ArticleMolecular and cellular biology2006
Regulation and role of Raf-1/B-Raf heterodimerization.
Article in Molecular and cellular biology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 211 papers.
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Who cites it
211 citing papers in PubMed, 414 citations in OpenAlex.
- Unveiling BRAF Mutations in Non-small Cell Lung Cancer: State of the Art and Future Perspectives.Lung · 2026Review
- Langerhans cell histiocytosis: molecular mechanisms underlying pathogenesis and emerging targeted therapeutics.Cancer metastasis reviews · 2026Review
- Discovery of Cyclic Peptides Targeting the BRAF Dimer Interface as Dual Inhibitors.ACS pharmacology & translational science · 2026Article
- Dual RAF inhibition outperforms RAF-MEK combinations for suppressing ERK signaling in KRAS mutant cells.NPJ systems biology and applications · 2026Article
- Deciphering molecular pathways in urological cancers: A gateway to precision therapeutics.Journal of advanced research · 2026Review
- Modulation of the 14-3-3σ/C-RAF "Auto"inhibited Complex by Molecular Glues.Journal of the American Chemical Society · 2026Article
- DA-Raf synergistically binds to the plasma membrane and Ras to suppress ERK signaling.Life science alliance · 2025Article
- Cryo-EM structures of CRAF/MEK1/14-3-3 complexes in autoinhibited and open-monomer states reveal features of RAF regulation.Nature communications · 2025Article
- Discovery of novel naphthalene-based diarylamides as pan-Raf kinase inhibitors with promising anti-melanoma activity: rational design, synthesis, in vitro and in silico screening.Archives of pharmacal research · 2025Article
- Histone deacetylases in the regulation of cell death and survival mechanisms in resistant BRAF-mutant cancers.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- The Raf/LIN-45 C-terminal distal tail segment negatively regulates signaling in Caenorhabditis elegans.Genetics · 2024Article
- Targeted protein degradation: advances in drug discovery and clinical practice.Signal transduction and targeted therapy · 2024Review
- Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells.Cell reports · 2024Article
- Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage.Nature communications · 2024Article
- The mTOR pathway controls phosphorylation of BRAF at T401.Cell communication and signaling : CCS · 2024Article
- Regulation of RAF family kinases: new insights from recent structural and biochemical studies.Biochemical Society transactions · 2024Review
- RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor.Oncogene · 2024Article
- Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node.Molecular oncology · 2024Review
- Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors.eLife · 2024Article
- Targeting RAF dimers in RAS mutant tumors: From biology to clinic.Acta pharmaceutica Sinica. B · 2024Review
151 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Ras-Raf-MEK-extracellular signal-regulated kinase (ERK) pathway participates in the control of many fundamental cellular processes including proliferation, survival, and differentiation. The pathway is deregulated in up to 30% of human cancers, often due to mutations in Ras and the B-Raf isoform. Raf-1 and B-Raf can form heterodimers, and this may be important for cellular transformation. Here, we have analyzed the biochemical and biological properties of Raf-1/B-Raf heterodimers. Isolated Raf-1/B-Raf heterodimers possessed a highly increased kinase activity compared to the respective homodimers or monomers. Heterodimers between wild-type Raf-1 and B-Raf mutants with low or no kinase activity still displayed elevated kinase activity, as did heterodimers between wild-type B-Raf and kinase-negative Raf-1. In contrast, heterodimers containing both kinase-negative Raf-1 and kinase-negative B-Raf were completely inactive, suggesting that the kinase activity of the heterodimer specifically originates from Raf and that either kinase-competent Raf isoform is sufficient to confer high catalytic activity to the heterodimer. In cell lines, Raf-1/B-Raf heterodimers were found at low levels. Heterodimerization was enhanced by 14-3-3 proteins and by mitogens independently of ERK. However, ERK-induced phosphorylation of B-Raf on T753 promoted the disassembly of Raf heterodimers, and the mutation of T753 prolonged growth factor-induced heterodimerization. The B-Raf T753A mutant enhanced differentiation of PC12 cells, which was previously shown to be dependent on sustained ERK signaling. Fine mapping of the interaction sites by peptide arrays suggested a complex mode of interaction involving multiple contact sites with a main Raf-1 binding site in B-Raf encompassing T753. In summary, our data suggest that Raf-1/B-Raf heterodimerization occurs as part of the physiological activation process and that the heterodimer has distinct biochemical properties that may be important for the regulation of some biological processes.
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