ArticleNature2011
A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.
Article in Nature, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 149 papers.
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Who cites it
149 citing papers in PubMed, 254 citations in OpenAlex.
- Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.IUBMB life · 2026Review
- In silico repurposing of clinically approved drugs as potential BRAF inhibitors: a pharmacophore-based virtual screening and experimental investigation.Cancer cell international · 2026Article
- A conserved dimerization element is required for protein kinase activation bybioRxiv : the preprint server for biology · 2026Article
- MAPK Pathway Inhibition Reshapes Kinase Chemical Probe Reactivity Reflecting Cellular Activation States.ACS bio & med chem Au · 2026Article
- Phosphoregulation of the novel hemi-arrestin MAPK scaffold Sms1 prevents untimely mating.Nature communications · 2026Article
- Structural basis for MEKK2 dimerization and substrate recognition.Nature communications · 2025Article
- Structural and evolutionary insights into understudied bacterial serine-threonine pseudokinase families.Biochemical Society transactions · 2025Review
- Kinase signaling cascades: an updated mechanistic landscape.Chemical science · 2025Review
- KSR2 Promotes Self-Renewal and Clonogenicity of Small Cell Lung Carcinoma.Molecular cancer research : MCR · 2025Article
- An atlas of bacterial serine-threonine kinases reveals functional diversity and key distinctions from eukaryotic kinases.Science signaling · 2025Article
- ERK pathway reactivation prevents anthrax toxin lethality in mice.Nature microbiology · 2025Article
- DCAF7 Acts as A Scaffold to Recruit USP10 for G3BP1 Deubiquitylation and Facilitates Chemoresistance and Metastasis in Nasopharyngeal Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- The CNK-HYP scaffolding complex promotes RAF activation by enhancing KSR-MEK interaction.Nature structural & molecular biology · 2024Article
- Targeting CRAF kinase in anti-cancer therapy: progress and opportunities.Molecular cancer · 2023Review
- Navigating the ERK1/2 MAPK Cascade.Biomolecules · 2023Review
- Interaction between Rumen Epithelial miRNAs-Microbiota-Metabolites in Response to Cold-Season Nutritional Stress in Tibetan Sheep.International journal of molecular sciences · 2023Article
- Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation.Science (New York, N.Y.) · 2023Article
- Evolutionary history of MEK1 illuminates the nature of deleterious mutations.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Evaluating the Pharmacokinetics and Pharmacodynamics of Chemotherapeutics within a Spatial SILAC-Labeled Spheroid Model System.Analytical chemistry · 2023Article
- Review
89 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
In metazoans, the Ras-Raf-MEK (mitogen-activated protein-kinase kinase)-ERK (extracellular signal-regulated kinase) signalling pathway relays extracellular stimuli to elicit changes in cellular function and gene expression. Aberrant activation of this pathway through oncogenic mutations is responsible for a large proportion of human cancer. Kinase suppressor of Ras (KSR) functions as an essential scaffolding protein to coordinate the assembly of Raf-MEK-ERK complexes. Here we integrate structural and biochemical studies to understand how KSR promotes stimulatory Raf phosphorylation of MEK (refs 6, 7). We show, from the crystal structure of the kinase domain of human KSR2 (KSR2(KD)) in complex with rabbit MEK1, that interactions between KSR2(KD) and MEK1 are mediated by their respective activation segments and C-lobe αG helices. Analogous to BRAF (refs 8, 9), KSR2 self-associates through a side-to-side interface involving Arg 718, a residue identified in a genetic screen as a suppressor of Ras signalling. ATP is bound to the KSR2(KD) catalytic site, and we demonstrate KSR2 kinase activity towards MEK1 by in vitro assays and chemical genetics. In the KSR2(KD)-MEK1 complex, the activation segments of both kinases are mutually constrained, and KSR2 adopts an inactive conformation. BRAF allosterically stimulates the kinase activity of KSR2, which is dependent on formation of a side-to-side KSR2-BRAF heterodimer. Furthermore, KSR2-BRAF heterodimerization results in an increase of BRAF-induced MEK phosphorylation via the KSR2-mediated relay of a signal from BRAF to release the activation segment of MEK for phosphorylation. We propose that KSR interacts with a regulatory Raf molecule in cis to induce a conformational switch of MEK, facilitating MEK's phosphorylation by a separate catalytic Raf molecule in trans.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.