ArticleProceedings of the National Academy of Sciences of the United States of America2007
A critical role for the E3-ligase activity of c-Cbl in VEGFR-2-mediated PLCgamma1 activation and angiogenesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 64 citations in OpenAlex.
- PTPN22 Dephosphorylates CBL to Inhibit PD-L1 Ubiquitination and Drive Immunosuppression in Renal Cell Carcinoma.International journal of biological sciences · 2026Article
- Post-translational modification gene signatures implicate FBXW7 in immune and vascular dysregulation of Moyamoya disease.Frontiers in genetics · 2025Article
- The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein.Nature communications · 2024Article
- Mettl13 protects against cardiac contractile dysfunction by negatively regulating C-Cbl-mediated ubiquitination of SERCA2a in ischemic heart failure.Science China. Life sciences · 2023Article
- Review
- Exploiting E3 ubiquitin ligases to reeducate the tumor microenvironment for cancer therapy.Experimental hematology & oncology · 2023Review
- A relatively low glucose promotes the proliferation of vascular endothelial cells by suppressing VEGFR2 O-GlcNAcylation and its proteasome degradation.International ophthalmology · 2023Article
- PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions.iScience · 2022Article
- Graphene-based nanomaterials for cancer therapy and anti-infections.Bioactive materials · 2022Review
- Knockout of c-Cbl slows EGFR endocytic trafficking and enhances EGFR signaling despite incompletely blocking receptor ubiquitylation.Pharmacology research & perspectives · 2021Article
- Article
- C-CBL is required for inhibition of angiogenesis through modulating JAK2/STAT3 activity in ROP development.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2020Article
- Photoelectrons Mediating Angiogenesis and Immunotherapy through Heterojunction Film for Noninvasive Disinfection.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
- Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene.Neurology. Genetics · 2020Article
- c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth.Scientific reports · 2019Article
- Review
- SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis.Nature communications · 2018Article
- c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/β-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation.The American journal of pathology · 2018Observational
- Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function.Biology open · 2017Article
- c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors.Oncotarget · 2016Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Activation of phospholipase Cgamma1 (PLCgamma1) by vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells in part is responsible for angiogenesis in vivo. The cellular mechanisms exerting negative control over PLCgamma1 activation, however, remain unaddressed. Here by using in vitro and in vivo binding assays, we show that the Casitas B-lineage lymphoma (c-Cbl) E3 ubiquitin ligase constitutively associates with PLCgamma1 via its C-terminal domain and conditionally interacts with VEGFR-2 via the N-terminal/TKB domain. Site-directed mutagenesis of VEGFR-2 showed that full activation of c-Cbl requires its direct association with phospho-tyrosines 1052 and 1057 of VEGFR-2 via its TKB domain and indirect association with phospho-tyrosine 1173 of VEGFR-2 via PLCgamma1. The tertiary complex formation between VEGFR-2, PLCgamma1 and c-Cbl selectively promotes ubiquitylation and suppression of tyrosine phosphorylation of PLCgamma1 by a proteolysis-independent mechanism. Further analysis showed that association of c-Cbl with VEGFR-2 does not impact ubiquitylation, down-regulation, or tyrosine phosphorylation of VEGFR-2. Silencing of c-Cbl by siRNA revealed that endogenous c-Cbl plays an inhibitory role in angiogenesis. Our data demonstrate that corecruitment of c-Cbl and PLCgamma1 to VEGFR-2 serves as a mechanism to fine-tune the angiogenic signal relay of VEGFR-2.
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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.