Affinage

KSR2

Kinase suppressor of Ras 2 · UniProt Q6VAB6

Length
950 aa
Mass
107.6 kDa
Annotated
2026-06-10
21 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KSR2 is a molecular scaffold for the RAF-MEK-ERK kinase module that integrates mitogenic signaling with cellular energy and calcium homeostasis (PMID:19563921, PMID:11882296). Like KSR1, it organizes the cascade to promote ERK activation, with a function evolutionarily conserved in the C. elegans ortholog ksr-2, which acts redundantly with ksr-1 to sustain MPK-1/ERK diphosphorylation during Ras-mediated germline signaling (PMID:11882296). Distinct from KSR1, KSR2 physically associates with AMP-activated protein kinase and governs AMPK-dependent glucose uptake and fatty acid oxidation (PMID:19883615); mechanistically, KSR2 competes with CRBN for the K52 site of AMPKα1, blocking CRL4A-mediated K48-linked polyubiquitination and proteasomal degradation to stabilize AMPKα1 (PMID:41424849). It is also selectively bound and dephosphorylated by calcineurin in response to Ca2+, which directs KSR2 localization and uniquely enables Ca2+-mediated ERK activation; through this calcineurin association KSR2 is further required for store-operated calcium entry, supporting STIM1/ORAI1 puncta formation (PMID:19560418, PMID:24672054). These activities make KSR2 a node coordinating substrate utilization and energy balance: rare human loss-of-function variants disrupt Raf-MEK-ERK signaling and impair cellular fatty acid and glucose oxidation in obese individuals, defects rescuable by metformin (PMID:24209692). In vivo, KSR2 acts in the brain to regulate energy balance via feeding and adaptive thermogenesis, with additional peripheral roles (PMID:28180061), and autonomously controls bone formation by biasing marrow adipocyte versus osteoblast fate (PMID:36342465). In cancer contexts, KSR2's scaffold and AMPK-coupled functions support anchorage-independent growth, ERK-dependent self-renewal in SCLC-A cells, and MAPK hyperactivation with drug resistance through partners including 14-3-3ζ (PMID:22801368, PMID:40063515, PMID:35468812).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2002 Medium

    Established that the KSR2 ortholog functions in the Ras/Raf/MEK/ERK cascade in vivo, fixing KSR proteins as positive regulators of ERK activation rather than passive bystanders.

    Evidence C. elegans genetic epistasis with ksr-1;ksr-2 double mutants and anti-dpERK immunofluorescence

    PMID:11882296

    Open questions at the time
    • Does not address mammalian KSR2-specific biochemistry
    • Redundancy with ksr-1 obscures KSR2-unique functions
  2. 2009 High

    Distinguished KSR2 from KSR1 by showing it physically engages AMPK and calcineurin, revealing KSR2 as an integrator of metabolic and calcium signaling beyond simple MAPK scaffolding.

    Evidence Reciprocal Co-IP, proteomics comparison of KSR1 vs KSR2 partners, phosphosite mapping, RNAi-based Ca2+/ERK readouts, and KSR2-KO mouse metabolic phenotyping

    PMID:19560418 PMID:19883615

    Open questions at the time
    • Structural basis of calcineurin-dependent dephosphorylation sites not resolved
    • How AMPK binding mechanistically alters its activity not defined at this stage
  3. 2009 Medium

    Defined KSR2 as a RAF-MEK-ERK scaffold with RAF isoform preference distinct from KSR1, partially explaining functional divergence between the paralogs.

    Evidence Affinity purification/mass spectrometry of the KSR2 complex in HEK-293 cells +/- TNF-α

    PMID:19563921

    Open questions at the time
    • A-RAF preference inferred from complex composition, not confirmed by mutagenesis or reconstitution
    • Single lab
  4. 2012 Medium

    Separated KSR2's growth-promoting role from its MAPK role, showing anchorage-independent growth depends on AMPK rather than MEK/ERK signaling.

    Evidence KSR2 RNAi in tumor lines with constitutively active AMPK rescue, MEK inhibition, and ERK-interaction-deficient mutant in colony assays

    PMID:22801368

    Open questions at the time
    • Single lab
    • Generality across tumor types not established
  5. 2013 High

    Connected KSR2 mechanistic function to human disease, showing rare variants disrupt ERK signaling and substrate oxidation in obesity and are pharmacologically rescuable.

    Evidence Sequencing of 2,101 obese individuals/1,536 controls with functional ERK, fatty acid and glucose oxidation assays and metformin rescue

    PMID:24209692

    Open questions at the time
    • Tissue-of-origin for human metabolic defect not resolved by cellular assays
    • Whether AMPK or ERK arm dominates the human phenotype unclear
  6. 2014 Medium

    Extended KSR2's calcineurin partnership to a defined cell-biological output—store-operated calcium entry—linking it to STIM1/ORAI1 and cytoskeletal organization.

    Evidence KSR2-KO and shKSR2 cells with Ca2+ flux, STIM1/ORAI1 puncta imaging, cytoskeleton analysis, and calcineurin inhibition

    PMID:24672054

    Open questions at the time
    • Direct molecular link between KSR2 and STIM1/ORAI1 not established
    • Single lab
  7. 2016 Medium

    Localized KSR2's energy-balance function to the brain while revealing it also acts non-autonomously on hepatic GH/JAK2/STAT5-IGF-1 signaling, showing multi-tissue contributions.

    Evidence Nestin-Cre conditional KO metabolic phenotyping and KSR2-KO GH stimulation with hepatocyte and adenoviral IGF-1 rescue

    PMID:27561547 PMID:28180061

    Open questions at the time
    • Identity of peripheral tissues accounting for leptin/AICAR phenotype unknown
    • Mediator of cell non-autonomous hepatic effect unidentified
  8. 2022 Medium

    Broadened KSR2's roles to bone formation and cancer drug resistance, and introduced 14-3-3ζ as a stabilizing physical partner that amplifies MAPK signaling.

    Evidence Osteoblast-specific conditional KO with micro-CT/pair-feeding; Co-IP and co-overexpression/knockdown of 14-3-3ζ with MAPK and sorafenib-resistance readouts

    PMID:35468812 PMID:36342465

    Open questions at the time
    • Single lab for each finding
    • Mechanism by which 14-3-3ζ elevates KSR2 levels undefined
  9. 2025 Medium

    Demonstrated that KSR2's tumor-initiating function in SCLC-A is strictly ERK-interaction-dependent, validating the scaffold's MAPK arm as a driver in this context.

    Evidence KSR2 depletion with ERK-interaction-deficient mutant rescue in colony-forming and in vivo tumor initiation assays

    PMID:40063515

    Open questions at the time
    • Single lab
    • Relationship to AMPK-dependent growth seen in other tumors not reconciled
  10. 2026 Medium

    Resolved the molecular mechanism of AMPK regulation, showing KSR2 stabilizes AMPKα1 by competing with CRBN at the K52 site to block CRL4A-mediated degradation.

    Evidence Co-IP and competition/ubiquitination assays with CRISPR editing and endothelial KSR2 overexpression/KO and ApoE double-KO atherosclerosis models

    PMID:41424849

    Open questions at the time
    • 2026 publication not yet independently replicated
    • Whether this competition operates outside endothelium not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KSR2's three biochemical activities—RAF-MEK-ERK scaffolding, AMPKα1 stabilization, and calcineurin-mediated calcium coupling—are coordinated within a single cell and which arm dominates in each tissue remains unresolved.
  • No integrated structural model of KSR2 engaging RAF, AMPK, and calcineurin simultaneously
  • Tissue-specific weighting of each activity not mapped
  • Subcellular localization dynamics underlying signal switching uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2
Partners
AMPKARAFCRBNORAI1PPP3 (CALCINEURIN)STIM1YWHAZ
Complex memberships
RAF-MEK-ERK module

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 KSR2 physically interacts with and modulates the activity of AMP-activated protein kinase (AMPK), regulating AMPK-dependent glucose uptake and fatty acid oxidation in mouse embryonic fibroblasts and glycolysis in a neuronal cell line. Co-immunoprecipitation, cellular metabolic assays (glucose uptake, fatty acid oxidation, glycolysis) in MEFs and neuronal cells, KSR2 knockout mice with metabolic phenotyping and hyperinsulinemic-euglycemic clamp studies Cell metabolism High 19883615
2009 Calcineurin selectively interacts with KSR2 (but not KSR1) and dephosphorylates KSR2 on specific sites in response to Ca2+ signals, thereby regulating KSR2 localization and activity; KSR2 uniquely promotes Ca2+-mediated ERK cascade activation in pancreatic beta-cells and neuroblastoma cells. Proteomics/mass spectrometry comparison of KSR1 vs KSR2 binding partners, Co-IP, phosphorylation mapping, KSR2 depletion (RNAi) with Ca2+-stimulated ERK activation readout in INS1 and NG108 cells Molecular cell High 19560418
2009 KSR2 functions as a scaffold for the RAF-MEK-ERK kinase module (similar to KSR1) but shows distinct RAF isoform specificity: KSR2 preferentially mediates A-RAF signaling whereas KSR1 mediates c-RAF signaling. Functional proteomics (affinity purification/mass spectrometry) of the KSR2 complex in HEK-293 cells with and without TNF-α stimulation, identifying ~100 associated proteins Biochimica et biophysica acta Medium 19563921
2013 Rare human KSR2 variants disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation; these metabolic defects can be ameliorated by metformin treatment. Sequencing of 2,101 obese individuals and 1,536 controls; functional assays of KSR2 mutants in transfected cells measuring ERK signaling, fatty acid oxidation, and glucose oxidation; metformin rescue experiments Cell High 24209692
2012 KSR2 promotes ERK activation and cell transformation via its scaffold function, but its role in supporting anchorage-independent growth of tumor cells is dependent on AMPK signaling rather than MAP kinase signaling; constitutive AMPK activation complements KSR2 loss in metabolic signaling and anchorage-independent growth. KSR2 RNAi in MIN6 and NG108-15 tumor cell lines; rescue with constitutively active AMPK; MEK inhibition; expression of KSR2 mutant unable to interact with ERK; colony formation and proliferation assays Molecular and cellular biology Medium 22801368
2014 KSR2, through its associated calcineurin, is required for optimal store-operated calcium entry (SOCE); KSR2 deficiency impairs STIM1/ORAI1 puncta formation correlated with cytoskeleton disorganization, and calcineurin-dependent SOCE is KSR2-dependent. KSR2-knockout lymphocytes and fibroblasts, shKSR2 knockdown cells; Ca2+ flux measurements; STIM1/ORAI1 puncta imaging; cytoskeleton analysis; calcineurin inhibitor experiments Molecular biology of the cell Medium 24672054
2002 In C. elegans, ksr-2 (ortholog of mammalian KSR2) is required for Ras-mediated signaling during germline meiotic progression and acts redundantly with ksr-1; ksr-2; ksr-1 double mutants show severely reduced or absent diphosphorylated MPK-1 ERK, supporting KSR's role in promoting Raf/MEK/ERK cascade activation. C. elegans genetic analysis; double mutant construction; anti-dpERK immunofluorescence to quantify activated ERK levels Current biology : CB Medium 11882296
2016 Brain-specific (Nestin-Cre driven) KSR2 deletion recapitulates obesity and glucose intolerance of global KSR2 knockout, demonstrating that KSR2 functions in the brain to regulate energy balance via feeding behavior and adaptive thermogenesis; however, brain KSR2 alone does not fully account for leptin sensitivity and AICAR response, indicating additional peripheral tissue roles. Conditional knockout using Nes-Cre × KSR2fl/fl; metabolic phenotyping including body composition, food intake, cold tolerance, glucose tolerance, insulin levels, AICAR and leptin response Molecular metabolism Medium 28180061
2016 KSR2 disruption causes selective impairment of hepatic GH-stimulated JAK2/STAT5 signaling and reduced IGF-1/IGFBP3 expression in neonatal mice; this effect is cell non-autonomous, as isolated KSR2-null primary hepatocytes show normal GH-stimulated STAT5 phosphorylation, and IGF-1 restoration rescues body length defects. KSR2 knockout mouse GH injection studies; measurement of JAK2 and STAT5 phosphorylation in liver vs skeletal muscle; primary hepatocyte isolation and GH stimulation; adenoviral IGF-1 rescue experiment Scientific reports Medium 27561547
2022 14-3-3ζ physically complexes with KSR2, elevates KSR2 protein levels, and co-overexpression of both proteins hyperactivates MAPK signaling and confers sorafenib resistance in HCC cells. Co-immunoprecipitation; co-overexpression and knockdown experiments; MAPK signaling assays; flow cytometry for sorafenib resistance Biomarker research Medium 35468812
2022 KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in bone marrow; osteoblast-specific conditional deletion of KSR2 autonomously regulates bone formation, distinct from its hypothalamic role in feeding. Global KSR2 knockout mice (two genetic backgrounds); osteoblast-specific conditional KSR2 deletion; pair-feeding experiments; micro-CT and histology eLife Medium 36342465
2025 The self-renewal and clonogenicity-promoting function of KSR2 in SCLC-A cells is dependent on KSR2's interaction with ERK; a KSR2 mutant unable to interact with ERK fails to support colony formation and tumor initiation. KSR2 depletion in SCLC-A cell lines; colony-forming assay in vitro; tumor initiation assay in vivo; KSR2 ERK-interaction-deficient mutant rescue experiments Molecular cancer research : MCR Medium 40063515
2026 KSR2 competes with CRBN for binding to the K52 site of AMPKα1, inhibiting CRL4A E3 ubiquitin ligase complex-mediated K48-linked polyubiquitination and proteasomal degradation of AMPKα1, thereby stabilizing AMPKα1 and maintaining AMPK signaling in endothelial cells. Co-IP, CRISPR/Cas9 gene editing, endothelial-specific KSR2 overexpression (AAV9-ICAM2), global KSR2 KO and double KO (KSR2/ApoE) mouse models, atherosclerosis assays, ubiquitination assays Theranostics Medium 41424849
2020 SF3B1 promotes KSR2 expression by facilitating maturation of KSR2 pre-mRNA; loss of SF3B1 reduces KSR2 mRNA maturation and expression, and rescuing KSR2 expression partially restores cell growth upon SF3B1 knockdown in endometrial cancer cells. RNA-seq after SF3B1 knockdown; alternative splicing analysis; KSR2 rescue experiment in SF3B1-depleted cells measuring proliferation Cell death & disease Medium 33040078

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. Cell 145 24209692
2009 KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell metabolism 123 19883615
2009 KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals. Molecular cell 102 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 91 11882296
2020 Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation. Cell death & disease 57 33040078
2012 Kinase suppressor of Ras 2 (KSR2) regulates tumor cell transformation via AMPK. Molecular and cellular biology 53 22801368
2009 Proteomic characterization of the dynamic KSR-2 interactome, a signaling scaffold complex in MAPK pathway. Biochimica et biophysica acta 32 19563921
2016 Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis. Molecular metabolism 18 28180061
2014 The KSR2-calcineurin complex regulates STIM1-ORAI1 dynamics and store-operated calcium entry (SOCE). Molecular biology of the cell 15 24672054
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
2022 Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity. eLife 7 36342465
2022 KSR2-14-3-3ζ complex serves as a biomarker and potential therapeutic target in sorafenib-resistant hepatocellular carcinoma. Biomarker research 5 35468812
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 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
2025 KSR2 Promotes Self-Renewal and Clonogenicity of Small Cell Lung Carcinoma. Molecular cancer research : MCR 1 40063515
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 KSR2 functions as a metabolic checkpoint for anti-PD-1 resistance by reprogramming glucose metabolism. Cancer immunology, immunotherapy : CII 0 42012646
2025 Obese-diabetic female Ksr2 knockout mice develop brittle bones near end of life. JBMR plus 0 40303835

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