shank1–3) via a two-point attachment: the Shank SH3 domain and the N-terminal proline-rich region bind the C-terminal region of Densin-180. Coexpression of Shank3 abrogates Densin-180-induced dendritic branching and redirects Densin-180 into postsynaptic clusters; Shank blocks delta-catenin binding to Densin-180, suggesting Shank suppresses a Densin-180/delta-catenin branching pathway. Yeast two-hybrid, coimmunoprecipitation, overexpression in hippocampal neurons, morphological analysis of dendritic branching The Journal of neuroscience Medium 15647492
2005 Shank2 (NHE3-binding PDZ scaffold) regulates epithelial NHE3: Shank2 knockdown decreases NHE3 protein expression and activity but amplifies cAMP inhibitory effect, establishing Shank2 as a modulator of transepithelial salt/water transport. RNAi stable knockdown in Caco-2 cells, NHE3 activity assay, western blot The Journal of biological chemistry Medium 16293618
2004 IRSp53 links Shank1 to PSD-95 via a PDZ binding motif at its C terminus (binding PSD-95 second PDZ domain); IRSp53 induces filopodia and targets PSD-95 into these processes; in brain, the shank1/IRSp53/PSD-95 triple complex is detected by coimmunoprecipitation. Coimmunoprecipitation from brain, immunocytochemistry, heterologous expression in HEK cells Journal of neurochemistry Medium 15255944
2009 Soluble beta-amyloid(1-40) induces rapid declustering of Shank1 from synapses through NMDAR activity and ERK pathway activation (not proteasome activity and not VDCC); this is distinct from Homer1b declustering which requires both NMDAR and VDCC activity and involves PI3K/calcineurin. Treatment of fronto-cortical neurons with Abeta, pharmacological inhibitors, immunofluorescence quantification of synaptic clusters PloS one Medium 19547699
2012 Shank2-/- mice (exons 6-7 deletion) show a marked decrease in NMDA receptor function, and direct stimulation of NMDARs with D-cycloserine or positive allosteric modulation of mGluR5 (which enhances NMDAR function) normalizes NMDAR function and improves social interaction, establishing reduced NMDAR function as a causal synaptic mechanism in Shank2-/- ASD-like behavior. Electrophysiology in Shank2-/- mice, pharmacological rescue (D-cycloserine, mGluR5 PAM), behavioral assays Nature High 22699620
2012 Genetic deletion of ProSAP1/Shank2 results in brain-region-specific upregulation of ionotropic glutamate receptors at synapses, increased ProSAP2/Shank3 levels, fewer dendritic spines, reduced basal synaptic transmission, reduced mEPSC frequency, and enhanced NMDAR-mediated excitatory currents. Genetic KO mouse, electrophysiology (mEPSC, NMDAR-mediated currents), western blot of synaptic proteins, morphological spine analysis Nature High 22699619
2011 SHANK2 variants identified in ASD patients were associated with reduced synaptic density at dendrites in neuronal cell cultures, compared to variants found only in controls, demonstrating functional consequences of ASD-associated SHANK2 mutations at the synapse level. Neuronal cell culture transfection, immunostaining quantification of synaptic density PLoS genetics Medium 22346768
2011 ASD-associated SHANK2 mutations (L1008_P1009dup, T1127M, R462X) affect spine volume and SHANK2 cluster size; R462X fails to rescue spine volume and dendritic branching and lacks postsynaptic clustering (most severe); T1127M fails to rescue spine volume in knockdown neurons. rAAV-SHANK2-R462X expression in mouse neurons produces a dominant-negative reduction in miniature AMPAR currents and dose-dependent altered cognitive behavior. Knockdown-rescue experiments in hippocampal neurons, morphological analysis, rAAV in vivo expression, electrophysiology (mEPSC), behavioral testing Human molecular genetics High 21994763
2014 Syndapin I directly interacts with ProSAP1/Shank2 via its SH3 domain; syndapin I deficiency phenocopies ProSAP1/Shank2 knockout (reduced mEPSC frequency, reduced spine and synapse density) and impairs synaptic ProSAP1/Shank2 distribution, placing syndapin I as an upstream postsynaptic coordinator that acts via Shank2. Gene knockout, RNAi in individual neurons, direct SH3-domain interaction assays, ultra-high-resolution imaging of endogenous syndapin I, electrophysiology (mEPSC) The Journal of cell biology High 24751538
2015 Pan-Shank knockdown (>75%) in hippocampal neurons reduces mushroom spine density, decreases spine actin levels, and increases sensitivity to actin depolymerization. A SHANK2 mutant lacking the proline-rich cortactin-binding motif (SHANK2-ΔPRO) cannot rescue these defects and cannot rescue cortactin stabilization or spontaneous synapse remodeling, establishing Shank–cortactin interaction as required for actin cytoskeleton maintenance in spines. miRNA-based pan-Shank knockdown in rat hippocampal neurons, Latrunculin A sensitivity, cortactin single-molecule tracking PALM, morphological analysis, rescue with SHANK2-ΔPRO mutant The European journal of neuroscience High 26547831
2016 Shank2 deletion restricted to cerebellar Purkinje cells (Pcp2-Cre;Shank2fl/fl) reduces excitatory synapse density, decreases GluD2 and PSD-93 protein levels, and impairs motor coordination, demonstrating a cell-autonomous role of Shank2 in cerebellar Purkinje cell excitatory synapse maintenance. Conditional KO mouse, electron microscopy synapse quantification, western blot of synaptic proteins, motor coordination behavioral assays (Erasmus test) The Journal of neuroscience High 27903723
2016 Loss of Shank2 in cerebellar Purkinje cells impairs PC intrinsic plasticity, abolishes long-term potentiation at parallel fibre–PC synapses, and enhances inhibitory input onto PCs; PC-specific Shank2 KO replicates simple spike irregularity and establishes cerebellar dependence of motor learning and social interaction ASD-like phenotypes. PC-specific Shank2 KO (Pcp2-Cre), in vivo electrophysiology (simple spike recording), ex vivo slice electrophysiology (LTP induction, inhibitory currents), behavioral assays Nature communications High 27581745
2016 Shank regulates postsynaptic Wnt signaling by modulating internalization of the Wnt receptor Frizzled2 (Fz2) at Drosophila NMJ synapses; loss and overexpression of Shank both cause defects in bouton number and maturation, and Shank controls noncanonical Wnt signaling in the postsynaptic cell. Drosophila Shank null and overexpression genetics, immunostaining for Fz2 internalization, synapse morphology quantification The Journal of neuroscience Medium 27225771
2016 A binding site preceding the canonical PDZ domain of Shank, together with an elongated PDZ BC loop, forms a second binding interface for a sequence upstream of the SAPAP PDZ-binding motif, producing several-hundred-fold higher Shank/SAPAP binding affinity. This enhanced affinity is required for Shank synaptic targeting and Shank-induced synaptic activity increase. Structural/biochemical binding affinity measurements, deletion and point mutants, neuronal synaptic targeting assay, electrophysiology of synaptic activity Proceedings of the National Academy of Sciences of the United States of America High 27185935
2017 The SPN domain of SHANK3 (and SHANK1) is a Ras-association domain with high affinity for GTP-bound Rap1 and R-Ras; SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras at the plasma membrane, limiting their bioavailability. SHANK3 silencing increases plasma membrane Rap1 activity, cell spreading, migration, and invasion. ASD-related SPN domain mutations (R12C, L68P) disrupt G-protein interaction and fail to counteract integrin activation along the Rap1-RIAM-talin axis. Crystal structure of SHANK3 N-terminal region, GTPase binding assays, SHANK silencing with cell spreading/migration/invasion assays, ASD mutation functional analysis in cancer cells and neurons Nature cell biology High 28263956
2017 Loss of Shank1 or Shank2 (but not Shank3) by knockdown reduces the number of AMPAR-containing synapses at hippocampal SC-CA1 synapses without affecting unitary AMPAR response; only combined Shank1+Shank2 knockdown additionally reduces NMDAR-mediated response. Molecular replacement shows the intact SAM domain is required for maintaining glutamatergic synaptic transmission. Lentivirus-mediated knockdown, molecular replacement with wild-type and SAM mutants, dual whole-cell patch clamp in hippocampal slice culture eNeuro High 29250591
2018 SHANK2 loss-of-function mutations in ASD iPSC-derived neurons increase dendrite length, complexity, synapse number, and spontaneous EPSC frequency (hyperconnectivity phenotype), phenocopied in gene-edited homozygous SHANK2 KO cells and rescued by gene correction. Activity-dependent dendrite extension is impaired in SHANK2-mutant neurons. iPSC-derived cortical neurons from ASD donors, sparse coculture connectivity assay, gene editing (CRISPR), gene correction, morphological analysis, patch-clamp electrophysiology, transcriptome analysis Nature neuroscience High 30911184
2018 Shank2 and Shank3 mediate a zinc-dependent regulation of AMPAR function and subunit switch from GluA2-lacking to GluA2-containing AMPARs; elevated zinc lengthens AMPAR current decay and reduces inward rectification, and both Shank2 and Shank3 are necessary for the zinc-sensitive enhancement of AMPAR-mediated transmission and for removal of GluA1 while recruiting GluA2 at Shank puncta. Hippocampal neuron electrophysiology, zinc application, Shank2/3 knockdown, immunostaining quantification of AMPAR subunits at synapses Frontiers in molecular neuroscience Medium 30524232
2018 SHANK2 deletion in excitatory neurons (CaMKII-Cre) produces social interaction deficits, hyperactivity, and hippocampal synaptic transmission changes; deletion in GABAergic inhibitory neurons (Viaat-Cre) produces social communication deficits, repetitive self-grooming, and striatal synaptic transmission changes, demonstrating cell-type-specific Shank2 contributions to synaptic and behavioral phenotypes. Conditional KO mice (cell-type-specific Cre lines), electrophysiology of hippocampal and striatal synaptic transmission, behavioral battery The Journal of neuroscience High 29572432
2018 Early (P7–P21) NMDAR hyperfunction in Shank2-/- mice precedes and drives the later (post-P21) NMDAR hypofunction; chronic suppression of early NMDAR hyperfunction with memantine (P7–P21) prevents NMDAR hypofunction and autistic-like social behaviors at later stages, establishing a causal developmental sequence. Electrophysiology at preweaning and postweaning stages of Shank2-/- mice, chronic memantine treatment, behavioral assays at later stages Biological psychiatry High 30466882
2019 Shank scaffolds couple the postsynaptic density endocytic zone to control mGluR5 trafficking: Shank knockdown significantly reduces agonist-induced internalization of synaptic mGluR5; rescue requires intact Homer1b/c-, Dynamin2-, and Cortactin-binding motifs of Shank; Shank knockdown reduces the number of synapses associated with an endocytic zone. An ASD-associated SHANK2 mutation similarly disrupts mGluR5 internalization. Shank knockdown in hippocampal neurons, rescue with wild-type and domain mutant Shanks, fluorescence imaging of mGluR5 internalization, ASD mutation functional testing Cell reports High 31597090
2020 PRMT7 arginine methyltransferase methylates SHANK2 at R240 (di-methylation); R240 methylation exposes the ANK domain by disrupting an SPN-ANK intramolecular blockade, promoting co-accumulation of dynamin2, talin, FAK, and cortactin with SHANK2 on endosomes and activating endosomal FAK/cortactin signaling to promote breast cancer metastasis. Co-IP of PRMT7–SHANK2 complex, in vitro methylation assay, domain structural analysis, endosomal localization imaging, FAK/cortactin phosphorylation assays, in vivo xenograft tumor model eLife High 32844749
2020 Epithelial Shank2 binds to aPKC and colocalizes with it at apical junctional regions; the N-terminal SPN domain of Shank2 is required for its junctional localization and binds the active (GTP-bound) form of Rap1 small GTPase; Shank2 knockdown causes defects in tight junction formation, and this requires active Rap1 signaling. Co-IP of Shank2-aPKC, SPN domain-Rap1 binding assay, shRNA knockdown in epithelial cells, immunofluorescence of tight junction markers Cell reports High 32268103
2020 SHANK2 overexpression in cancer cells deregulates Hippo signaling through competitive binding for a LATS1 activator; SHANK2 depletion in cancer cell lines with deregulated Hippo restores signaling and ceases proliferation; forced SHANK2 expression inhibits neuroblastoma cell growth and accelerates neuronal differentiation. Genome-wide Drosophila screen (Prosap identified as Hippo regulator), human cancer cell line overexpression/depletion, Hippo pathway reporter assays, in vivo tumor formation assay, forced expression in neuroblastoma cells Protein & cell Medium 32661924
2021 POSH scaffold protein directly interacts with both PSD-95 and SHANK2/3 at excitatory synapses; POSH conditional KO disrupts normal synaptic clustering of the NMDAR/PSD-95/SHANK complex and impairs dendritic spine development and glutamatergic transmission, demonstrating POSH as an organizational component of the NMDAR/PSD-95/SHANK complex. Direct interaction assays (Co-IP), conditional KO mice, dendritic spine morphology analysis, electrophysiology of glutamatergic transmission, behavioral assays Cell reports High 35385725
2021 Shank2-/- mice show decreased mGluR5 and phospho-ERK1/2 expression in brain; patient hiPSC-derived neurons with heterozygous SHANK2 deletion show reduced signaling molecules in the ERK-MAP kinase pathway, decreased mGluR5, and dysregulated excitatory signaling, identifying the mGluR5–ERK1/2 pathway as downstream of SHANK2. Western blot of brain samples from Shank2-/- mice, hiPSC-derived neurons with patient SHANK2 deletion, RNA-seq Frontiers in molecular neuroscience Medium 34899182
2021 SHANK2A overexpression mediates redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, impairing synaptic plasticity in basal dendrites; overexpression also reduces social interaction and increases excitatory noise in olfactory cortex. The extrasynaptic SHANK2A(R462X) variant does not impair hippocampal synaptic plasticity but alters presynaptic/axonal signaling protein expression. Conditional overexpression of wild-type and ASD mutant SHANK2A, electrophysiology of synaptic plasticity, immunostaining of AMPAR subunit distribution, in vivo olfactory cortex recordings, behavioral assays Molecular psychiatry Medium 34021263
2021 NMDARs in cortical parvalbumin (Pv) interneurons cooperate with gap junctions to promote high-frequency (>80 Hz) burst firing; Shank2-/- Pv neurons show decreased NMDAR activity that suppresses NMDAR–gap junction cooperation, impairing burst firing and cortical social cognition. Optogenetic boosting of Pv neuronal bursts (requiring gap junctions) rescues cortical social cognition in Shank2-/- mice. Shank2-/- mice, cortical Pv neuron electrophysiology (NMDAR and gap junction pharmacology), in vivo cortical social representation imaging, optogenetic Pv neuron stimulation, behavioral social cognition assays Nature communications High 34433814
2018 miR-137 directly targets the 3'UTR of SHANK2 in a site-specific manner; miR-137 overexpression in hippocampal neurons significantly lowers endogenous Shank2 protein levels without affecting mRNA, while miR-137 inhibition increases Shank2 protein, indicating translational repression of SHANK2 by miR-137. Luciferase reporter assays (wild-type and mutated 3'UTR), miR-137 overexpression/inhibition in hippocampal neurons, western blot and qRT-PCR Journal of neurodevelopmental disorders Medium 29665782

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 879 10433269
1999 Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 841 10433268
2001 Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 587 11498055
2012 Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 564 22699620
2017 SHANK proteins: roles at the synapse and in autism spectrum disorder. Nature reviews. Neuroscience 530 28179641
2012 Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 511 22699619
2014 Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS genetics 479 25188300
2000 The Shank family of scaffold proteins. Journal of cell science 458 10806096
2010 Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nature genetics 420 20473310
2013 Modeling autism by SHANK gene mutations in mice. Neuron 398 23583105
2012 Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS genetics 325 22346768
2002 ProSAP/Shank proteins - a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. Journal of neurochemistry 276 12065602
2005 Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 242 15814786
1999 Characterization of the Shank family of synaptic proteins. Multiple genes, alternative splicing, and differential expression in brain and development. The Journal of biological chemistry 236 10506216
2005 G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain. The Journal of neuroscience : the official journal of the Society for Neuroscience 217 15689540
1999 Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density. The Journal of neuroscience : the official journal of the Society for Neuroscience 207 10414979
2016 Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism. Molecular brain 205 26819149
2011 Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies. Trends in cell biology 195 21840719
2016 Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice. Nature communications 167 27581745
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
2019 SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons. Nature neuroscience 136 30911184
2003 The Shank family of postsynaptic density proteins interacts with and promotes synaptic accumulation of the beta PIX guanine nucleotide exchange factor for Rac1 and Cdc42. The Journal of biological chemistry 135 12626503
2015 Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders. Journal of neurochemistry 133 26338675
2001 Sharpin, a novel postsynaptic density protein that directly interacts with the shank family of proteins. Molecular and cellular neurosciences 126 11178875
2005 Association of CaV1.3 L-type calcium channels with Shank. The Journal of neuroscience : the official journal of the Society for Neuroscience 124 15689539
2004 Differential expression and dendritic transcript localization of Shank family members: identification of a dendritic targeting element in the 3' untranslated region of Shank1 mRNA. Molecular and cellular neurosciences 113 15121189
2011 Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology. Human molecular genetics 111 21994763
2001 Synaptic scaffolding proteins in rat brain. Ankyrin repeats of the multidomain Shank protein family interact with the cytoskeletal protein alpha-fodrin. The Journal of biological chemistry 109 11509555
2013 The Autism ProSAP1/Shank2 mouse model displays quantitative and structural abnormalities in ultrasonic vocalisations. Behavioural brain research 107 23994547
2004 Linkage of the actin cytoskeleton to the postsynaptic density via direct interactions of Abp1 with the ProSAP/Shank family. The Journal of neuroscience : the official journal of the Society for Neuroscience 101 15014124
2017 SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. Nature cell biology 100 28263956
2002 ProSAP/Shank postsynaptic density proteins interact with insulin receptor tyrosine kinase substrate IRSp53. Journal of neurochemistry 100 12421375
2005 C-terminal synaptic targeting elements for postsynaptic density proteins ProSAP1/Shank2 and ProSAP2/Shank3. Journal of neurochemistry 99 15659222
2004 Direct interaction of GluRdelta2 with Shank scaffold proteins in cerebellar Purkinje cells. Molecular and cellular neurosciences 95 15207857
2014 Ultrasonic vocalizations in Shank mouse models for autism spectrum disorders: detailed spectrographic analyses and developmental profiles. Neuroscience and biobehavioral reviews 92 24726578
2010 Shank-interacting protein-like 1 promotes tumorigenesis via PTEN inhibition in human tumor cells. The Journal of clinical investigation 91 20458142
2016 Whole-genome sequencing in multiplex families with psychoses reveals mutations in the SHANK2 and SMARCA1 genes segregating with illness. Molecular psychiatry 84 27001614
2008 Scaffolding proteins at the postsynaptic density: shank as the architectural framework. Handbook of experimental pharmacology 81 18491060
2000 The calcium-independent receptor for alpha-latrotoxin from human and rodent brains interacts with members of the ProSAP/SSTRIP/Shank family of multidomain proteins. The Journal of biological chemistry 77 10964907
2013 A role for synaptic zinc in ProSAP/Shank PSD scaffold malformation in autism spectrum disorders. Developmental neurobiology 76 23650259
2005 Postsynaptic shank antagonizes dendrite branching induced by the leucine-rich repeat protein Densin-180. The Journal of neuroscience : the official journal of the Society for Neuroscience 75 15647492
2016 Cerebellar Shank2 Regulates Excitatory Synapse Density, Motor Coordination, and Specific Repetitive and Anxiety-Like Behaviors. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 27903723
2004 A functional role of postsynaptic density-95-guanylate kinase-associated protein complex in regulating Shank assembly and stability to synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience 72 15496675
2005 The interaction of phospholipase C-beta3 with Shank2 regulates mGluR-mediated calcium signal. The Journal of biological chemistry 70 15632121
2009 Disassembly of shank and homer synaptic clusters is driven by soluble beta-amyloid(1-40) through divergent NMDAR-dependent signalling pathways. PloS one 69 19547699
2000 The G protein-coupled receptor CL1 interacts directly with proteins of the Shank family. The Journal of biological chemistry 69 10958799
2015 Identification and functional characterization of rare SHANK2 variants in schizophrenia. Molecular psychiatry 67 25560758
2004 Insulin receptor substrate of 53 kDa links postsynaptic shank to PSD-95. Journal of neurochemistry 66 15255944
2011 Systems analysis identifies an essential role for SHANK-associated RH domain-interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses. Proceedings of the National Academy of Sciences of the United States of America 61 21709223
2018 Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2-/- Mice. Biological psychiatry 57 30466882
2013 Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci. Clinical genetics 57 23350639
2013 Shank mutant mice as an animal model of autism. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 57 24298145
2006 Recurrent coamplification of cytoskeleton-associated genes EMS1 and SHANK2 with CCND1 in oral squamous cell carcinoma. Genes, chromosomes & cancer 56 16235239
2018 Shank and Zinc Mediate an AMPA Receptor Subunit Switch in Developing Neurons. Frontiers in molecular neuroscience 55 30524232
2017 Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI insight 54 29046483
2016 Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice. Neuropharmacology 53 27544825
2018 Cell-Type-Specific Shank2 Deletion in Mice Leads to Differential Synaptic and Behavioral Phenotypes. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 29572432
2018 Distinct Phenotypes of Shank2 Mouse Models Reflect Neuropsychiatric Spectrum Disorders of Human Patients With SHANK2 Variants. Frontiers in molecular neuroscience 50 30072871
2015 Shank-cortactin interactions control actin dynamics to maintain flexibility of neuronal spines and synapses. The European journal of neuroscience 50 26547831
2005 Shank2 associates with and regulates Na+/H+ exchanger 3. The Journal of biological chemistry 47 16293618
2003 Inhibitory regulation of cystic fibrosis transmembrane conductance regulator anion-transporting activities by Shank2. The Journal of biological chemistry 45 14679199
2017 Shank Proteins Differentially Regulate Synaptic Transmission. eNeuro 43 29250591
2016 Shank Modulates Postsynaptic Wnt Signaling to Regulate Synaptic Development. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 27225771
2020 Biocontrol of tobacco black shank disease (Phytophthora nicotianae) by Bacillus velezensis Ba168. Pesticide biochemistry and physiology 41 32359551
2014 ProSAP1 and membrane nanodomain-associated syndapin I promote postsynapse formation and function. The Journal of cell biology 41 24751538
2004 The postsynaptic scaffold proteins ProSAP1/Shank2 and Homer1 are associated with glutamate receptor complexes at rat retinal synapses. The Journal of comparative neurology 38 15236236
2016 Reduced acute nociception and chronic pain in Shank2-/- mice. Molecular pain 37 27145803
2020 Differentially altered social dominance- and cooperative-like behaviors in Shank2- and Shank3-mutant mice. Molecular autism 36 33126897
2016 A binding site outside the canonical PDZ domain determines the specific interaction between Shank and SAPAP and their function. Proceedings of the National Academy of Sciences of the United States of America 36 27185935
2012 Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 36 22245542
2021 Excitatory synapses and gap junctions cooperate to improve Pv neuronal burst firing and cortical social cognition in Shank2-mutant mice. Nature communications 35 34433814
2004 Characterization of an ankyrin repeat-containing Shank2 isoform (Shank2E) in liver epithelial cells. The Biochemical journal 35 14977424
2022 Shank postsynaptic scaffolding proteins in autism spectrum disorder: Mouse models and their dysfunctions in behaviors, synapses, and molecules. Pharmacological research 32 35792298
2018 Shank2 Deletion in Parvalbumin Neurons Leads to Moderate Hyperactivity, Enhanced Self-Grooming and Suppressed Seizure Susceptibility in Mice. Frontiers in molecular neuroscience 32 29970987
2018 Sex Hormones Regulate SHANK Expression. Frontiers in molecular neuroscience 32 30319350
2018 Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models. Frontiers in molecular neuroscience 30 29970989
2020 meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes. Clinical epigenetics 26 32616021
2018 Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism. Frontiers in molecular neuroscience 26 29970986
2002 Origin of the Black Shank Resistance Gene, Ph, in Tobacco Cultivar Coker 371-Gold. Plant disease 26 30818499
2018 Effect of the autism-associated lncRNA Shank2-AS on architecture and growth of neurons. Journal of cellular biochemistry 25 30160788
2021 Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders. Molecular psychiatry 24 34021263
2013 Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. PloS one 24 23468870
2022 POSH regulates assembly of the NMDAR/PSD-95/Shank complex and synaptic function. Cell reports 23 35385725
2020 Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma. Genome research 23 32796005
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
2021 SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(-/-) Mice. Frontiers in molecular neuroscience 22 34899182
2020 Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2. Genes, brain, and behavior 22 33347690
2019 Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5. Cell reports 22 31597090
2013 Alternative polyadenylation and differential expression of Shank mRNAs in the synaptic neuropil. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 21 24298140
2006 Expression of postsynaptic density proteins of the ProSAP/Shank family in the thymus. Histochemistry and cell biology 21 16758162
2018 A direct regulatory link between microRNA-137 and SHANK2: implications for neuropsychiatric disorders. Journal of neurodevelopmental disorders 20 29665782
2001 The cortactin-binding postsynaptic density protein proSAP1 in non-neuronal cells. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20 11304802
2021 Genetic Overlap Between Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in SHANK2 Gene. Frontiers in neuroscience 19 33986640
2020 Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling. eLife 19 32844749
2022 Shank2/3 double knockout-based screening of cortical subregions links the retrosplenial area to the loss of social memory in autism spectrum disorders. Molecular psychiatry 18 36100669
2021 SHANK2 mutations impair apoptosis, proliferation and neurite outgrowth during early neuronal differentiation in SH-SY5Y cells. Scientific reports 18 33483523
2020 Shank2 Binds to aPKC and Controls Tight Junction Formation with Rap1 Signaling during Establishment of Epithelial Cell Polarity. Cell reports 18 32268103
2020 SHANK2 is a frequently amplified oncogene with evolutionarily conserved roles in regulating Hippo signaling. Protein & cell 18 32661924
2018 Defective Synapse Maturation and Enhanced Synaptic Plasticity in Shank2 Δex7-/- Mice. eNeuro 18 30023428
2015 Tobacco serine/threonine protein kinase gene NrSTK enhances black shank resistance. Genetics and molecular research : GMR 18 26662438

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