ArticleThe Journal of biological chemistry2010
The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating affinity for the ubiquitin-conjugating enzyme.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 37 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
- The cuproptosis-related gene UBE2D2 functions as an immunotherapeutic and prognostic biomarker in pan-cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2024Article
- In Vitro Ubiquitination Platform Identifies Methyl Ellipticiniums as Ubiquitin Ligase Inhibitors.SLAS discovery : advancing life sciences R & D · 2021Article
- Loss of function Cbl-c mutations in solid tumors.PloS one · 2019Article
- Cbl interacts with multiple E2s in vitro and in cells.PloS one · 2019Article
- Casitas B-lineage lymphoma linker helix mutations found in myeloproliferative neoplasms affect conformation.BMC biology · 2016Article
- Molecular pathways: cbl proteins in tumorigenesis and antitumor immunity-opportunities for cancer treatment.Clinical cancer research : an official journal of the American Association for Cancer Research · 2015Review
- Article
- Cbl-family ubiquitin ligases and their recruitment of CIN85 are largely dispensable for epidermal growth factor receptor endocytosis.The international journal of biochemistry & cell biology · 2014Article
- CD2-associated protein (CD2AP) enhances casitas B lineage lymphoma-3/c (Cbl-3/c)-mediated Ret isoform-specific ubiquitination and degradation via its amino-terminal Src homology 3 domains.The Journal of biological chemistry · 2014Article
- E3 ubiquitin ligase Cbl-b in innate and adaptive immunity.Cell cycle (Georgetown, Tex.) · 2014Review
- RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination.Biochimica et biophysica acta · 2014Review
- Molecular mechanisms of SH2- and PTB-domain-containing proteins in receptor tyrosine kinase signaling.Cold Spring Harbor perspectives in biology · 2013Review
- Allosteric regulation of E2:E3 interactions promote a processive ubiquitination machine.The EMBO journal · 2013Article
- Essentiality of a non-RING element in priming donor ubiquitin for catalysis by a monomeric E3.Nature structural & molecular biology · 2013Article
- Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl-family ubiquitin ligases.Biochimica et biophysica acta · 2013Review
- Article
- CIN85 phosphorylation is essential for EGFR ubiquitination and sorting into multivesicular bodies.Molecular biology of the cell · 2012Article
- Cbl exposes its RING finger.Nature structural & molecular biology · 2012Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Cbl proteins are ubiquitin ligases (E3s) that play a significant role in regulating tyrosine kinase signaling. There are three mammalian family members: Cbl, Cbl-b, and Cbl-c. All have a highly conserved N-terminal tyrosine kinase binding domain, a catalytic RING finger domain, and a C-terminal proline-rich domain that mediates interactions with Src homology 3 (SH3) containing proteins. Although both Cbl and Cbl-b have been studied widely, little is known about Cbl-c. Published reports have demonstrated that the N terminus of Cbl and Cbl-b have an inhibitory effect on their respective E3 activity. However, the mechanism for this inhibition is still unknown. In this study we demonstrate that the N terminus of Cbl-c, like that of Cbl and Cbl-b, inhibits the E3 activity of Cbl-c. Furthermore, we map the region responsible for the inhibition to the EF-hand and SH2 domains. Phosphorylation of a critical tyrosine (Tyr-341) in the linker region of Cbl-c by Src or a phosphomimetic mutation of this tyrosine (Y341E) is sufficient to increase the E3 activity of Cbl-c. We also demonstrate for the first time that phosphorylation of Tyr-341 or the Y341E mutation leads to a decrease in affinity for the ubiquitin-conjugating enzyme (E2), UbcH5b. The decreased affinity of the Y341E mutant Cbl-c for UbcH5b results in a more rapid turnover of bound UbcH5b coincident with the increased E3 activity. These data suggest that the N terminus of Cbl-c contributes to the binding to the E2 and that phosphorylation of Tyr-341 leads to a decrease in affinity and an increase in the E3 activity of Cbl-c.
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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.