Affinage

CNKSR2

Connector enhancer of kinase suppressor of ras 2 · UniProt Q8WXI2

Round 2 corrected
Length
1034 aa
Mass
117.5 kDa
Annotated
2026-04-28
85 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNKSR2 is a multidomain scaffold protein that organizes signaling complexes at neuronal synapses and in cancer cell migration by bridging Ras/MAPK pathway components, small GTPase regulators, and postsynaptic density proteins. At excitatory synapses, CNKSR2 links PSD-95 and Densin-180 into ternary complexes, recruits and activates the kinase TNIK, spatially modulates Rac GTP/GDP cycling through its constitutive partner ARHGAP39/Vilse, and stabilizes AMPA receptor surface expression via PSD-95, thereby controlling dendritic spine morphogenesis and postsynaptic glutamatergic transmission (PMID:10207009, PMID:12390249, PMID:24656827, PMID:36803960, PMID:40010432). In non-neuronal contexts, CNKSR2 couples AXL receptor signaling to ARF6/RAC1-driven migration through cytohesin GEFs and the adaptor SAMD12, and its stability is maintained by Smurf2-mediated non-degradative ubiquitination and by CYTH2 binding (PMID:37322019, PMID:29534682, PMID:34800437). Loss-of-function mutations in CNKSR2 cause X-linked intellectual disability with seizures and language impairment (epilepsy–aphasia spectrum), and conditional deletion in anterior cingulate cortex excitatory neurons is sufficient to produce vocal communication deficits (PMID:22511892, PMID:34580165, PMID:39694826).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Establishing CNKSR2 as a synaptic scaffold: discovery of its PDZ-binding motif-mediated interactions with PSD-95 and S-SCAM placed it within the postsynaptic density complex, answering how this novel neuronal protein integrates into synaptic architecture.

    Evidence Co-immunoprecipitation from rat synaptosomes, yeast two-hybrid, domain-deletion localization in transfected cells

    PMID:10207009

    Open questions at the time
    • No functional consequence of disrupting these interactions was tested
    • Endogenous stoichiometry unknown
  2. 2002 High

    Defining CNKSR2 as an obligatory molecular bridge: demonstration that CNKSR2 is required to link Densin-180 to PSD-95 in a ternary complex resolved how these two PSD proteins associate and revealed CNKSR2's non-redundant scaffolding role.

    Evidence Ternary complex reconstitution in transfected cells, Co-IP from rat brain, domain mapping

    PMID:12390249

    Open questions at the time
    • Functional consequence of disrupting the ternary complex in neurons not tested
    • Multimerization role unexplored
  3. 2003 High

    Connecting CNKSR2 to the Ras/MAPK cascade: identification of interactions with RAF1, Ral GTPase, and RalGDS-family GEFs established CNKSR2 as a Ras-effector scaffold, extending its function beyond static PSD scaffolding to active signaling pathway organization.

    Evidence Co-IP, GST pulldown domain mapping, MAPK-dependent phosphorylation, subcellular fractionation in MDCK cells

    PMID:14597674

    Open questions at the time
    • Endogenous Ras-pathway scaffolding not shown in neurons at this stage
    • Specific Ras isoform selectivity not determined
  4. 2004 High

    Demonstrating stimulus-specific signaling: siRNA knockdown revealed CNKSR2 is required for NGF- but not EGF-induced ERK activation, answering whether CNKSR2 provides pathway selectivity and linking its scaffold function to neuronal differentiation.

    Evidence siRNA knockdown in PC12 cells, ERK activation immunoblots, morphological cytoskeletal readouts

    PMID:15028221

    Open questions at the time
    • Mechanism of stimulus selectivity not defined
    • Whether selectivity applies in primary neurons untested
  5. 2008 High

    Structural basis for SAM-domain-mediated complex assembly: the crystal structure of the Drosophila CNK SAM domain bound to HYP revealed the heterodimeric interface critical for RAF signaling, providing the first atomic-level insight into how CNK-family scaffolds nucleate kinase complexes.

    Evidence X-ray crystallography, mutagenesis, in vivo Drosophila rescue assays

    PMID:18287031

    Open questions at the time
    • Human CNKSR2 SAM domain structure not solved
    • Whether the same heterodimer mode operates with mammalian partners remains inferential
  6. 2014 High

    Revealing CNKSR2 as a Rac-GTP/GDP cycling modulator: the constitutive CNKSR2–Vilse/ARHGAP39 interaction and its requirement for dendritic spine morphogenesis answered how CNKSR2 spatially regulates small GTPase signaling at spines, unifying its scaffold and morphogenesis roles.

    Evidence Endogenous IP-MS interactome, domain-deletion mutagenesis, shRNA knockdown and rescue in hippocampal neurons, spine morphometry

    PMID:24656827

    Open questions at the time
    • Whether Vilse-independent CNK2 functions contribute to spine formation not dissected
    • Temporal dynamics of Rac cycling at spines not measured
  7. 2018 High

    Defining CNKSR2 protein stability regulation: Smurf2 was shown to ubiquitinate CNKSR2 in a non-degradative manner that protects it from proteasomal turnover, establishing a post-translational mechanism controlling CNKSR2 abundance relevant to cancer cell proliferation.

    Evidence Co-IP, surface plasmon resonance, ubiquitination assays, proteasome inhibitor experiments in breast cancer cells

    PMID:29534682

    Open questions at the time
    • Ubiquitin chain type not characterized
    • Whether this stabilization mechanism operates in neurons unknown
  8. 2021 High

    In vivo loss-of-function phenotyping: Cnksr2 knockout mice displayed seizures, vocalization loss, and synaptic proteome remodeling, directly establishing CNKSR2 as essential for neural circuit function and modeling the human epilepsy-aphasia syndrome.

    Evidence Cnksr2 KO mouse, EEG, behavioral assays, quantitative synaptic proteomics, immunolocalization at excitatory and inhibitory synapses

    PMID:34580165

    Open questions at the time
    • Causal contribution of individual synaptic protein changes not delineated
    • Inhibitory synapse-specific role of CNKSR2 not functionally tested
  9. 2021 High

    CYTH2-dependent stabilization and dentate gyrus development: CYTH2 binding prevents CNKSR2 proteasomal degradation and the complex is required for granule cell differentiation, revealing a second stability-control mechanism and a neurodevelopmental role beyond synapse organization.

    Evidence Co-IP, in vivo shRNA knockdown via stereotaxic injection in mouse, immunohistochemistry, cell positioning analysis

    PMID:34800437

    Open questions at the time
    • How CYTH2 binding blocks CNKSR2 degradation mechanistically is unresolved
    • Relationship to Smurf2-mediated stabilization not explored
  10. 2023 High

    CNKSR2 controls AMPA receptor surface expression: genetic ablation of CNKSR2 impaired PSD-95 localization and reduced surface AMPA receptors and postsynaptic responses, answering a longstanding question about the functional consequence of the PSD-95–CNKSR2 scaffold interaction for glutamatergic transmission.

    Evidence MAGUIN KO neurons, surface AMPA receptor immunostaining, whole-cell patch-clamp electrophysiology

    PMID:36803960

    Open questions at the time
    • Specific AMPA receptor subunit dependence not determined
    • Whether inhibitory receptor trafficking is also affected untested
  11. 2023 High

    Cancer migration mechanism: CNKSR2 was shown to couple AXL receptor signaling to ARF6/RAC1-driven migration via cytohesin GEFs and SAMD12, with ablation reducing metastasis in vivo, answering how CNKSR2 scaffold function is co-opted in cancer.

    Evidence Co-IP, proximity ligation assay, GTPase activity assays, CRISPR/shRNA ablation, mouse xenograft metastasis model

    PMID:37322019

    Open questions at the time
    • Applicability beyond the tested cancer cell lines not established
    • Whether neuronal CNKSR2–cytohesin signaling uses the same AXL-dependent mechanism unknown
  12. 2025 High

    SAMD12 as a competitive regulator of CNKSR2–TNIK complexes: quantitative binding assays showed SAMD12 displaces MAP4K kinases (including TNIK) from CNKSR2, and ectopic SAMD12 disrupts synapse development, establishing CNKSR2 as both a scaffold and an activator of TNIK and identifying SAMD12 as a natural antagonist.

    Evidence Biochemical affinity measurements, competitive displacement assays, Co-IP, neuronal synapse morphology readouts

    PMID:40010432

    Open questions at the time
    • Endogenous SAMD12 expression levels in brain regions not quantified
    • Whether SAMD12 regulation is developmentally dynamic remains unknown
  13. 2024 High

    Circuit-level dissection: conditional deletion in ACC excitatory neurons sufficed to reproduce vocalization deficits, dissociating the communication phenotype from seizures and anxiety and identifying the critical neuronal population for CNKSR2-dependent vocal communication.

    Evidence Cre-lox conditional KO mice, stereotaxic viral Cre delivery to ACC, EEG, behavioral assays

    PMID:39694826

    Open questions at the time
    • Molecular mechanism downstream of CNKSR2 loss in ACC neurons not defined
    • Whether restoration of CNKSR2 in ACC can rescue established deficits untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Several major mechanistic questions remain: (1) the structural basis of human CNKSR2 scaffold assembly is unknown; (2) how the two protein-stability mechanisms (Smurf2 and CYTH2) are coordinated is unresolved; (3) the specific contribution of CNKSR2 at inhibitory synapses has not been functionally dissected; and (4) whether CNKSR2's centrosomal role is relevant in vivo remains unvalidated.
  • No crystal or cryo-EM structure of mammalian CNKSR2
  • Smurf2 vs CYTH2 stabilization interplay untested
  • Inhibitory synapse function of CNKSR2 not explored beyond localization

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6
Localization
GO:0005886 plasma membrane 3 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 7 R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 3
Partners
ARHGAP39CYTH2DLG4LRFN1RAF1SAMD12SMURF2TNIK
Complex memberships
CNKSR2–CYTH2 complexCNKSR2–Vilse/ARHGAP39 complexPSD-95/Densin-180/CNKSR2 ternary complex

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 CNKSR2 (MAGUIN-1) was identified as a novel neuronal scaffold protein that interacts via its C-terminal PDZ-binding motif with the PDZ domains of PSD-95/SAP90 and S-SCAM. MAGUIN-1 localizes to the plasma membrane via its pleckstrin homology (PH) domain and C-terminal region, and is co-immunoprecipitated with PSD-95/SAP90 and S-SCAM from rat crude synaptosome, indicating it is a component of the postsynaptic density complex. Co-immunoprecipitation from rat synaptosome, domain-deletion localization experiments, yeast two-hybrid The Journal of biological chemistry High 10207009
2002 MAGUIN-1/CNKSR2 bridges Densin-180 and PSD-95 by forming a ternary complex: the PDZ domain of Densin-180 binds the C-terminal PDZ-binding motif of MAGUIN-1, while the first PDZ domain of PSD-95 binds MAGUIN-1 separately. Densin-180 cannot associate with PSD-95 in the absence of MAGUIN-1, establishing CNKSR2 as an obligatory linker between these two synaptic scaffold proteins. MAGUIN-1 also forms dimers/multimers via its C-terminal leucine-rich region. Co-immunoprecipitation from rat brain, yeast two-hybrid domain mapping, transfected cell ternary complex assays, co-localization in hippocampal neurons Genes to cells : devoted to molecular & cellular mechanisms High 12390249
2003 The human CNKSR2 protein (CNK2A and splice variant CNK2B) interacts with the Ras effector proteins RAF1 (mapped to the regulatory and kinase domains of Raf and the C-terminal half of CNK2) and with Ral signaling components including Ral GTPase and the RalGDS family member Rlf (mapped to the GEF domain of Rlf). CNK2 is phosphorylated in a MAPK-dependent manner in vivo and localizes to both membrane and cytoplasmic fractions, with full-length CNK2 at the lateral plasma membrane in MDCK cells. Co-immunoprecipitation, GST pulldown domain mapping, subcellular fractionation, confocal localization in MDCK cells FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 14597674
2004 CNK2/CNKSR2 is required for NGF- but not EGF-induced ERK activation in neuronal precursor cells, demonstrating stimulus-specific scaffold function. CNK2 additionally couples NGF signaling to membrane/cytoskeletal remodeling through a separate, essential contribution, indicating that it integrates multiple regulatory pathways needed for neuronal differentiation. siRNA knockdown in PC12 cells, ERK activation assays (immunoblot), morphological readouts of cytoskeletal remodeling Current biology : CB High 15028221
2008 The SAM domain of Drosophila CNK (the ortholog of CNKSR2) forms a 1:1 heterodimer with the SAM domain of HYP, as determined by X-ray crystal structure. This specific SAM-SAM dimerization mode is essential for RAF kinase signaling in vivo and facilitates recruitment of KSR to form the CNK/HYP/KSR regulatory complex. X-ray crystallography, in vitro mutagenesis, in vivo Drosophila signaling rescue assays Proceedings of the National Academy of Sciences of the United States of America High 18287031
2011 Loss-of-function deletion of the CNKSR2 gene (removing 15 of 21 exons) causes X-linked intellectual disability with epilepsy, establishing CNKSR2 as a causative gene for NS-XLID. High brain expression and postsynaptic density localization support its role in RAS/MAPK-dependent synaptic signal transduction. Copy number analysis (array CGH), gene expression profiling, known PSD localization data Molecular syndromology Medium 22511892
2014 CNKSR2 (CNK2) interacts constitutively with Vilse/ARHGAP39 via the WW domains of Vilse and a proline-rich motif in CNK2. CNK2 complexes are enriched for Rac/Cdc42 signaling components (Rac1, α/β-PIX, GIT1/2, PAK3/4, cytohesins). CNK2 acts as a spatial modulator of Rac GTP/GDP cycling during dendritic spine morphogenesis; disruption of the CNK2–Vilse interaction impairs spine formation by unbalancing RacGDP/GTP levels. Mass spectrometry interactome of endogenous CNK2, co-immunoprecipitation, domain-deletion mutagenesis, shRNA knockdown and rescue experiments in hippocampal neurons, spine morphology quantification Current biology : CB High 24656827
2014 Smurf2 E3 ubiquitin ligase physically interacts with CNKSR2 and regulates AKT-dependent cell proliferation and invasion of breast cancer cells through the PI3K-PTEN-AKT-FoxO3a pathway in a CNKSR2-dependent manner. Silencing Smurf2 downregulates CNKSR2 and suppresses breast cancer cell growth. siRNA knockdown, co-immunoprecipitation, cell proliferation/invasion assays, cell cycle analysis, western blotting Cell division Medium 25191523
2018 Smurf2 physically associates with CNKSR2 (confirmed by co-immunoprecipitation, indirect immunofluorescence, and surface plasmon resonance) and acts as a positive regulator of CNKSR2 stability: Smurf2 ubiquitinates CNKSR2 but protects it from proteasomal degradation. Smurf2 knockdown leads to enhanced polyubiquitination and proteasomal degradation of CNKSR2, reducing breast cancer cell proliferation and clonogenic survival. Co-immunoprecipitation, surface plasmon resonance, indirect immunofluorescence, ubiquitination assays, proteasome inhibitor experiments, siRNA knockdown BMC cancer High 29534682
2020 CNK2/CNKSR2 modulates the size of the postsynaptic density (PSD) in neurons and directs the subcellular localization of the regulatory kinase TNIK to dendritic spines. Both CNK2 and TNIK localize postsynaptically in hippocampal neurons; CNK2 expression is critical for maintaining TNIK at appropriate levels and location, establishing a functional scaffold–kinase relationship. Immunofluorescence co-localization with synaptic markers, overexpression and knockdown experiments in neurons, PSD size morphometry Scientific reports Medium 32235845
2021 Cnksr2 knockout mice display spontaneous electrographic seizures, increased neural activity, anxiety, impaired learning/memory, and progressive loss of ultrasonic vocalizations. In vivo quantitative proteomics shows that Cnksr2 anchors key binding partners at synapses, and its loss significantly alters the synaptic proteome including proteins implicated in epilepsy. Cnksr2 is localized at both excitatory and inhibitory postsynapses in cortical, striatal, and cerebellar regions. Cnksr2 KO mouse model, EEG, behavioral assays, in vivo quantitative proteomics, immunolocalization The Journal of neuroscience : the official journal of the Society for Neuroscience High 34580165
2021 CNKSR2 forms a molecular complex with the ARF-GEF CYTH2 in the hippocampal dentate gyrus, and CYTH2 binding prevents proteasomal degradation of CNKSR2. Silencing either CNKSR2 or CYTH2 in vivo causes abnormal positioning of granule cell precursors at the granule cell layer–hilus boundary with characteristics of immature neurons, demonstrating that the CNKSR2–CYTH2 complex is necessary for dentate granule cell development and differentiation. Co-immunoprecipitation, shRNA in vivo knockdown in mouse via stereotaxic injection, immunohistochemistry, cell positioning quantification The Journal of biological chemistry High 34800437
2023 CNK2/CNKSR2 promotes cancer cell migration by coupling the pro-metastatic receptor tyrosine kinase AXL to ARF6 GTPase activation. AXL signaling drives PI3K-dependent recruitment of CNK2 to the plasma membrane; CNK2 then stimulates ARF6 by associating with cytohesin ARF-GEFs and a novel adaptor SAMD12. ARF6-GTP coordinates RAC1 activation and RHOA inhibition to generate motile forces. Genetic ablation of CNK2 or SAMD12 reduces metastasis in a mouse xenograft model. Co-immunoprecipitation, proximity ligation assay, GTPase activity assays, shRNA/CRISPR ablation, live-cell migration assays, mouse xenograft metastasis model Nature communications High 37322019
2023 s-Afadin (a splice variant of afadin) preferentially binds MAGUIN/CNKSR2 over l-afadin in vivo and in vitro. Genetic ablation of MAGUIN impairs PSD-95 localization and AMPA receptor surface accumulation in cultured hippocampal neurons and reduces postsynaptic glutamatergic responses (without affecting presynaptic release), establishing CNKSR2 as a regulator of PSD-95-dependent AMPA receptor surface localization. Co-immunoprecipitation in vivo and in vitro, MAGUIN KO neurons, surface AMPA receptor immunostaining, whole-cell patch-clamp electrophysiology The Journal of biological chemistry High 36803960
2023 CNKSR2 functions downstream of retinoic acid (RA) signaling in the chick forebrain roof plate, where its knockdown phenocopies RA signaling inhibition (defective invagination, reduced cell proliferation, altered patterning). CNKSR2 exerts these effects by modulating the Ras/Raf/MEK signaling pathway, as demonstrated by epistasis experiments. In ovo siRNA knockdown in chick embryo, morphological analysis, BrdU proliferation assay, pharmacological MEK inhibition epistasis Development (Cambridge, England) Medium 36734326
2024 CNKSR2 interacts with the microtubule motor protein DYNC1H1 and the centrosome marker CEP290, and localizes to centrosomes in neurons. Downregulation of CNKSR2 in Neuro-2A cells alters expression of numerous centrosomal genes and impairs centrosome-related functions including cell size, cell proliferation, and motility, revealing a previously unknown cytoplasmic/centrosomal role for CNKSR2. Immunoprecipitation–mass spectrometry, bioinformatic enrichment analysis, co-localization immunofluorescence, CNKSR2 siRNA knockdown with centrosome functional assays Neural regeneration research Medium 39359098
2025 SAMD12 (and its homolog SAMD10) binds CNKSR1/2/3 scaffold proteins with exceptionally high affinity and quantitatively displaces MAP4K kinases (MAP4K4, MINK1, TNIK) from CNKSR2 complexes. CNKSR2 acts as both a scaffold and an activator of TNIK during neuronal synapse development; ectopic SAMD12 expression alters synapse development by inhibiting TNIK activity through its dissociation from CNKSR2. Biochemical binding assays (affinity measurements), competitive displacement assays, co-immunoprecipitation, ectopic expression in neurons with synapse morphology readout Journal of molecular biology High 40010432
2024 CNKSR2 interacts with RSK kinases through a DDVF-like short linear motif (SLiM), using the same docking interface exploited by viral and bacterial pathogen proteins. This interaction was confirmed by co-immunoprecipitation, and the RSK docking site appears to participate in negative feedback regulation of the RAS-ERK MAPK pathway. AlphaFold docking prediction, co-immunoprecipitation, RSK docking-site mutagenesis with ERK activation readout bioRxiv (preprint)preprint Low bio_10.1101_2024.08.08.607128
2024 Conditional deletion of Cnksr2 specifically in excitatory neurons recapitulates anxiety and ultrasonic vocalization (USV) deficits seen in global KO mice. Further restriction of Cnksr2 deletion to excitatory neurons of the anterior cingulate cortex (ACC) is sufficient to produce USV impairments, dissociating the communication deficit from seizure and anxiety phenotypes and identifying the ACC excitatory neuron population as the critical locus for CNKSR2-dependent vocal communication. Conditional (Cre-lox) neuronal subtype-specific KO mice, EEG, behavioral assays (USV, anxiety, learning), stereotaxic viral Cre delivery to ACC eNeuro High 39694826

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Biological insights from 108 schizophrenia-associated genetic loci. Nature 5878 25056061
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2005 The DNA sequence of the human X chromosome. Nature 816 15772651
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2006 Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular psychiatry 345 17043677
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
1998 Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 190 10048485
2013 KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. Cell 141 24209692
2009 KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell metabolism 120 19883615
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2009 KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals. Molecular cell 101 19560418
2002 C. elegans ksr-1 and ksr-2 have both unique and redundant functions and are required for MPK-1 ERK phosphorylation. Current biology : CB 90 11882296
1995 [IMAGE: molecular integration of the analysis of the human genome and its expression]. Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie 70 7757816
1999 MAGUIN, a novel neuronal membrane-associated guanylate kinase-interacting protein. The Journal of biological chemistry 66 10207009
2022 Proteome-scale mapping of binding sites in the unstructured regions of the human proteome. Molecular systems biology 61 35044719
2002 Densin-180, a synaptic protein, links to PSD-95 through its direct interaction with MAGUIN-1. Genes to cells : devoted to molecular & cellular mechanisms 60 12390249
2004 Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. Genome research 57 15342556
2014 The CNK2 scaffold interacts with vilse and modulates Rac cycling during spine morphogenesis in hippocampal neurons. Current biology : CB 54 24656827
2006 Uncovering quantitative protein interaction networks for mouse PDZ domains using protein microarrays. Journal of the American Chemical Society 54 16637659
2020 Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation. Cell death & disease 53 33040078
2012 Kinase suppressor of Ras 2 (KSR2) regulates tumor cell transformation via AMPK. Molecular and cellular biology 53 22801368
2017 Evaluation of the Immunomodulatory Activity of the Chicken NK-Lysin-Derived Peptide cNK-2. Scientific reports 51 28332637
2003 Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 50 14597674
2013 The kinases LF4 and CNK2 control ciliary length by feedback regulation of assembly and disassembly rates. Current biology : CB 48 24184104
2004 CNK2 couples NGF signal propagation to multiple regulatory cascades driving cell differentiation. Current biology : CB 48 15028221
2011 Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability. Molecular syndromology 47 22511892
2022 NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia. Nature immunology 46 36138187
2014 Absent CNKSR2 causes seizures and intellectual, attention, and language deficits. Annals of neurology 45 25223753
2009 Genome-wide association study of biochemical traits in Korcula Island, Croatia. Croatian medical journal 42 19260141
2008 CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling. Proceedings of the National Academy of Sciences of the United States of America 41 18287031
2014 Smurf2 E3 ubiquitin ligase modulates proliferation and invasiveness of breast cancer cells in a CNKSR2 dependent manner. Cell division 38 25191523
2022 A BioID-Derived Proximity Interactome for SARS-CoV-2 Proteins. Viruses 37 35337019
2022 Quantitative fragmentomics allow affinity mapping of interactomes. Nature communications 33 36115835
2009 Proteomic characterization of the dynamic KSR-2 interactome, a signaling scaffold complex in MAPK pathway. Biochimica et biophysica acta 32 19563921
2022 Genome-wide CRISPR screens using isogenic cells reveal vulnerabilities conferred by loss of tumor suppressors. Science advances 28 35559673
2017 Frequency of CNKSR2 mutation in the X-linked epilepsy-aphasia spectrum. Epilepsia 27 28098945
2015 CNKSR2 deletions: a novel cause of X-linked intellectual disability and seizures. American journal of medical genetics. Part A 27 25754917
2016 Systematic Identification of Oncogenic EGFR Interaction Partners. Journal of molecular biology 21 27956147
2021 CNKSR2-related neurodevelopmental and epilepsy disorder: a cohort of 13 new families and literature review indicating a predominance of loss of function pathogenic variants. BMC medical genomics 19 34266427
2018 Regulation of CNKSR2 protein stability by the HECT E3 ubiquitin ligase Smurf2, and its role in breast cancer progression. BMC cancer 19 29534682
2019 A de novo variant in the X-linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient. Molecular genetics & genomic medicine 17 31414730
2018 CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome: A case report and review of literature. World journal of clinical cases 16 30397616
2016 Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis. Molecular metabolism 16 28180061
2014 The KSR2-calcineurin complex regulates STIM1-ORAI1 dynamics and store-operated calcium entry (SOCE). Molecular biology of the cell 15 24672054
2021 Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 34580165
2022 Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders. Cells 13 35053419
2021 The synaptic scaffolding protein CNKSR2 interacts with CYTH2 to mediate hippocampal granule cell development. The Journal of biological chemistry 12 34800437
2020 Disease-associated synaptic scaffold protein CNK2 modulates PSD size and influences localisation of the regulatory kinase TNIK. Scientific reports 12 32235845
2021 MiR-3138 deteriorates the insulin resistance of HUVECs via KSR2/AMPK/GLUT4 signaling pathway. Cell cycle (Georgetown, Tex.) 11 33509040
2016 Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2). Scientific reports 10 27561547
2020 Exons deletion of CNKSR2 gene identified in X-linked syndromic intellectual disability. BMC medical genetics 9 32245427
2023 CNK2 promotes cancer cell motility by mediating ARF6 activation downstream of AXL signalling. Nature communications 8 37322019
2021 CNKSR2 gene mutation leads to Houge type of X-linked syndromic mental retardation: A case report and review of literature. Medicine 8 34114993
2022 Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity. eLife 7 36342465
2020 Psychomotor development and attention problems caused by a splicing variant of CNKSR2. BMC medical genomics 7 33298018
2017 The KSR2-rs7973260 Polymorphism is Associated with Metabolic Phenotypes, but Not Psychological Phenotypes, in Chinese Elders. Genetic testing and molecular biomarkers 5 28537769
2024 CNKSR2 interactome analysis indicates its association with the centrosome/microtubule system. Neural regeneration research 4 39359098
2023 s-Afadin binds to MAGUIN/Cnksr2 and regulates the localization of the AMPA receptor and glutamatergic synaptic response in hippocampal neurons. The Journal of biological chemistry 4 36803960
2022 KSR2-14-3-3ζ complex serves as a biomarker and potential therapeutic target in sorafenib-resistant hepatocellular carcinoma. Biomarker research 4 35468812
2022 Case report: Phenotype expansion and analysis of TRIO and CNKSR2 variations. Frontiers in neurology 4 36105777
2024 Identification of KSR2 Variants in Pediatric Patients with Severe Early-Onset Obesity from Qatar. Genes 2 39202327
2024 The bta-miR-22-3p can alleviate LPS-induced inflammatory response in yak endometrial epithelial cells by targeting KSR2. Microbial pathogenesis 2 39510361
2023 CNKSR2, a downstream mediator of retinoic acid signaling, modulates the Ras/Raf/MEK pathway to regulate patterning and invagination of the chick forebrain roof plate. Development (Cambridge, England) 2 36734326
2023 A Novel Neuroimaging Phenotype in the X-Linked Intellectual Disability with a Missense Mutation of CNKSR2 Gene. Neurology India 2 37929438
2025 Identification of Houge type of X-linked syndromic mental retardation caused by CNKSR2 truncated variants. Italian journal of pediatrics 1 39920708
2025 KSR2 Promotes Self-Renewal and Clonogenicity of Small Cell Lung Carcinoma. Molecular cancer research : MCR 1 40063515
2024 Hemizygous splicing variant in CNKSR2 results in X-linked intellectual developmental disorder. Molecular genetics & genomic medicine 1 38337158
2024 Novel Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of CNKSR2 in the Houge Type of X-Linked Syndromic Intellectual Development Disorder (MRXSHG). American journal of medical genetics. Part A 1 39707601
2019 Expression analysis of LTR-derived miR-1269a and target gene, KSR2 in Sebastes schlegelii. Genes & genomics 1 31721105
2026 Endothelial KSR2 regulated by genetic variation protects against atherosclerosis through AMPKα1 stabilization. Theranostics 0 41424849
2026 Identification and structural characterisation of a novel mutation in the CNKSR2 gene associated with Houge-Type X-Linked Intellectual Developmental Disorder. Journal of human genetics 0 41946974
2026 KSR2 functions as a metabolic checkpoint for anti-PD-1 resistance by reprogramming glucose metabolism. Cancer immunology, immunotherapy : CII 0 42012646
2026 CNKSR2 scaffold function in the mammalian nervous system. Biological chemistry 0 42035360
2025 SAMD12 as a Master Regulator of MAP4Ks by Decoupling Kinases From the CNKSR2 Scaffold. Journal of molecular biology 0 40010432
2025 Obese-diabetic female Ksr2 knockout mice develop brittle bones near end of life. JBMR plus 0 40303835
2025 Identification of CNKSR2 Pathogenic Variant and Detection of Strong XCI in a Female Patient With Severe DEE-SWAS and Phenotype Expansion in Male Patients. Clinical genetics 0 40873128
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