ArticleNature structural & molecular biology2012
Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl.
Article in Nature structural & molecular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers.
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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.
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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
121 citing papers in PubMed, 200 citations in OpenAlex.
- Trial
- Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family.Human genetics · 2015Trial
- LAG3 checkpoint function and its mechanism of action in therapeutic targeting.Nature reviews. Immunology · 2026Review
- Learning Protein-Protein Binding Free Energies from Interface Graphs and Physicochemical Descriptors.ACS physical chemistry Au · 2026Article
- Article
- RING finger E3 ubiquitin ligases: novel therapeutic opportunities in melanoma.Cellular & molecular biology letters · 2026Review
- Small-molecule CBLB inhibitor abolishes EGFR ubiquitination, reduces receptor endocytosis, and diminishes cell motility signaling.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Degrons and degradation signals beyond short linear motifs.Nature chemical biology · 2026Review
- FBXO22 targets ubiquitination and degradation of c-Cbl in leukemia.Scientific reports · 2026Article
- Small-molecule CBLB inhibitor abolishes EGFR ubiquitination, reduces receptor endocytosis and diminishes cell motility signaling.bioRxiv : the preprint server for biology · 2026Article
- E3 Ubiquitin ligases Cbl-b and c-Cbl maintain the homeostasis of macrophages by regulating the M-CSF/M-CSFR signaling axis.Cell death & disease · 2025Article
- Tuning ubiquitin transfer by RING E3 ubiquitin ligases through the linchpin residue.Life science alliance · 2025Article
- Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Beyond destruction: emerging roles of the E3 ubiquitin ligase Hakai.Cellular & molecular biology letters · 2025Review
- Mechanisms of Cbl-Mediated Ubiquitination of Proteins in T and Natural Killer Cells and Effects on Immune Cell Functions.Life (Basel, Switzerland) · 2024Review
- Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.The Journal of clinical investigation · 2024Article
- Article
- Autoinhibited Protein Database: a curated database of autoinhibitory domains and their autoinhibition mechanisms.Database : the journal of biological databases and curation · 2024Article
- Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant.American journal of medical genetics. Part A · 2024Article
- Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches.Molecular cancer · 2024Review
61 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Cbls are RING ubiquitin ligases that attenuate receptor tyrosine kinase (RTK) signal transduction. Cbl ubiquitination activity is stimulated by phosphorylation of a linker helix region (LHR) tyrosine residue. To elucidate the mechanism of activation, we determined the structures of human CBL, a CBL-substrate peptide complex and a phosphorylated-Tyr371-CBL-E2-substrate peptide complex, and we compared them with the known structure of a CBL-E2-substrate peptide complex. Structural and biochemical analyses show that CBL adopts an autoinhibited RING conformation, where the RING's E2-binding surface associates with CBL to reduce E2 affinity. Tyr371 phosphorylation activates CBL by inducing LHR conformational changes that eliminate autoinhibition, flip the RING domain and E2 into proximity of the substrate-binding site and transform the RING domain into an enhanced E2-binding module. This activation is required for RTK ubiquitination. Our results present a mechanism for regulation of c-Cbl's activity by autoinhibition and phosphorylation-induced activation.
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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.