ArticleNature communications2017
Evolution of AF6-RAS association and its implications in mixed-lineage leukemia.
Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
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- The dual Ras-association domains of Drosophila Canoe have differential roles in linking cell junctions to the cytoskeleton during morphogenesis.Journal of cell science · 2024Article
- Functional and structural insights into RAS effector proteins.Molecular cell · 2024Review
- Article
- The role of reciprocal fusions in MLL-r acute leukemia: studying the chromosomal translocation t(6;11).Oncogene · 2021Article
- Engineering of Biological Pathways: Complex Formation and Signal Transduction.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Thioridazine requires calcium influx to induce MLL-AF6-rearranged AML cell death.Blood advances · 2020Article
- Structure of the DOCK2-ELMO1 complex provides insights into regulation of the auto-inhibited state.Nature communications · 2020Article
- Conformational resolution of nucleotide cycling and effector interactions for multiple small GTPases determined in parallel.The Journal of biological chemistry · 2019Article
- Oligomeric self-association contributes to E2A-PBX1-mediated oncogenesis.Scientific reports · 2019Article
- New insights into RAS biology reinvigorate interest in mathematical modeling of RAS signaling.Seminars in cancer biology · 2019Review
- Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling.PLoS computational biology · 2018Article
- Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis.Genes & development · 2018Article
- A comprehensive analysis of RAS-effector interactions reveals interaction hotspots and new binding partners.The Journal of biological chemistryArticle
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization. We provide evidence that oligomerization is the dominant mechanism driving oncogenesis from rare MLL translocation partners and employ our mechanistic understanding of MLL-AF6 to examine how dimers induce leukemia. Proteomic data resolve association of dimerized MLL with gene expression modulators, and inhibiting dimerization disrupts formation of these complexes while completely abrogating leukemogenesis in mice. Oncogenic gene translocations are thus selected under pressure from protein structure/function, underscoring the complex nature of chromosomal rearrangements.
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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 Socratic graph.