ArticleProceedings of the National Academy of Sciences of the United States of America2011
Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 136 citations in OpenAlex.
- Langerhans cell histiocytosis: molecular mechanisms underlying pathogenesis and emerging targeted therapeutics.Cancer metastasis reviews · 2026Review
- 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
- NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress.Science advances · 2025Article
- An atlas of bacterial serine-threonine kinases reveals functional diversity and key distinctions from eukaryotic kinases.Science signaling · 2025Article
- Oncogenic non-V600 mutations evade the regulatory machinery of RAF including the Cdc37/Hsp90 chaperone and the 14-3-3 scaffold.Theranostics · 2025Article
- A conserved juxtamembrane motif in plant NFR5 receptors is essential for root nodule symbiosis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Targeting CRAF kinase in anti-cancer therapy: progress and opportunities.Molecular cancer · 2023Review
- Navigating the ERK1/2 MAPK Cascade.Biomolecules · 2023Review
- RAS-independent ERK activation by constitutively active KSR3 in non-chordate metazoa.Nature communications · 2023Article
- 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 · 2023Article
- Calculation of centralities in protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- KSR induces RAS-independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors.Molecular oncology · 2022Article
- The mechanism of activation of MEK1 by B-Raf and KSR1.Cellular and molecular life sciences : CMLS · 2022Article
- Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers.Cell reports · 2022Article
- Conformational control and regulation of the pseudokinase KSR via small molecule binding interactions.Methods in enzymology · 2022Article
- The stability of R-spine defines RAF inhibitor resistance: A comprehensive analysis of oncogenic BRAF mutants with in-frame insertion of αC-β4 loop.Science advances · 2021Article
- Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation.American journal of human genetics · 2021Article
- Drug resistance in targeted cancer therapies with RAF inhibitors.Cancer drug resistance (Alhambra, Calif.) · 2021Review
- Phosphoproteomics Meets Chemical Genetics: Approaches for Global Mapping and Deciphering the Phosphoproteome.International journal of molecular sciences · 2020Review
20 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Because mutations in RAS and BRAF represent the most common mutations found in human tumors, identification of inhibitors has been a major goal. Surprisingly, new oncogenic BRAF specific inhibitors inhibit cells transformed with mutated BRAF but paradoxically stimulate the growth of cells transformed with RAS. Here, we show that the mechanism for activation is via drug-induced dimer formation between CRAF and kinase suppressor of Ras (KSR)1. To understand the function of KSR1, we generated a KSR1 mutant that cannot bind ATP but stabilizes the closed, active conformation of KSR1. Molecular modeling suggested that the mutant stabilizes the two hydrophobic spines critical for the closed active conformation. We, therefore, could use the mutant to discriminate between the scaffold versus kinase functions of KSR1. The KSR1 mutant bound constitutively to RAF and mitogen-activated protein kinase kinase (MEK) but could not reconstitute activity suggesting that the catalytic activity of KSR1 is required for its function. Analogous mutations in BRAF and CRAF allowed us to test the generality of the model. The mutation induced changes consistent with the active, closed conformation of both kinases and confirmed that BRAF functions distinctly from CRAF in the MAP kinase pathway. Not only does this work suggest that KSR1 may function as a kinase, we anticipate that the mutation that we generated may be broadly applicable to stabilize the closed conformation of other kinases many of which may also form dimers.
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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.