Affinage

CNKSR1

Connector enhancer of kinase suppressor of ras 1 · UniProt Q969H4

Length
720 aa
Mass
79.7 kDa
Annotated
2026-04-28
93 papers in source corpus 27 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNKSR1 is a multidomain scaffold protein that orchestrates signal transduction downstream of RAS, Rho GTPases, and receptor tyrosine kinases by assembling pathway-specific signaling complexes at the plasma membrane. Through its SAM domain heterodimer with HYP/AVVRK and direct contacts with both KSR and MEK, CNKSR1 forms a ring-like complex that promotes RAF-KSR heterodimerization and RAF catalytic activation, while a C-terminal inhibitory region (RIR) prevents basal signaling leakage and is counteracted by Src binding (PMID:14517245, PMID:38388830, PMID:15660123). Beyond the RAF-MEK-ERK cascade, CNKSR1 scaffolds Rho GEFs with MLK2/MKK7 to activate JNK signaling, interacts with cytohesins to promote insulin-stimulated PI3K/AKT activation, and gates EGFR/HER2 dephosphorylation by sequestering the phosphatase PTPRH until RhoB-GTP displaces it (PMID:15753034, PMID:20634316, PMID:34187934). Loss-of-function frameshift mutation in CNKSR1 causes syndromic autosomal recessive intellectual disability (PMID:30450701).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    The founding discovery that CNK physically interacts with RAF and is genetically required for RAS signaling established it as a scaffold linking RAS pathway activation to RAF regulation.

    Evidence Genetic modifier screen of ksr in Drosophila eye combined with co-immunoprecipitation and subcellular localization

    PMID:9814705

    Open questions at the time
    • No mammalian ortholog characterized
    • Mechanism by which CNK activates RAF unknown
    • Binding domains on RAF not mapped
  2. 1999 High

    Epistasis with RAS effector-loop mutants revealed that CNK operates in more than one RAS-effector branch — the N-terminus cooperates with the RAL pathway while the C-terminus regulates RAF — expanding CNK's role beyond simple RAF scaffolding.

    Evidence Overexpression with RAS effector loop mutants in Drosophila eye development

    PMID:10557308

    Open questions at the time
    • RAL-branch mechanism not defined at the molecular level
    • Whether the two branches function independently or coordinately was unclear
  3. 2003 High

    Domain dissection uncovered bimodal control of RAF: N-terminal SAM/CRIC domains activate RAF while a C-terminal RIR inhibits it, explaining how CNK prevents basal signaling yet enables stimulus-dependent activation.

    Evidence Domain deletion/mutation analysis with RNAi rescue in Drosophila S2 cells

    PMID:14517245

    Open questions at the time
    • Identity of the signal that relieves RIR-mediated inhibition unknown
    • No structural information on SAM/CRIC activation mechanism
  4. 2004 High

    Identification of GTP-dependent RhoA binding via the PH domain, plus interactions with Rhophilin and RalGDS, established human CNK1 as a node integrating Rho and Ras pathways in transcriptional control (SRF-dependent genes) and apoptosis (via RASSF1A/MST1).

    Evidence Yeast two-hybrid, co-immunoprecipitation, RNAi knockdown, and reporter assays in mammalian cells

    PMID:14749388 PMID:15075335

    Open questions at the time
    • Direct structural basis of RhoA-PH domain interaction unresolved
    • In vivo relevance of RASSF1A-CNK1-MST1 apoptotic axis not tested in animal models
  5. 2005 High

    Multiple studies converged to show that CNK1 scaffolds distinct MAPK modules — Src/Raf-1/ERK and Rho-GEF/MLK2/MKK7/JNK — and that Src binding to a conserved C-terminal region relieves the RAF-inhibitory region, answering the key question of how RIR-mediated repression is derepressed.

    Evidence Co-immunoprecipitation of trimeric Src-CNK1-Raf-1 complex, siRNA knockdown with ERK/JNK readouts in HeLa cells, Drosophila genetic allele mapping of Src42 binding site

    PMID:15660123 PMID:15753034 PMID:15845549

    Open questions at the time
    • Whether Src derepression requires catalytic activity or only SH2/SH3 docking in mammalian cells untested
    • Structural basis of JNK-branch scaffold assembly unknown
  6. 2006 High

    Discovery of the adaptor protein HYP (Hyphen/AVVRK) as the missing link that bridges CNK's SAM domain to KSR explained how CNK recruits KSR to RAF prior to signal activation.

    Evidence Genetic epistasis, co-immunoprecipitation, and RNAi in Drosophila S2 cells

    PMID:16600912

    Open questions at the time
    • Mammalian HYP ortholog function not yet validated
    • Stoichiometry of the CNK-HYP-KSR complex unknown
  7. 2008 High

    The crystal structure of the CNK-SAM/HYP-SAM heterodimer revealed a single-junction 1:1 interaction mode, and mutagenesis confirmed that this interface is essential for RAF signaling, providing the first atomic-resolution view of the scaffolding mechanism.

    Evidence X-ray crystallography with in vivo and in vitro mutagenesis validation

    PMID:18287031

    Open questions at the time
    • Full-length complex structure unavailable
    • Whether SAM-SAM interaction is regulated by post-translational modifications unknown
  8. 2010 High

    Mass spectrometry-based interactomics identified cytohesins as the major CNK1 binding partners and showed that CNK1 scaffolds cytohesin-2 membrane recruitment to activate PI3K/AKT signaling upon insulin stimulation, broadening CNK1's role beyond MAPK to metabolic signaling.

    Evidence Mass spectrometry interactome, co-immunoprecipitation, depletion/rescue, membrane fractionation

    PMID:20634316

    Open questions at the time
    • Whether CNK1-cytohesin interaction is conserved in all insulin-responsive tissues not tested
    • Relative contribution of CNK1 vs. other cytohesin scaffolds undetermined
  9. 2010 High

    CNK1 was shown to interact with AKT and drive AKT-dependent FoxO phosphorylation and NF-κB2 processing, linking scaffold function to pro-proliferative and pro-invasive transcriptional programs in breast cancer cells.

    Evidence Co-immunoprecipitation, siRNA knockdown, reporter assays, invasion assays in breast cancer cell lines

    PMID:20197385 PMID:20383191

    Open questions at the time
    • Whether CNK1-AKT interaction is direct or mediated by cytohesins not fully resolved
    • In vivo tumor model validation limited
  10. 2016 High

    AKT-dependent phosphorylation of Ser22 in the SAM domain was found to trigger CNK1 oligomerization and create a positive feedback loop with AKT, while optogenetic clustering revealed that CNK1 oligomerization state switches cell fate between differentiation (ERK) and proliferation (AKT).

    Evidence Phosphorylation site mapping by mass spectrometry, mutagenesis, optogenetic clustering with cell fate readouts

    PMID:27769899 PMID:27901111

    Open questions at the time
    • Structural basis of SAM-dependent oligomerization upon Ser22 phosphorylation unknown
    • Optogenetic findings require validation under endogenous expression levels
  11. 2017 High

    ERK-induced acetylation of Lys414 in the PH domain by CBP (reversed by SIRT2) was shown to drive CNK1 membrane recruitment and CRAF interaction, establishing a post-translational positive feedback loop sustaining ERK signaling.

    Evidence Mass spectrometry acetylation site identification, mutagenesis, co-immunoprecipitation, subcellular fractionation and live imaging

    PMID:28819643

    Open questions at the time
    • Whether acetylation and phosphorylation feedbacks operate simultaneously or sequentially not determined
    • In vivo acetylation dynamics not measured
  12. 2018 Medium

    A homozygous frameshift loss-of-function mutation in CNKSR1 was identified as the cause of syndromic autosomal recessive intellectual disability, establishing a human disease role and confirming CNK function in neuronal development.

    Evidence Next-generation sequencing in patient family, RT-PCR/western blot in lymphoblastoid cells, RNAi in Drosophila brain

    PMID:30450701

    Open questions at the time
    • Single family reported; replication in additional kindreds needed
    • Precise neuronal pathway disrupted in patients not identified
    • Mouse knockout model not reported
  13. 2019 Medium

    The PH domain was shown to preferentially bind PtdIns(4,5)P2, mediating colocalization with mutant KRAS; a small-molecule inhibitor of the PH domain (PHT-7.3) selectively blocked mutant-KRAS-driven cell growth, establishing CNK1 as a druggable target.

    Evidence In vitro lipid binding assay, molecular modeling, pharmacological inhibition and cell growth assays

    PMID:31040156

    Open questions at the time
    • No in vivo efficacy data for PHT-7.3
    • Selectivity across PH domain-containing proteins not fully profiled
  14. 2021 High

    A RhoB-GTP-gated mechanism was uncovered in which CNKSR1 sequesters PTPRH phosphatase, keeping EGFR/HER2 phosphorylated; RhoB-GTP accumulation displaces PTPRH from CNKSR1, enabling EGFR dephosphorylation — revealing a non-MAPK scaffolding function.

    Evidence Protein array binding screen, co-immunoprecipitation, siRNA knockdown with EGFR phosphorylation readout

    PMID:34187934

    Open questions at the time
    • Whether this mechanism operates at physiological CNKSR1 expression levels not confirmed
    • Structural basis of RhoB-GTP displacing PTPRH from CNKSR1 unknown
  15. 2023 Medium

    MEK inhibitor treatment was found to induce CNKSR1 membrane translocation and stabilization of phospho-AKT, revealing CNKSR1 as a mediator of adaptive resistance to targeted MAPK pathway therapy in cancer.

    Evidence siRNA knockdown, co-immunoprecipitation, subcellular fractionation, in vivo xenograft models

    PMID:36790955

    Open questions at the time
    • Patient-level validation of CNKSR1 as resistance biomarker lacking
    • Mechanism triggering CNKSR1 membrane translocation upon MEK inhibition not defined
  16. 2024 High

    Cryo-EM structure of the KSR-MEK-CNK-HYP complex revealed a ring-like architecture in which CNK simultaneously contacts both KSR and MEK, resolving how the scaffold stabilizes the KSR-MEK binary interaction that drives RAF-KSR heterodimerization and RAF activation.

    Evidence Cryo-EM at near-atomic resolution with in vitro reconstitution and mutagenesis-based functional validation

    PMID:38388830

    Open questions at the time
    • Structure determined with Drosophila proteins; human complex structure not yet solved
    • How post-translational modifications remodel the ring complex is unknown
    • RAS-GTP-induced conformational changes within the assembled complex not captured

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the full-length structure of mammalian CNKSR1 in complex with its partners, how multiple post-translational modifications (phosphorylation, acetylation) are integrated temporally to direct pathway switching, and the precise neuronal mechanism underlying CNKSR1-linked intellectual disability.
  • No mammalian full-length CNKSR1 complex structure
  • Temporal coordination of acetylation and phosphorylation feedbacks unresolved
  • Conditional knockout mouse models not reported
  • Role of CNKSR1 in neuronal signaling circuits mechanistically undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 6 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 15 R-HSA-5357801 Programmed Cell Death 1
Partners
AKT1CYTH2KSR1PTPRHRAF1RHOARHOBSRC
Complex memberships
CNK1-cytohesin signaling complexKSR-MEK-CNK-HYP complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Drosophila CNK (connector enhancer of KSR) physically interacts with RAF through its C-terminal portion and is required for RAS signaling upstream of or in parallel to RAF; CNK contains multiple protein-protein interaction domains and localizes to cell-cell contact regions Genetic screen (modifier of ksr phenotype), co-immunoprecipitation, subcellular localization Cell High 9814705
1999 The N-terminal portion of CNK cooperates with RAS (specifically the RAS(V12G37) effector loop mutant that activates the RAL pathway), while the C-terminal portion regulates RAF in the MAPK pathway, suggesting CNK functions in more than one pathway downstream of RAS Transfection/overexpression in Drosophila eye, epistasis with RAS effector loop mutants Proceedings of the National Academy of Sciences of the United States of America High 10557308
2003 Drosophila CNK has bimodal (antagonistic) properties toward RAF: the N-terminal SAM and CRIC domains are essential for RAF activation, while a C-terminal bipartite RAF-inhibitory region (RIR) inhibits RAF catalytic function; together these prevent signaling leakage in the absence of signal but enable potent RAF activation upon stimulation Transfection experiments, RNAi-based rescue assay in Drosophila S2 cells, domain deletion/mutation analysis The EMBO journal High 14517245
2004 Human CNK1 (CNKSR1) interacts with RhoA in a GTP-dependent manner through its PH domain; CNK1 depletion by RNAi inhibits Rho-induced gene expression via serum response factor but not Rho-induced stress fiber formation; CNK1 also associates with Rhophilin and RalGDS, linking Rho and Ras pathways Yeast two-hybrid, co-immunoprecipitation, RNAi knockdown, reporter assays Molecular and cellular biology High 14749388
2004 CNK1 binds directly to RASSF1A (and RASSF1C) and this interaction mediates association of CNK1 with MST1/MST2 kinases; co-expression of CNK1 with RASSF1A greatly augments CNK1-induced apoptosis; CNK1-induced apoptosis is suppressed by dominant-negative MST1/MST2 Co-immunoprecipitation, yeast two-hybrid, overexpression/apoptosis assays, dominant-negative suppression The Journal of biological chemistry High 15075335
2005 CNK1 acts as a scaffold mediating Src-dependent tyrosine phosphorylation and activation of Raf-1; CNK1 binds pre-activated Raf-1 and activated Src, forming a trimeric complex; siRNA knockdown of endogenous CNK1 interferes with Src-dependent ERK activation Co-immunoprecipitation, siRNA knockdown, kinase activity assay The Journal of biological chemistry High 15845549
2005 CNK1 interacts with Net1 or p115RhoGEF (Rho-specific GEFs) and with MLK2 and MKK7 (JNK cascade kinases); CNK1 acts cooperatively with these GEFs to activate JNK MAP kinase but not other Rho-mediated pathways; endogenous CNK1 is required for serum/S1P-stimulated Rho-dependent JNK activation in HeLa cells Co-immunoprecipitation, siRNA knockdown, reporter assays, kinase activation assays Current biology : CB High 15753034
2005 In Drosophila, the Src42 tyrosine kinase associates in an RTK-dependent manner with a conserved region of CNK located C-terminal to the RAF-inhibitory region (RIR), and this association counteracts the repressive RIR effect on RAF; derepression by Src42 depends on its SH3/SH2 domains but not its catalytic activity; several cnk loss-of-function alleles have mutations that impair Src42 binding Genetic allele mapping, co-immunoprecipitation, dominant-negative/kinase-dead Src constructs The EMBO journal High 15660123
2005 CNK1 binds the angiotensin II type 2 (AT2) receptor through its SAM and CRIC domains; the interaction is strengthened by a Ras-regulated linker region; endogenous CNK1 and AT2 receptor co-precipitate from mouse heart extracts Co-immunoprecipitation, domain mapping, pulldown from tissue extracts Biochemical and biophysical research communications Medium 16289034
2006 A KSR/CNK complex mediated by a novel SAM domain-containing protein HYP (Hyphen) regulates RAS-dependent RAF activation in Drosophila; KSR induces RAF activation via its kinase-like domain independently of its scaffolding property or kinase activity; KSR is recruited to RAF prior to signal activation by CNK/HYP Genetic epistasis, co-immunoprecipitation, RNAi in Drosophila S2 cells, domain-function analysis Genes & development High 16600912
2008 Crystal structure of the SAM domain of CNK in complex with the SAM domain of HYP reveals a 1:1 heterodimer with single-junction interaction mode; mutational analysis shows this specific dimerization is essential for RAF signaling and facilitates recruitment of KSR to form the CNK/HYP/KSR regulatory complex X-ray crystallography, in vitro and in vivo mutational analysis, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 18287031
2010 The major binding partners of CNK1 scaffold are cytohesins (Arf GEFs); CNK1 interacts constitutively with the coiled-coil domain of cytohesins via its C-terminal region; CNK1/cytohesin interaction facilitates membrane recruitment of cytohesin-2 following insulin stimulation and promotes PI3K/AKT cascade activation by generating PIP2-rich microenvironment for IRS1 recruitment Mass spectrometry interactome, co-immunoprecipitation, protein depletion/rescue, membrane fractionation Genes & development High 20634316
2010 CNK1 interacts with AKT and knockdown of CNK1 decreases AKT activity in breast cancer cells; CNK1 controls AKT-dependent phosphorylation of FoxO, and CNK1-induced proliferation is blocked by FoxO overexpression; CNK1 promotes NF-κB2 p100 processing to p52 and nuclear localization, driving MMP-9/MT1-MMP expression and cell invasion Co-immunoprecipitation, siRNA knockdown, reporter assays, proliferation/invasion assays Oncogene / Molecular cancer research High 20197385 20383191
2014 GEF-H1 acts as an adaptor linking PP2A B' subunits to KSR-1, mediating dephosphorylation of KSR-1 S392 and activation of MAPK signaling; this constitutes a positive feedback loop for the RAS/MAPK pathway independent of GEF-H1's RhoGEF activity Co-immunoprecipitation, phosphorylation assays, siRNA knockdown, xenograft models Cancer cell High 24525234
2014 EphrinB1 interacts with CNK1 in an EphB receptor-independent manner; co-transfection of ephrinB1 with CNK1 increases JNK phosphorylation; CNK1 overexpression alone activates RhoA, but both ephrinB1 and CNK1 are required for JNK phosphorylation; CNK1 depletion abrogates ephrinB1-mediated cell migration and JNK activation; adhesion to fibronectin or Src activity increases ephrinB1/CNK1 binding Co-immunoprecipitation, siRNA knockdown, kinase activation assays, cell migration assays The Journal of biological chemistry High 24825906
2016 AKT phosphorylates CNKSR1/CNK1 at Ser22 within the SAM domain, triggering SAM domain-dependent oligomerization; oligomeric CNK1 increases affinity for active AKT (positive feedback); phosphorylation of Thr8 within the SAM domain by EGF signaling prevents AKT binding and antagonizes CNK1-mediated AKT signaling Phosphorylation site mapping (mass spectrometry), mutagenesis, co-immunoprecipitation, oligomerization assays Biochimica et biophysica acta. Molecular cell research High 27769899
2015 PDGF induces phosphorylation of CNK1 at Tyr26; Src induces phosphorylation at Tyr519 and Tyr665; phosphorylation of Tyr519 recruits CNK1 to the nucleus; additional Tyr26 phosphorylation enables SRE-dependent gene expression; phosphorylation-deficient mutants promote MMP14 promoter activity; PDGF-stimulated Src recruits CNK1 to plasma membrane Phosphorylation site mapping, phosphomimetic/deficient mutants, subcellular localization, reporter assays Biochimica et biophysica acta Medium 26319181
2017 ERK signaling induces acetylation of CNK1 at Lys414 (in the PH domain) by the acetyltransferase CBP; SIRT2 deacetylates CNK1; acetylation drives membrane localization of CNK1 in growth factor-stimulated cells and promotes interaction with CRAF, stimulating ERK-dependent cell proliferation and migration; constitutively acetylated or membrane-anchored CNK1 mutants constitutively activate this positive feedback Mass spectrometry (acetylation site ID), mutagenesis, co-immunoprecipitation, subcellular fractionation/live imaging, proliferation/migration assays Science advances High 28819643
2021 CNKSR1 serves as a scaffold that interacts with RhoB-GTP (identified via human protein arrays) and with PTPRH (protein tyrosine phosphatase receptor type H) at the plasma membrane; when RhoB is degraded by CUL3/KCTD10, CNKSR1 binds PTPRH and inactivates its EGFR phosphatase activity; accumulation of RhoB-GTP displaces PTPRH from CNKSR1, releasing active PTPRH to dephosphorylate/suppress EGFR and HER2 Protein array binding screen, co-immunoprecipitation, siRNA knockdown, membrane fractionation Life science alliance High 34187934
2019 The PH domain of CNK1 (CNKSR1) binds PtdIns(4,5)P2 with higher affinity than PtdIns(3,4,5)P3 and mediates plasma membrane colocalization with mutant KRAS; a small molecule (PHT-7.3) that binds selectively to the CNK1 PH domain prevents its plasma membrane colocalization with mutant KRAS and blocks mutant-KRAS but not wild-type KRAS cancer cell growth In vitro lipid binding assay, molecular modeling, cell imaging, pharmacological inhibition, cell growth assays Cancer research Medium 31040156
2023 MEK inhibition in CNKSR1-high cancer cells induces translocation of CNKSR1 to the plasma membrane where it interacts with and stabilizes phosphorylated AKT, activating PI3K/AKT signaling as an adaptive resistance mechanism; this is associated with reduced FoxO1 nuclear translocation siRNA knockdown, co-immunoprecipitation, subcellular fractionation, pharmacological inhibition, in vivo xenograft Molecular cancer research : MCR Medium 36790955
2024 Cryo-EM structure of the minimal Drosophila KSR-MEK-CNK-HYP complex reveals a ring-like arrangement; CNK simultaneously engages both KSR and MEK, stabilizing their binary interaction; CNK-HYP scaffolding complex promotes RAF activation by enhancing KSR-MEK interaction, which in turn drives RAF-KSR heterodimerization and RAF catalytic activation Cryo-EM structure determination, in vitro binding assays, mutagenesis, functional RAF activation assays Nature structural & molecular biology High 38388830
2018 CNKSR1 (human KSR1 ortholog context): CNKSR1 loss-of-function frameshift mutation causes syndromic autosomal recessive intellectual disability; RNAi knockdown of cnk (CNKSR1 ortholog) in Drosophila brain causes defects in eye and mushroom body structures Next-generation sequencing, RT-PCR/western blot (patient lymphoblastoid cells), RNAi in Drosophila American journal of medical genetics. Part B, Neuropsychiatric genetics Medium 30450701
2003 Human CNK2 (CNK2A and splice variant CNK2B) interacts with Raf through the Raf regulatory and kinase domains as well as the C-terminal half of CNK2; CNK2 also interacts with Ral GTPase and RalGDS family member Rlf via the GEF domain; CNK2 localizes to lateral plasma membrane in MDCK cells Co-immunoprecipitation, domain mapping, subcellular fractionation/imaging FASEB journal Medium 14597674
2016 Optogenetic clustering of CNK1 reveals that low-intensity light/low EGF drives CNK1-RAF interaction and ERK-dependent differentiation, while higher intensity/higher EGF drives active AKT binding to CNK1 which phosphorylates and inhibits RAF; CNK1 acts as a molecular switch controlling differentiation vs. proliferation decisions Optogenetic clustering (light-controlled oligomerization), co-immunoprecipitation, kinase activity assays, cell fate assays Scientific reports Medium 27901111
2004 Leukocyte-specific protein 1 (LSP1) associates with KSR, MEK1 and ERK2, and targets them to peripheral actin filaments; LSP1-associated MEK1 is activated by anti-IgM in a PKCβI-dependent manner; this places CNKSR1/KSR as part of a cytoskeletal signaling complex Co-immunoprecipitation, confocal microscopy, kinase activation assay Journal of cell science Medium 15090600

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 KSR, a novel protein kinase required for RAS signal transduction. Cell 331 8521512
1995 The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 259 8521513
1995 The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell 248 8521514
2002 Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Molecular and cellular biology 230 11940661
1996 KSR modulates signal propagation within the MAPK cascade. Genes & development 218 8946910
2011 A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK. Nature 210 21441910
2001 KSR: a MAPK scaffold of the Ras pathway? Journal of cell science 193 11309192
2002 KSR is a scaffold required for activation of the ERK/MAPK module. Genes & development 184 11850406
1999 Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. Molecular and cellular biology 174 9858547
1998 Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK. Current biology : CB 170 9427629
1997 The protein kinase KSR interacts with 14-3-3 protein and Raf. Current biology : CB 150 9115393
1998 CNK, a RAF-binding multidomain protein required for RAS signaling. Cell 148 9814705
1997 KSR stimulates Raf-1 activity in a kinase-independent manner. Proceedings of the National Academy of Sciences of the United States of America 143 9371754
2020 Structural basis for the action of the drug trametinib at KSR-bound MEK. Nature 135 32927473
1998 Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Current biology : CB 131 9427625
2007 KSR and CNK: two scaffolds regulating RAS-mediated RAF activation. Oncogene 118 17496912
2018 MEK drives BRAF activation through allosteric control of KSR proteins. Nature 109 29433126
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
1998 The kinase suppressor of Ras (KSR) modulates growth factor and Ras signaling by uncoupling Elk-1 phosphorylation from MAP kinase activation. The EMBO journal 87 9501093
2014 The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1. Cancer cell 84 24525234
2016 Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling. Nature 82 27556948
2004 The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death. The Journal of biological chemistry 80 15075335
2002 Solution structure and functional analysis of the cysteine-rich C1 domain of kinase suppressor of Ras (KSR). Journal of molecular biology 75 11786023
2004 Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways. Molecular and cellular biology 67 14749388
2005 Association of CNK1 with Rho guanine nucleotide exchange factors controls signaling specificity downstream of Rho. Current biology : CB 63 15753034
2010 The CNK1 scaffold binds cytohesins and promotes insulin pathway signaling. Genes & development 61 20634316
1999 Functional analysis of CNK in RAS signaling. Proceedings of the National Academy of Sciences of the United States of America 61 10557308
2003 Modulation of KSR activity in Caenorhabditis elegans by Zn ions, PAR-1 kinase and PP2A phosphatase. The EMBO journal 55 14685271
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
2006 A KSR/CNK complex mediated by HYP, a novel SAM domain-containing protein, regulates RAS-dependent RAF activation in Drosophila. Genes & development 48 16600912
1999 KSR-1 binds to G-protein betagamma subunits and inhibits beta gamma-induced mitogen-activated protein kinase activation. The Journal of biological chemistry 47 10075696
2005 CNK1 is a scaffold protein that regulates Src-mediated Raf-1 activation. The Journal of biological chemistry 46 15845549
2005 The rationale for deltanoids in therapy for myeloid leukemia: role of KSR-MAPK-C/EBP pathway. The Journal of steroid biochemistry and molecular biology 45 16046262
2016 Phosphorylation of Rap1 by cAMP-dependent Protein Kinase (PKA) Creates a Binding Site for KSR to Sustain ERK Activation by cAMP. The Journal of biological chemistry 43 28003362
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
2008 The Caenorhabditis elegans ekl (enhancer of ksr-1 lethality) genes include putative components of a germline small RNA pathway. Genetics 38 18245826
2004 Leukocyte-specific protein 1 targets the ERK/MAP kinase scaffold protein KSR and MEK1 and ERK2 to the actin cytoskeleton. Journal of cell science 36 15090600
2003 Bimodal regulation of RAF by CNK in Drosophila. The EMBO journal 36 14517245
2004 Kinase suppressor of RAS (KSR) amplifies the differentiation signal provided by low concentrations 1,25-dihydroxyvitamin D3. Journal of cellular physiology 33 14755538
2012 A CC-SAM, for coiled coil-sterile α motif, domain targets the scaffold KSR-1 to specific sites in the plasma membrane. Science signaling 32 23250398
2009 Proteomic characterization of the dynamic KSR-2 interactome, a signaling scaffold complex in MAPK pathway. Biochimica et biophysica acta 32 19563921
2017 KSR as a therapeutic target for Ras-dependent cancers. Expert opinion on therapeutic targets 29 28333549
2022 KSR induces RAS-independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors. Molecular oncology 27 35313064
2017 Membrane localization of acetylated CNK1 mediates a positive feedback on RAF/ERK signaling. Science advances 27 28819643
2010 CNK1 is a novel Akt interaction partner that promotes cell proliferation through the Akt-FoxO signalling axis. Oncogene 27 20383191
2006 Induction of kinase suppressor of RAS-1(KSR-1) gene by 1, alpha25-dihydroxyvitamin D3 in human leukemia HL60 cells through a vitamin D response element in the 5'-flanking region. Oncogene 26 16732322
2017 The use of KnockOut serum replacement (KSR) in three dimensional rat testicular cells co-culture model: An improved male reproductive toxicity testing system. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 25 28478099
2014 EphrinB1 interacts with CNK1 and promotes cell migration through c-Jun N-terminal kinase (JNK) activation. The Journal of biological chemistry 25 24825906
2010 CNK1 promotes invasion of cancer cells through NF-kappaB-dependent signaling. Molecular cancer research : MCR 25 20197385
2007 CNK/T-cell brain lymphoma associated with Epstein-Barr virus in a patient with AIDS. Neuropathology : official journal of the Japanese Society of Neuropathology 25 17899696
2005 Src42 binding activity regulates Drosophila RAF by a novel CNK-dependent derepression mechanism. The EMBO journal 25 15660123
1991 Effects of thyrotropin-releasing hormone and a related analog, CNK-602A, on long-term potentiation in the mossy fiber-CA3 pathway of guinea pig hippocampal slices. Brain research 25 1933301
2002 KSR--a regulator and scaffold protein of the MAPK pathway. Science's STKE : signal transduction knowledge environment 24 12060787
2019 An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors. Cancer research 23 31040156
2005 The scaffold protein CNK1 interacts with the angiotensin II type 2 receptor. Biochemical and biophysical research communications 22 16289034
2002 MAP kinase module: the Ksr connection. Current biology : CB 22 12007434
2011 Complexity in KSR function revealed by Raf inhibitor and KSR structure studies. Small GTPases 19 22292131
2005 Caenorhabditis elegans CNK-1 promotes Raf activation but is not essential for Ras/Raf signaling. Proceedings of the National Academy of Sciences of the United States of America 19 16085714
1983 Sibship with 17-ketosteroid reductase (17-KSR) deficiency and hypothyroidism. Lack of linkage of histocompatibility leucocyte antigen and 17-KSR loci. The Journal of clinical endocrinology and metabolism 19 6574136
2017 A tyrosinase, mTyr-CNK, that is functionally available as a monophenol monooxygenase. Scientific reports 16 29222480
2011 CNK1 and other scaffolds for Akt/FoxO signaling. Biochimica et biophysica acta 16 21320536
2006 KSR regulation of the Raf-MEK-ERK cascade. Methods in enzymology 15 16757327
2021 CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP. Life science alliance 14 34187934
2014 KSR-based medium improves the generation of high-quality mouse iPS cells. PloS one 14 25171101
1996 Long-term antiepileptic effects of chronic intake of CNK-602A, a thyrotropin-releasing hormone analogue, on spontaneously epileptic rats. Epilepsia 14 8603636
2017 Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization. EMBO reports 13 29263201
2012 Application of K/Sr co-doped calcium polyphosphate bioceramic as scaffolds for bone substitutes. Journal of materials science. Materials in medicine 13 22311075
2016 Optogenetic clustering of CNK1 reveals mechanistic insights in RAF and AKT signalling controlling cell fate decisions. Scientific reports 12 27901111
2017 Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer. BMC cancer 10 28732488
2017 The scaffolding protein Cnk binds to the receptor tyrosine kinase Alk to promote visceral founder cell specification in Drosophila. Science signaling 9 29066538
2011 Simulating EGFR-ERK signaling control by scaffold proteins KSR and MP1 reveals differential ligand-sensitivity co-regulated by Cbl-CIN85 and endophilin. PloS one 9 21829671
2008 Systemic analysis of TGFbeta proteomics revealed involvement of Plag1/CNK1/RASSF1A/Src network in TGFbeta1-dependent activation of Erk1/2 and cell proliferation. Proteomics 9 18821524
2005 Bioluminescence resonance energy transfer identify scaffold protein CNK1 interactions in intact cells. FEBS letters 8 15670823
2016 AKT-dependent phosphorylation of the SAM domain induces oligomerization and activation of the scaffold protein CNK1. Biochimica et biophysica acta. Molecular cell research 7 27769899
2015 Differential tyrosine phosphorylation controls the function of CNK1 as a molecular switch in signal transduction. Biochimica et biophysica acta 7 26319181
2002 Effects of prenyl pyrophosphates on the binding of S-Ras proteins with KSR. The Journal of experimental zoology 6 12410604
2018 CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 5 30450701
2014 Targeting cysteine rich C1 domain of Scaffold protein Kinase Suppressor of Ras (KSR) with anthocyanidins and flavonoids - a binding affinity characterization study. Bioinformation 5 25352726
2024 The CNK-HYP scaffolding complex promotes RAF activation by enhancing KSR-MEK interaction. Nature structural & molecular biology 4 38388830
2023 Live-cell target engagement of allosteric MEKi on MEK-RAF/KSR-14-3-3 complexes. Nature chemical biology 4 37919548
2021 Maintenance of mouse trophoblast stem cells in KSR-based medium allows conventional 3D culture. The Journal of reproduction and development 4 33746143
2024 LSP1 promotes the progression of acute myelogenous leukemia by regulating KSR/ERK signaling pathway and cell migration. Hematology (Amsterdam, Netherlands) 3 38511641
2010 A useful cell system for studying the regulation of 17HSD/KSR type 2 activity and expression in ovarian epithelial cancer. The Journal of steroid biochemistry and molecular biology 3 20600897
2023 Scaffolding Protein Connector Enhancer of Kinase Suppressor of Ras 1 (CNKSR1) Regulates MAPK Inhibition Responsiveness in Pancreas Cancer via Crosstalk with AKT Signaling. Molecular cancer research : MCR 2 36790955
2022 Conformational control and regulation of the pseudokinase KSR via small molecule binding interactions. Methods in enzymology 2 35525547
2008 Knockout serum replacement (KSR) has a suppressive effect on Sendai virus-mediated transduction of cynomolgus ES cells. Cloning and stem cells 2 18729764
2024 Identification of CNKSR1 as a biomarker for "cold" tumor microenvironment in lung adenocarcinoma: An integrative analysis based on a novel workflow. Heliyon 1 38628722
2024 G.3.2 is a novel allele of the gene connector enhancer of ksr ( cnk ) in Drosophila melanogaster. microPublication biology 1 39399787
2021 On the CN-K coordination modes in Kn[M6-n(CN)6]·xH2O: first evidence of CN-K electron-deficient bonding. Dalton transactions (Cambridge, England : 2003) 1 33514974
2025 Gene model for the ortholog of cnk in Drosophila erecta. bioRxiv : the preprint server for biology 0 40832204
2007 [Construction, expression and purification of kinase suppressor of Ras, KSR]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 21114928
2006 [Construction of eukaryotic expression vectors of carboxyl terminus and amino terminus of kinase suppressor of Ras (KSR) and their expression in 293T cell line]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 21144295