ArticleThe Journal of biological chemistry2010
The loss of Cbl-phosphatidylinositol 3-kinase interaction perturbs RANKL-mediated signaling, inhibiting bone resorption and promoting osteoclast survival.
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 25 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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Who cites it
25 citing papers in PubMed, 34 citations in OpenAlex.
- Article
- Wnt-associated adult stem cell marker Lgr6 is required for osteogenesis and fracture healing.Bone · 2023Article
- A single-cell interactome of human tooth germ from growing third molar elucidates signaling networks regulating dental development.Cell & bioscience · 2021Article
- Article
- PI3K activation increases SDF-1 production and number of osteoclast precursors, and enhances SDF-1-mediated osteoclast precursor migration.Bone reports · 2019Article
- Feedback regulation of RTK signaling in development.Developmental biology · 2019Review
- A PDGFRβ-PI3K signaling axis mediates periosteal cell activation during fracture healing.PloS one · 2019Article
- The Hajdu Cheney Mutation Is a Determinant of B-Cell Allocation of the Splenic Marginal Zone.The American journal of pathology · 2018Article
- Structural Determinants of the Gain-of-Function Phenotype of Human Leukemia-associated Mutant CBL Oncogene.The Journal of biological chemistry · 2017Article
- Article
- miR-216a rescues dexamethasone suppression of osteogenesis, promotes osteoblast differentiation and enhances bone formation, by regulating c-Cbl-mediated PI3K/AKT pathway.Cell death and differentiation · 2015Article
- Role of Cbl-PI3K Interaction during Skeletal Remodeling in a Murine Model of Bone Repair.PloS one · 2015Article
- Loss of Cbl-PI3K interaction in mice prevents significant bone loss following ovariectomy.Bone · 2014Article
- Phosphorylation of c-Cbl and p85 PI3K driven by all-trans retinoic acid and CD38 depends on Lyn kinase activity.Cellular signalling · 2014Article
- Loss of Cbl-PI3K interaction enhances osteoclast survival due to p21-Ras mediated PI3K activation independent of Cbl-b.Journal of cellular biochemistry · 2014Article
- Identification and validation of quantitative trait loci (QTL) for canine hip dysplasia (CHD) in German Shepherd Dogs.PloS one · 2014Article
- Effects of isoform-selective phosphatidylinositol 3-kinase inhibitors on osteoclasts: actions on cytoskeletal organization, survival, and resorption.The Journal of biological chemistry · 2013Article
- The role of E3 ubiquitin ligase Cbl proteins in β-elemene reversing multi-drug resistance of human gastric adenocarcinoma cells.International journal of molecular sciences · 2013Article
- TULA-2, a novel histidine phosphatase, regulates bone remodeling by modulating osteoclast function.Cellular and molecular life sciences : CMLS · 2013Article
- E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis.Cell death & disease · 2013Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Cbl is an adaptor protein and an E3 ligase that plays both positive and negative roles in several signaling pathways that affect various cellular functions. Tyrosine 737 is unique to Cbl and is phosphorylated by Syk and Src family kinases. Phosphorylated Cbl Tyr(737) creates a binding site for the p85 regulatory subunit of PI3K, which also plays an important role in the regulation of bone resorption by osteoclasts. To investigate the role of Cbl-PI3K interaction in bone homeostasis, we examined the knock-in mice (Cbl(YF/YF)) in which the PI3K binding site in Cbl is ablated due to the mutation in the regulatory tyrosine. We report that in Cbl(YF/YF) mice, despite increased numbers of osteoclasts, bone volume is increased due to defective osteoclast function. Additionally, in ex vivo cultures, mature Cbl(YF/YF) osteoclasts showed an increased ability to survive in the presence of RANKL due to delayed onset of apoptosis. RANKL-mediated signaling is perturbed in Cbl(YF/YF) osteoclasts, and most interestingly, AKT phosphorylation is up-regulated, suggesting that the lack of PI3K sequestration by Cbl results in increased survival and decreased bone resorption. Cumulatively, these in vivo and in vitro results show that, on one hand, binding of Cbl to PI3K negatively regulates osteoclast differentiation, survival, and signaling events (e.g. AKT phosphorylation), whereas on the other hand it positively influences osteoclast function.
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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.