Affinage

KSR1

Kinase suppressor of Ras 1 · UniProt Q8IVT5

Length
923 aa
Mass
102.2 kDa
Annotated
2026-06-10
82 papers in source corpus 43 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KSR1 is a molecular scaffold of the Ras/MAPK cascade that assembles Raf, MEK, and ERK into functional signaling complexes and tunes the amplitude, duration, and subcellular location of ERK output (PMID:15121859, PMID:25002533). Originally defined genetically as a positive, Raf-related mediator of Ras signaling that acts downstream of or parallel to Ras and is required for maximal MPK-1/ERK diphosphorylation (PMID:8521513, PMID:8521514, PMID:11882296), KSR1 binds MEK constitutively (via an intact catalytic domain) and recruits activated ERK inducibly, an interaction functionally required for downstream cellular responses such as neurite outgrowth and post-DNA-damage cell-cycle re-entry (PMID:10891492, PMID:19147494). Its activity is set largely by regulated membrane translocation: in resting cells C-TAK1/MARK2 phosphorylation of Ser392 creates a 14-3-3γ binding site that anchors KSR1 in the cytoplasm, while PP2A — recruited through the adaptor GEF-H1 — dephosphorylates this site to release KSR1 to the plasma membrane where it colocalizes with Ras and Raf (PMID:11741534, PMID:18426801, PMID:24525234, PMID:22206009). Membrane targeting is mediated by the CC-SAM domain, which binds lipid directly, and KSR1 also engages caveolin-1 to redistribute MEK/ERK into caveolar fractions and Ca2+/calmodulin via its CA3 domain to promote translocation and ERK complex formation (PMID:23250398, PMID:25002533, PMID:33766558, PMID:38591710). Within the scaffold KSR1 nucleates additional Raf-activating machinery, recruiting CK2 to phosphorylate the Raf N-region and undergoing salt-bridge-dependent homo- and BRAF-heterodimerization that is essential for signaling (PMID:17174095, PMID:37316874). Beyond passive scaffolding KSR1 possesses intrinsic serine kinase activity independent of bound MEK and can directly phosphorylate MEK1 in vitro, an activity coupled to TNF-induced survival signaling (PMID:21144847, PMID:15084597). KSR1 abundance is controlled by praja2-mediated ubiquitination and proteasomal degradation and by caspase cleavage during apoptosis, which destroys scaffold function and yields a dominant-negative C-terminal fragment (PMID:27195677, PMID:17613518). Through these mechanisms KSR1 governs diverse outputs including adipogenesis, oncogenic Ras-driven transformation and senescence, and metabolic/translational programs (PGC1α/ERRα, Myc and EPSTI1 translation) that operate partly independent of ERK (PMID:15121859, PMID:21518958, PMID:16107706, PMID:33970103, PMID:29259016), and it has been identified as a scaffold of the Hippo pathway binding YAP, MST1, and LATS1 (PMID:41326667). KSR1-RAF scaffolding complexes also drive adaptive resistance to RAF and MEK inhibitors (PMID:36493900, PMID:41654519).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1995 High

    Established the existence and genetic placement of KSR as a positive Ras-pathway component, defining the central question of how a Raf-related kinase promotes Ras signaling.

    Evidence Genetic suppressor screen and epistasis analysis in C. elegans vulval development

    PMID:8521513 PMID:8521514

    Open questions at the time
    • Did not establish biochemical mechanism or direct partners
    • Whether kinase activity is required left open
  2. 2002 High

    Showed KSR is required for the Raf/MEK/ERK cascade itself, linking the genetic phenotype to a direct biochemical readout of ERK activation.

    Evidence ksr-2;ksr-1 double-mutant analysis with dpERK western blot in C. elegans

    PMID:11882296

    Open questions at the time
    • Redundancy complicates assigning specific molecular role
    • Does not distinguish scaffolding from catalytic contribution
  3. 2000 High

    Demonstrated that KSR1 physically binds MEK through its catalytic domain and that this binding is functionally essential, establishing the scaffolding model in mammalian cells.

    Evidence Co-IP, mutagenesis, and NGF-induced neurite outgrowth in PC12 cells

    PMID:10891492

    Open questions at the time
    • ERK binding mode not resolved
    • Did not address membrane translocation triggers
  4. 2001 High

    Defined the phosphoswitch controlling KSR1 localization: C-TAK1 phosphorylation of Ser392 imposes 14-3-3-dependent cytoplasmic retention relieved upon stimulation, answering how membrane recruitment is gated.

    Evidence Co-IP, phospho-mapping, subcellular imaging, mutagenesis in mammalian cells

    PMID:11741534

    Open questions at the time
    • Phosphatase reversing Ser392 not yet identified
    • In vivo physiological context of the switch unaddressed
  5. 2003 High

    Identified PP2A as the constitutive KSR1-associated phosphatase that dephosphorylates the 14-3-3 site to enable membrane recruitment, completing the recruitment cycle.

    Evidence Mass spectrometry of KSR1 complex, Co-IP, PP2A inhibition, phospho-analysis

    PMID:12932319

    Open questions at the time
    • How growth factor induces PR55B subunit binding not defined
    • Adaptor linking PP2A to KSR1 not yet known
  6. 2004 High

    Quantified KSR1 as a concentration-dependent rheostat, showing optimal expression maximizes Raf/MEK/ERK association and that both deletion and overexpression impair signaling and transformation.

    Evidence KSR1-/- MEF reconstitution with titrated expression, ERK assays, soft agar; plus Ser392/Thr274 mutagenesis kinetics and stability

    PMID:15121859 PMID:15371409

    Open questions at the time
    • Structural basis of optimal stoichiometry unresolved
    • Phosphodegron coupling to stability incompletely mapped
  7. 2004 High

    Resolved a long-standing controversy by demonstrating KSR1 possesses intrinsic kinase activity independent of bound MEK1.

    Evidence Two-stage in vitro reconstitution kinase assay with high-salt MEK depletion and kinase-inactive mutant

    PMID:15084597

    Open questions at the time
    • Physiological substrate not identified in this study
    • Catalytic significance in vivo unclear
  8. 2006 High

    Identified CK2 within the KSR1 scaffold as a Raf N-region kinase, explaining how KSR1 promotes Raf activation rather than only colocalization.

    Evidence MS of KSR1 complex, Co-IP, domain mapping, kinase assays

    PMID:17174095

    Open questions at the time
    • How CK2 docking is regulated by stimulation unknown
    • Structural arrangement of CK2-KSR1-Raf not defined
  9. 2008 High

    Defined 14-3-3γ isoform specificity and the E3 ligase IMP as opposing brakes on scaffold assembly, refining how KSR1 oligomerization and inactivity are enforced.

    Evidence In vitro/in vivo binding, RNAi, Xenopus oocyte assays (14-3-3γ); Co-IP and ubiquitin assays (IMP)

    PMID:18332145 PMID:18426801

    Open questions at the time
    • IMP study Medium-confidence single lab
    • How Ras-GTP triggers IMP autoubiquitination mechanistically incomplete
  10. 2010 High

    Demonstrated KSR1 directly phosphorylates kinase-inactive MEK1 and that this catalytic function contributes to TNF-induced survival, establishing MEK1 as a KSR1 substrate.

    Evidence Recombinant kinase assay, D683A/D700A mutant, cell survival assay

    PMID:21144847

    Open questions at the time
    • In vivo significance of KSR1 catalysis versus scaffolding unresolved
    • Stoichiometry relative to Raf-driven MEK phosphorylation unknown
  11. 2012 High

    Mapped the structural determinant of membrane targeting (CC-SAM helix α3) and a parallel ER-tethering mechanism via VRK2A, defining how KSR1 is compartmentalized.

    Evidence NMR, lipid-binding, mutagenesis, imaging (CC-SAM); Co-IP, fractionation, SEC (VRK2A)

    PMID:22752157 PMID:23250398

    Open questions at the time
    • VRK2A study Medium-confidence single lab
    • Switch between ER retention and PM targeting not integrated
  12. 2013 High

    Identified GEF-H1 as the adaptor coupling PP2A to KSR1 in oncogenic RAS, and defined external inhibitory inputs (AMPK-BRAF, MARK2) regulating scaffold engagement and physiology.

    Evidence Co-IP, phospho-assays, siRNA in KRAS cells (GEF-H1); in vitro kinase and double-KO mouse (MARK2); kinase assay and Co-IP (AMPK-BRAF)

    PMID:22206009 PMID:24095280 PMID:24525234

    Open questions at the time
    • MARK2 study Medium-confidence
    • Tissue-specific integration of opposing inputs incomplete
  13. 2011 Medium

    Established ERK-mediated feedback phosphorylation of KSR1 as a mechanism limiting signal duration and controlling synaptic localization and plasticity.

    Evidence Western blot, imaging, electrophysiology, MEK inhibitor in hippocampal neurons

    PMID:21471251

    Open questions at the time
    • Single lab
    • Feedback phosphosites not exhaustively mapped
  14. 2011 Medium

    Linked KSR1 to membrane microdomain organization (caveolin-1) and to cellular processes beyond proliferation—immune synapse ERK recruitment and Ras-induced senescence.

    Evidence Co-IP, fractionation, KSR1-/- MEF reconstitution (caveolin-1); KSR1-/- cells, imaging, NK cytotoxicity (immune synapse)

    PMID:19139278 PMID:25002533

    Open questions at the time
    • Immune-synapse study Medium-confidence single lab
    • How caveolin recruitment couples to senescence not mechanistically closed
  15. 2016 High

    Defined praja2 as the physiological E3 ligase degrading KSR1 to terminate ERK signaling, and an ELK4-KDM5A axis controlling praja2 levels and thus KSR1 stability.

    Evidence Co-IP, ubiquitination/proteasome assays, in vivo tumor (praja2); ChIP, luciferase, CHX chase (ELK4-KDM5A)

    PMID:27195677 PMID:34372882

    Open questions at the time
    • ELK4-KDM5A arm Medium-confidence single lab
    • Signal triggering growth-factor-induced KSR1 ubiquitination not fully defined
  16. 2016 Medium

    Extended KSR1 to ERK-independent and translational outputs—PGC1α/ERRα metabolism, Myc translation, and later EPSTI1-driven EMT—broadening its role beyond canonical MAPK scaffolding.

    Evidence KSR1-/- reconstitution and rescue, metabolic and soft-agar assays (PGC1α); polysome/translation analysis (Myc); CRISPR KO and rescue, invasion assays (EPSTI1)

    PMID:21518958 PMID:27273865 PMID:33970103

    Open questions at the time
    • Mechanism coupling scaffold to translational control unresolved
    • All single-lab studies
  17. 2017 Medium

    Showed oncogenic RAS/BRAF drives perinuclear/endosomal relocalization of KSR1-CK2-pERK complexes that serve as a platform for C/EBPβ activation during senescence, adding a spatial dimension to scaffold function.

    Evidence Confocal imaging, KSR1-/- MEFs, inhibitors, Rab11 colocalization, C/EBPβ phospho-assay

    PMID:29259016

    Open questions at the time
    • Single lab
    • Trigger for endosomal redistribution not fully defined
  18. 2018 Medium

    Identified additional scaffold antagonists (Erbin, Merlin/NF2) that displace KSR1 from or restrict its Raf binding, integrating tumor-suppressor control of signal amplitude.

    Evidence Co-IP/displacement assays, knockdown/overexpression, 3D culture and tumor models (Erbin); Co-IP, proteomics in schwannoma (Merlin)

    PMID:26549023 PMID:29980571

    Open questions at the time
    • Both Medium-confidence single-lab
    • Structural basis of displacement unresolved
  19. 2022 Medium

    Resolved the dimerization basis of scaffold function—salt-bridge-dependent KSR1 homo- and KSR1/BRAF heterodimers essential for signaling—and a structural rationale for why KSR1 is a weak MEK kinase relative to BRAF.

    Evidence Split Nanoluc PPI assay with interface mutants in living cells (dimerization); molecular dynamics simulation (catalytic comparison)

    PMID:35508574 PMID:37316874

    Open questions at the time
    • MD study is computational with no experimental validation
    • Dimer stoichiometry in vivo not directly measured
  20. 2024 High

    Provided structural detail of Ca2+/calmodulin binding to the KSR1 CA3 domain and demonstrated functionally that this engagement promotes EGF-induced ERK activation.

    Evidence NMR, modeling, Phe355Asp mutagenesis, binding and ERK activation assays (building on 2021 calmodulin binding)

    PMID:33766558 PMID:38591710

    Open questions at the time
    • How Ca2+ signals are physiologically integrated with growth-factor cues unclear
    • Downstream effect on Raf recruitment not detailed
  21. 2025 Medium

    Discovered KSR1 functions as a Hippo-pathway scaffold binding YAP, MST1, and LATS1, expanding its role to a second major signaling network.

    Evidence Co-IP, knockdown/overexpression, YAP reporter assay, RhoA pathway analysis

    PMID:41326667

    Open questions at the time
    • Single lab single paper
    • Whether Hippo scaffolding is separable from MAPK scaffolding unknown
  22. 2025 Medium

    Defined KSR1 as a driver of therapeutic resistance and immune modulation: RAS-mediated ARAF-KSR1 and SHP2-released KSR1 complexes sustain MAPK under RAF/MEK inhibition, and soluble uric acid binds KSR1 to drive CD8+ T-cell exhaustion.

    Evidence Co-IP, drug-resistance and combination assays, knockdowns, xenografts (ARAF/SHP2); direct UA-KSR1 binding, knockdown, Tim-3 KO, tumor models (uric acid)

    PMID:36493900 PMID:41654519 PMID:42118604

    Open questions at the time
    • All Medium-confidence single-lab studies
    • Direct small-molecule binding site on KSR1 for uric acid not structurally mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KSR1's intrinsic catalytic activity, its scaffolding of canonical MAPK, and its newer roles in the Hippo pathway and translational/metabolic control are integrated within a single protein remains unresolved.
  • No unified structural model of full-length KSR1 in complex with Raf/MEK/ERK
  • Relative in vivo weight of catalysis versus scaffolding unquantified
  • Mechanism coupling KSR1 to translational control of Myc/EPSTI1 undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1640170 Cell Cycle 1 R-HSA-5357801 Programmed Cell Death 1
Partners
14-3-3GAMMABRAFCALMODULINCAVEOLIN-1CK2MEK1PP2AYAP
Complex memberships
KSR1-CK2 complexKSR1-Raf-MEK-ERK scaffold complexKSR1-YAP-MST1-LATS1 Hippo complexVRK2A-KSR1-MEK1 ER complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 C. elegans ksr-1 encodes a novel putative Raf-related Ser/Thr kinase that positively mediates Ras signaling; genetic epistasis analysis placed ksr-1 downstream of or in parallel to let-60 ras, required for maximal stimulation of vulval fates by the Ras pathway. Genetic suppressor screen, epistasis analysis, gene cloning Cell High 8521513 8521514
2001 C-TAK1 kinase constitutively associates with mammalian KSR1 and phosphorylates Ser392, conferring 14-3-3 binding and cytoplasmic sequestration in unstimulated cells; upon signal activation, Ser392 phosphorylation is reduced, allowing the KSR1 complex to translocate to the plasma membrane where it colocalizes with activated Ras and Raf-1 to facilitate MEK and MAPK activation. Co-immunoprecipitation, phosphorylation mapping, subcellular fractionation/imaging, mutagenesis Molecular cell High 11741534
2003 Protein phosphatase PP2A constitutively associates (core subunits PR65A and catalytic C) with the N-terminal domain of KSR1; upon growth factor treatment, regulatory subunit PR55B binding is induced. PP2A dephosphorylates the critical 14-3-3 binding site on KSR1 (and Raf-1), enabling membrane recruitment of KSR1 and activation of KSR1-associated MEK and ERK. Mass spectrometry of KSR1 complex, co-immunoprecipitation, pharmacological PP2A inhibition, phosphorylation analysis Current biology : CB High 12932319
2002 In C. elegans, ksr-1 and ksr-2 act redundantly; ksr-2;ksr-1 double mutants show severely reduced or absent diphosphorylated MPK-1 ERK, strongly supporting a model where KSR acts to promote activation or maintenance of the Raf/MEK/ERK kinase cascade. Double-mutant genetic analysis, ERK phosphorylation western blot Current biology : CB High 11882296
2006 Casein kinase 2 (CK2) holoenzyme constitutively binds the basic surface region of the KSR1 atypical C1 domain; this KSR1/CK2 interaction is required for maximal growth-factor-induced phosphorylation of C-Raf and B-Raf on the activating N-region serine, and for downstream MEK and ERK activation, identifying CK2 as a Raf N-region kinase within the KSR1 scaffold complex. Mass spectrometry of KSR1 complex, co-immunoprecipitation, domain-mapping mutagenesis, kinase activity assays Current biology : CB High 17174095
2000 B-KSR1, a brain-specific KSR1 splice variant, constitutively associates with MEK (requiring an intact kinase domain for MEK binding) and inducibly associates with activated MAPK; all loss-of-function mutations in the catalytic domain that abolish MEK binding also abolish the ability to augment NGF-induced neurite outgrowth, demonstrating that MEK binding is functionally essential. Co-immunoprecipitation, mutagenesis, PC12 cell differentiation assay, MEK inhibitor treatment Molecular and cellular biology High 10891492
1999 KSR1 binds directly to G-protein βγ subunits via its CA3 domain (containing the cysteine-rich zinc finger-like domain); LPA-induced KSR1 translocation to the plasma membrane is blocked by pertussis toxin but not dominant-negative Ras; overexpression of KSR1 inhibits βγ-induced MAPK activation. Yeast two-hybrid screen, co-immunoprecipitation, deletion analysis, pertussis toxin treatment, MAPK activation assay The Journal of biological chemistry Medium 10075696
2004 Phosphorylation of KSR1 at Ser392 and Thr274 regulates subcellular localization, protein stability, and duration of ERK activation. A KSR1 double mutant (T274V/S392A) promotes sustained ERK activation and accelerated cell-cycle progression in response to both PDGF and EGF, and is more stable than wild-type KSR1. Site-directed mutagenesis, cell proliferation assays, ERK phosphorylation kinetics, KSR1-/- MEF reconstitution The Journal of biological chemistry High 15371409
2004 KSR1 concentration-dependently regulates ERK activation intensity and duration: deletion of KSR1 eliminates prolonged ERK activation; low re-expression rescues signaling and transformation, while supraphysiologic expression inhibits these responses. Maximal association with all Raf/MEK/ERK cascade members occurs at the optimal KSR1 expression level. KSR1-/- MEF reconstitution with titrated expression, ERK activation assays, soft agar transformation assay Molecular and cellular biology High 15121859
2008 14-3-3γ specifically binds KSR1 in an isoform-specific manner via its C-terminal stretch; this interaction protects KSR1 from EGF-induced dephosphorylation, impairs KSR1-mediated ERK2 activation and Ras signaling in Xenopus oocytes, and serves as the cytosolic anchor keeping KSR1 inactive. RNA interference of 14-3-3γ causes accumulation of KSR1 at the plasma membrane. In vitro binding assay, co-immunoprecipitation, Xenopus oocyte ERK activation assay, RNAi, confocal microscopy The Journal of biological chemistry High 18426801
2008 IMP (E3 ubiquitin ligase) limits KSR1-dependent assembly of multivalent Raf·MEK complexes by disrupting KSR1 homo-oligomerization and B-Raf/c-Raf hetero-oligomerization, thereby impairing MEK recruitment to activated Raf and c-Raf kinase activation. Ras-GTP-induced IMP autoubiquitination relieves this constraint. Co-immunoprecipitation, ubiquitin ligase assay, RNAi, protein complex analysis The Journal of biological chemistry Medium 18332145
2010 Recombinant wild-type KSR1 (but not kinase-inactive D683A/D700A KSR1) undergoes serine autophosphorylation, phosphorylates MBP, and directly phosphorylates kinase-inactive MEK1 in vitro. KSR1-mediated TNF-induced cell survival requires both KSR1 kinase activity and MEK kinase activity, establishing KSR1 as a functional protein kinase with MEK1 as a substrate. Recombinant protein production in E. coli, in vitro kinase assay, site-directed mutagenesis (D683A/D700A), cell survival assay Experimental cell research High 21144847
2004 KSR1 kinase activity is an intrinsic property independent of associated MEK1: high-salt washing depleting 90% of KSR1-bound MEK1, or pre-treatment with MEK inhibitor PD98059 inactivating bound MEK1, did not alter KSR1 kinase activity in a two-stage in vitro reconstitution assay. A kinase-inactive KSR1 (D683A/D700A) that retains MEK1 binding lacks kinase activity. In vitro two-stage reconstitution kinase assay, high-salt MEK depletion, MEK inhibitor treatment, kinase-inactive mutagenesis The Journal of biological chemistry High 15084597
2011 RAF inhibitors induce KSR1 binding to wild-type and oncogenic B-RAF (including V600E) but not C-RAF; this requires direct drug binding to B-RAF and conserved dimer interface residues in both proteins but is independent of RAS binding. KSR1 competes with C-RAF for inhibitor-induced B-RAF binding and thereby alters ERK cascade signaling. Co-immunoprecipitation in multiple cell lines, dimer interface mutagenesis, RAF inhibitor treatment panel Current biology : CB High 21458265
2012 VRK2A retains a fraction of KSR1 complexes on the endoplasmic reticulum surface by direct interaction between their C-terminal regions; MEK1 is incorporated into the basal VRK2A-KSR1 complex independently via the KSR1 CA5 region and VRK2A N-terminus. VRK2A overexpression increases KSR1 in the particulate fraction and prevents ERK1/2 incorporation after EGF stimulation, compartmentalizing MAPK signaling. Co-immunoprecipitation, subcellular fractionation, size-exclusion chromatography, VRK2A knockdown Cellular and molecular life sciences : CMLS Medium 22752157
2012 The KSR1 CC-SAM domain (composed of a coiled coil and sterile α motif) targets KSR1 to specific signaling sites at the plasma membrane; membrane binding is mediated by helix α3 of the CC motif and mutations in α3 abolish plasma membrane targeting. The CC-SAM domain binds directly to micelles and bicelles in vitro. NMR spectroscopy, cell imaging, mutagenesis, in vitro lipid-binding assay Science signaling High 23250398
2011 ERK1/2 directly phosphorylates KSR1 as a feedback mechanism; expression of feedback-deficient KSR1 promotes sustained ERK1/2 activation. In hippocampal neurons, feedback phosphorylation of KSR1 by ERK reduces KSR1 localization to dendritic spines (reversible by tetrodotoxin or PD184352), and restricts potentiation of excitatory postsynaptic currents. Western blot, immunocytochemistry, confocal imaging, electrophysiology, MEK inhibitor treatment FASEB journal Medium 21471251
2013 GEF-H1 acts as an adaptor protein linking PP2A B' subunits to KSR-1, thereby mediating dephosphorylation of KSR-1 Ser392 and activation of MAPK signaling in a positive feedback loop for oncogenic RAS. This function is independent of GEF-H1's RhoGEF activity. Co-immunoprecipitation, phosphorylation assay, siRNA knockdown, KRAS-transformed cell assays Cancer cell High 24525234
2013 AMPK phosphorylates BRAF at Ser729, which promotes BRAF association with 14-3-3 proteins and disrupts BRAF interaction with the KSR1 scaffolding protein, leading to attenuation of MEK-ERK signaling and impaired cell proliferation. In vitro kinase assay, co-immunoprecipitation, mutagenesis, cell proliferation assay Molecular cell High 24095280
2016 Praja2 (PJA2) is the E3 ubiquitin ligase that ubiquitylates KSR1, leading to proteasomal degradation; growth factor/hormone stimulation induces KSR1 polyubiquitination coincident with decline in ERK1/2 signaling. Praja2-dependent KSR1 degradation modulates ERK activity in cancer cells and maintains pluripotency in embryonic stem cells. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, knockdown/overexpression, in vivo tumor assay Cell death & disease High 27195677
2016 ELK4 transcriptionally activates KDM5A, which removes H3K4me3 from the PJA2 promoter to suppress PJA2 expression; reduced PJA2 decreases ubiquitination and degradation of KSR1, thereby increasing KSR1 protein stability and promoting MAPK signaling and tumor progression. Dual luciferase reporter, ChIP assay, Co-IP, cycloheximide chase (protein stability), gain/loss-of-function assays Journal of translational medicine Medium 34372882
2011 KSR1 knockout in MEFs abrogates KSR1-mediated redistribution of MEK and ERK to caveolin-1-rich fractions; KSR1 physically interacts with caveolin-1, and this interaction is essential for optimal growth-factor-induced early-phase ERK activation, H-RasV12-induced senescence, and transformation. Co-immunoprecipitation, subcellular fractionation, KSR1-/- MEF reconstitution, transformation assay, mutagenesis Molecular and cellular biology High 25002533
2009 KSR1 is required for cell cycle reinitiation following DNA interstrand cross-link-induced G2/M arrest; a KSR1 mutant unable to bind ERK fails to rescue cell cycle re-entry, but constitutively active ERK alone is insufficient, demonstrating a specific requirement for the KSR1-ERK physical interaction in post-damage cell cycle recovery. KSR1-/- MEF reconstitution, cell cycle analysis, ERK binding mutant, gamma-H2AX foci assay The Journal of biological chemistry Medium 19147494
2007 KSR1 undergoes caspase-dependent cleavage in apoptotic cells; cleavage destroys the scaffolding function of full-length KSR1 and generates a stable C-terminal fragment that inhibits ERK activation. A cleavage-resistant KSR1 maintains higher phosphoERK levels and reduces apoptotic signaling in response to TNFα/cycloheximide, whereas constitutive expression of the C-terminal fragment enhances apoptosis. Caspase cleavage assays, site-directed mutagenesis (cleavage-resistant mutant), ERK phosphorylation assay, cell death assay, in vivo mammary involution model The Journal of biological chemistry High 17613518
2011 KSR1 is required for efficient NK cell-mediated cytolysis and granule polarization; KSR1 is recruited to the immunological synapse during T-cell activation, and membrane recruitment of KSR1 is required for recruitment of active ERK to the synapse. KSR1-/- mouse cells, single-cell ERK activation analysis, confocal imaging, NK cytotoxicity assay Molecular and cellular biology Medium 19139278
2011 KSR1 regulates PGC1α and ERRα expression to support oncogenic Ras-dependent anchorage-independent growth and metabolic capacity; this pathway is independent of ERK. Ectopic PGC1α rescues ERRα expression and anchorage-independent growth in KSR1-null RasV12 MEFs; PGC1α requires ERRα interaction for this rescue. KSR1-/- MEF reconstitution, ectopic expression rescue, ERRα inhibitor, metabolic assays, soft agar assay Molecular and cellular biology Medium 21518958
2005 KSR1 expression level titrates ERK and RSK activation to control adipogenic potential: KSR1 deletion prevents adipogenesis; low KSR1 rescues it by coordinating ERK and RSK activation with C/EBPβ synthesis and phosphorylation at the required moment; elevated KSR1 causes high sustained ERK that phosphorylates and inhibits PPARγ, blocking adipogenesis. KSR1-/- adipogenesis assay, KSR1 titration reconstitution, ERK/RSK activation kinetics, PPARγ phosphorylation assay Molecular and cellular biology High 16107706
2021 KSR1 and ERK promote EMT-like phenotype through preferential translation of EPSTI1 mRNA; EPSTI1 is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. Ectopic EPSTI1 in KSR1-null CRC cells restores N-cadherin, ZEB1/Slug expression, migration, invasion, and anchorage-independent growth. KSR1 CRISPR knockout, ectopic expression rescue, migration/invasion assay, cadherin switching analysis eLife Medium 33970103
2021 Calmodulin binds directly to KSR1 in a Ca2+-dependent manner (both in vitro with purified proteins and from mammalian cell lysates); calmodulin antagonist CGS9343B impairs EGF-induced ERK activation in KSR1-overexpressing MEFs, blocks EGF-induced KSR1 membrane translocation, and impairs formation of KSR1-ERK and KSR1-pERK complexes. In vitro binding with purified proteins, co-immunoprecipitation, confocal microscopy, calmodulin antagonist treatment The Journal of biological chemistry High 33766558
2024 Ca2+/calmodulin binds to the CA3 domain of KSR1 in a collapsed mode engaging the α-helical KSR1-CA3 via hydrophobic interactions; mutation of KSR1-Phe355 to Asp reduces Ca2+/CaM binding by 76% and significantly impairs EGF-induced ERK activation, establishing that Ca2+/CaM binding to KSR1 promotes MAPK signaling. NMR spectroscopy, in silico molecular modeling, site-directed mutagenesis, in vitro binding assay, ERK activation assay Protein science High 38591710
2016 KSR1 promotes translation of Myc protein by a posttranscriptional mechanism in colon tumor cells; KSR1 and EPHB4 jointly support tumor survival through Myc and PGC1β expression, with KSR1 acting primarily at the translational level. KSR1 knockdown/overexpression, polysome profiling/translation analysis, western blotting, colony assay Molecular and cellular biology Medium 27273865
2017 Oncogenic RAS and BRAF induce perinuclear relocalization of KSR1, CK2, and p-ERK1/2 to recycling endosomes and distinct endosomal populations; this spatial reorganization requires endocytosis, MEK-ERK and CK2 kinase activities, and the presence of KSR1. Perinuclear signaling complexes provide an essential platform for C/EBPβ phosphorylation and activation during RAS-induced senescence. Immunofluorescence/confocal imaging, KSR1 knockout MEFs, pharmacological inhibitors, Rab11 co-localization, C/EBPβ phosphorylation assay Cancer research Medium 29259016
2011 MARK2 binds and phosphorylates KSR1 on Ser392 in peripheral tissues; disruption of KSR1 in mark2-/- mice reverses the increased insulin sensitivity caused by MARK2 deletion, suggesting MARK2 negatively regulates insulin sensitivity through inhibitory phosphorylation of KSR1. Co-immunoprecipitation, in vitro kinase assay, double-knockout mouse model, glucose/insulin tolerance tests PloS one Medium 22206009
2018 Erbin interacts with KSR1 and displaces it from the RAF/MEK/ERK complex to prevent signal propagation; Erbin loss increases amplitude and duration of RAS/RAF signaling and promotes EMT. Co-immunoprecipitation, Erbin knockdown/overexpression, ERK pathway activation assays, 3D culture, mouse tumor model Cancer research Medium 29980571
2016 KSR1 is a novel binding partner of Merlin (NF2 tumor suppressor); Merlin suppresses KSR1 function by inhibiting the binding between KSR1 and c-Raf, as demonstrated by immunoprecipitation. Proteomic analysis further identifies E3 ubiquitin ligase CRL4(DCAF1) as a KSR1-interacting protein. Co-immunoprecipitation, proteomics, functional knockdown assays in schwannoma cells Oncogene Medium 26549023
2013 KSR1 overexpression decreases DBC1 phosphorylation, which reduces DBC1-SIRT1 interaction, enabling SIRT1 to deacetylate p53, thereby reducing p53 transcriptional activity. This positions KSR1 in a DBC1-SIRT1-p53 regulatory network in breast cancer cells. SILAC quantitative mass spectrometry, co-immunoprecipitation, luciferase reporter assay, western blotting British journal of cancer Medium 24129246
2022 Molecular dynamics simulations reveal that B-Raf's αG-helix Arg662 (vs. KSR1's Ala826 at equivalent position) is key: B-Raf Arg662 orients MEK1 Ser218 toward ATP for phosphorylation through interactions with the MEK1 activation loop, while KSR1 Ala826 results in fewer interactions with MEK1 A-loop, yielding a more flexible A-loop. The KSR1 P-rich loop of MEK1 plays a decisive role in MEK1 A-loop accessibility. Molecular dynamics simulation Cellular and molecular life sciences : CMLS Low 35508574
2022 SHP2 physically interacts with KSR1 through its protein tyrosine phosphatase domain; during adaptive resistance to MEK inhibitors, activated SHP2 impairs this interaction with KSR1, releasing KSR1 to activate KSR1 and promote MAPK signaling. A KSR1 activating mutation (S269A) reduces the synergistic anti-proliferative effect of SHP2 and MEK inhibitor co-treatment. Co-immunoprecipitation (domain mapping), KSR1 knockdown, KSR1 S269A activating mutation, cell viability/proliferation assay, xenograft model Cancer letters Medium 36493900
2023 KRASG12V promotes homo- and heterodimerization of BRAF via its RAS-binding domain; substantial KSR1 homo- and KSR1/BRAF heterodimerization occurs even without activated RAS and requires a salt bridge between the CC-SAM domain of KSR1 and the BRAF-specific region. The dimer interface is less critical for dimerization per se but essential for downstream signaling. Split Nanoluc luciferase complementation assay in living cells, loss-of-function dimerization interface mutants, RAF inhibitor treatment Cell communication and signaling : CCS Medium 37316874
2025 KSR1 constitutively binds to YAP and MST1 and forms a complex with LATS1, functioning as a previously unrecognized scaffold of the Hippo pathway; KSR1 modulates YAP protein levels and transcriptional activity at least in part through the RhoA/actin axis. Co-immunoprecipitation, KSR1 knockdown/overexpression, YAP activity reporter assay, RhoA pathway analysis Communications biology Medium 41326667
2025 Resistance to pan-RAF inhibitor exarafenib involves formation of RAS-mediated ARAF-KSR1 scaffolding complexes that maintain MAPK signaling despite drug treatment; this bypass is driven by RTK activation and RAS-GTP accumulation that specifically promotes ARAF-KSR1 complex assembly under drug pressure. Co-immunoprecipitation, drug resistance assays, ARAF/KSR1 knockdown, MEK inhibitor combination studies Nature communications Medium 41654519
2026 Soluble uric acid (UA) directly binds the KSR1 scaffold and hyperactivates MEK-ERK signaling, leading to chronic MAPK stimulation that upregulates inhibitory receptors (PD-1, Tim-3) on CD8+ T cells and promotes their exhaustion. Genetic disruption of the UA-KSR1-MAPK axis via Ksr1 knockdown restored T-cell effector activity. Direct binding assay (UA-KSR1), MEK-ERK phosphorylation analysis, Ksr1 knockdown, Tim-3 KO mouse model, in vivo tumor model Cancer research Medium 42118604

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 260 8521513
2003 Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Current biology : CB 255 12932319
1995 The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell 248 8521514
2001 C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Molecular cell 242 11741534
2004 The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells. Molecular and cellular biology 127 15121859
2013 Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Molecular cell 116 24095280
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 91 11882296
2014 The RhoGEF GEF-H1 is required for oncogenic RAS signaling via KSR-1. Cancer cell 85 24525234
2006 CK2 Is a component of the KSR1 scaffold complex that contributes to Raf kinase activation. Current biology : CB 77 17174095
2000 Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling. Molecular and cellular biology 70 10891492
2011 RAF inhibitor-induced KSR1/B-RAF binding and its effects on ERK cascade signaling. Current biology : CB 68 21458265
2005 The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis. Molecular and cellular biology 67 16107706
2004 Phosphorylation regulates KSR1 stability, ERK activation, and cell proliferation. The Journal of biological chemistry 63 15371409
2016 MicroRNA-497 inhibits tumor growth and increases chemosensitivity to 5-fluorouracil treatment by targeting KSR1. Oncotarget 50 26673620
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
2021 ELK4 promotes the development of gastric cancer by inducing M2 polarization of macrophages through regulation of the KDM5A-PJA2-KSR1 axis. Journal of translational medicine 43 34372882
2011 Kinase suppressor of ras 1 (KSR1) regulates PGC1α and estrogen-related receptor α to promote oncogenic Ras-dependent anchorage-independent growth. Molecular and cellular biology 42 21518958
2008 The Caenorhabditis elegans ekl (enhancer of ksr-1 lethality) genes include putative components of a germline small RNA pathway. Genetics 38 18245826
2013 The dual function of KSR1: a pseudokinase and beyond. Biochemical Society transactions 36 23863182
2009 KSR1 modulates the sensitivity of mitogen-activated protein kinase pathway activation in T cells without altering fundamental system outputs. Molecular and cellular biology 36 19188442
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
2023 SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status. Proceedings of the National Academy of Sciences of the United States of America 28 37972068
2016 KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors. Molecular and cellular biology 28 27273865
2012 VRK2 anchors KSR1-MEK1 to endoplasmic reticulum forming a macromolecular complex that compartmentalizes MAPK signaling. Cellular and molecular life sciences : CMLS 28 22752157
2011 KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels. The American journal of pathology 28 21435442
2008 The functional interaction of 14-3-3 proteins with the ERK1/2 scaffold KSR1 occurs in an isoform-specific manner. The Journal of biological chemistry 28 18426801
2022 The mechanism of activation of MEK1 by B-Raf and KSR1. Cellular and molecular life sciences : CMLS 27 35508574
2018 Erbin Suppresses KSR1-Mediated RAS/RAF Signaling and Tumorigenesis in Colorectal Cancer. Cancer research 26 29980571
2010 KSR1 protects from interleukin-10 deficiency-induced colitis in mice by suppressing T-lymphocyte interferon-γ production. Gastroenterology 26 20875416
2016 praja2 regulates KSR1 stability and mitogenic signaling. Cell death & disease 25 27195677
2015 Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells. Oncology reports 25 25962735
2014 Caveolin-1 is required for kinase suppressor of Ras 1 (KSR1)-mediated extracellular signal-regulated kinase 1/2 activation, H-RasV12-induced senescence, and transformation. Molecular and cellular biology 24 25002533
2004 Inflammatory bowel disease reveals the kinase activity of KSR1. The Journal of clinical investigation 22 15520853
2010 KSR1 is a functional protein kinase capable of serine autophosphorylation and direct phosphorylation of MEK1. Experimental cell research 19 21144847
2009 The mitogen-activated protein kinase scaffold KSR1 is required for recruitment of extracellular signal-regulated kinase to the immunological synapse. Molecular and cellular biology 19 19139278
2008 IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholds. The Journal of biological chemistry 19 18332145
2021 Calmodulin influences MAPK signaling by binding KSR1. The Journal of biological chemistry 18 33766558
2021 KSR1- and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition. eLife 18 33970103
2011 Compartmentalization of the MAPK scaffold protein KSR1 modulates synaptic plasticity in hippocampal neurons. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 21471251
2015 The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors. Oncogene 17 26549023
2013 SILAC-based phosphoproteomics reveals an inhibitory role of KSR1 in p53 transcriptional activity via modulation of DBC1. British journal of cancer 17 24129246
2022 Sulfated alginate oligosaccharide exerts antitumor activity and autophagy induction by inactivating MEK1/ERK/mTOR signaling in a KSR1-dependent manner in osteosarcoma. Oncogenesis 16 35418575
2009 KSR1 is required for cell cycle reinitiation following DNA damage. The Journal of biological chemistry 15 19147494
2022 SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity. Cancer letters 14 36493900
2017 Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets. Cancer research 14 29259016
2014 KSR1 regulates BRCA1 degradation and inhibits breast cancer growth. Oncogene 14 24909178
2013 Terbinafine inhibits KSR1 and suppresses Raf-MEK-ERK signaling in oral squamous cell carcinoma cells. Neoplasma 14 23581412
2012 Pravastatin normalizes ET-1-induced contraction in the aorta of type 2 diabetic OLETF rats by suppressing the KSR1/ERK complex. American journal of physiology. Heart and circulatory physiology 14 22886408
2011 Regulation of glucose homeostasis by KSR1 and MARK2. PloS one 14 22206009
2007 Caspase-dependent cleavage disrupts the ERK cascade scaffolding function of KSR1. The Journal of biological chemistry 14 17613518
2006 Ras-sensitive IMP modulation of the Raf/MEK/ERK cascade through KSR1. Methods in enzymology 14 16757328
2023 Analysis of RAS and drug induced homo- and heterodimerization of RAF and KSR1 proteins in living cells using split Nanoluc luciferase. Cell communication and signaling : CCS 13 37316874
2024 KSR1 Knockout Mouse Model Demonstrates MAPK Pathway's Key Role in Cisplatin- and Noise-induced Hearing Loss. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 38548338
2024 Step-wise evolution of azole resistance through copy number variation followed by KSR1 loss of heterozygosity in Candida albicans. PLoS pathogens 12 39213436
2021 Praja2 suppresses the growth of gastric cancer by ubiquitylation of KSR1 and inhibiting MEK-ERK signal pathways. Aging 12 33461174
2008 Downregulation of KSR1 in pancreatic cancer xenografts by antisense oligonucleotide correlates with tumor drug uptake. Cancer biology & therapy 12 18719367
2004 The kinase activity of kinase suppressor of Ras1 (KSR1) is independent of bound MEK. The Journal of biological chemistry 12 15084597
2023 Kinase Suppressor of RAS 1 (KSR1) Maintains the Transformed Phenotype of BRAFV600E Mutant Human Melanoma Cells. International journal of molecular sciences 9 37511580
2015 KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in thyroid cancer. Journal of molecular endocrinology 9 25608512
2015 Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer. Breast cancer research and treatment 8 26022350
2025 LINC02167 stabilizes KSR1 mRNA in an m5C-dependent manner to regulate the ERK/MAPK signaling pathway and promotes colorectal cancer metastasis. Journal of experimental & clinical cancer research : CR 6 40234937
2018 Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer. PloS one 6 29596465
2016 Stabilization of C-RAF:KSR1 complex by DiRas3 reduces availability of C-RAF for dimerization with B-RAF. Cellular signalling 6 27368419
2023 KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss. bioRxiv : the preprint server for biology 5 38014104
2025 KSR1 Mediates Small Cell Lung Carcinoma Tumor Initiation and Cisplatin Resistance. Molecular cancer research : MCR 4 39927878
2024 Disruption of Ca2+/calmodulin:KSR1 interaction lowers ERK activation. Protein science : a publication of the Protein Society 4 38591710
2024 ZC3H13 promotes autophagy in bladder cancer through m6A methylation modification of PJA2 and ubiquitination of KSR1. Human cell 4 39614918
2011 Kinase suppressor of Ras (KSR1) modulates multiple kit-ligand-dependent mast cell functions. Experimental hematology 4 21726514
2024 Development of Genetically Encoded Fluorescent KSR1-Based Probes to Track Ceramides during Phagocytosis. International journal of molecular sciences 3 38474242
2018 Effect of lentiviral vector-mediated KSR1 gene silencing on the proliferation of renal tubular epithelial cells and expression of inflammatory factors in a rat model of ischemia/reperfusion injury. Acta biochimica et biophysica Sinica 3 30020400
2026 Pan-RAF inhibitor exarafenib targets BRAF class II/III NSCLC and reveals ARAF-KSR1 resistance and combination strategies. Nature communications 2 41654519
2025 KSR1 mediates small-cell lung carcinoma tumor initiation and cisplatin resistance. bioRxiv : the preprint server for biology 2 38464216
2025 Targeting Kinase Suppressor of Ras 1 (KSR1) for Cancer Therapy. Pharmaceutics 2 41155983
2014 Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer. The pharmacogenomics journal 2 25287073
2025 Kinase suppressor of Ras 1 (KSR1) promotes liver carcinogenesis via activation of the RAS/RAF/MEK/ERK signaling pathway. JHEP reports : innovation in hepatology 1 41078702
2011 Genetic disruption of the scaffolding protein, Kinase Suppressor of Ras 1 (KSR1), differentially regulates GM-CSF-stimulated hyperproliferation in hematopoietic progenitors expressing activating PTPN11 mutants D61Y and E76K. Leukemia research 1 21555152
2010 Backbone and side chain 1H, 15N and 13C assignments of the KSR1 CA1 domain. Biomolecular NMR assignments 1 20737253
2026 Soluble Uric Acid Drives CD8⁺ T-cell Exhaustion by Inducing KSR1-Mediated MAPK Hyperactivation. Cancer research 0 42118604
2025 The KSR1/MEK/ERK signaling pathway promotes the progression of intrauterine adhesions. Cellular signalling 0 40089092
2025 Targeting BRAF Class II and III Mutations in NSCLC with the pan-RAF inhibitor Exarafenib Reveals ARAF-KSR1-Mediated Resistance and Rational Combination Strategies. Research square 0 41282105
2025 KSR1 is a scaffold for the Hippo signaling pathway. Communications biology 0 41326667
2019 Defective spermatogenesis and testosterone levels in kinase suppressor of Ras1 (KSR1)-deficient mice. Reproduction, fertility, and development 0 30981290

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