Gene Summary

Gene:CBL; Cbl proto-oncogene
Aliases: CBL2, NSLL, C-CBL, RNF55, FRA11B
Summary:This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase CBL
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Acute Myeloid Leukaemia (AML)CBL and Acute Myeloid Leukaemia View Publications54
Breast CancerProto-Oncogene Proteins c-cbl and Breast Cancer View Publications34
Lung CancerCBL and Lung Cancer View Publications30
Myelodysplastic SyndromesCBL and Myelodysplastic Syndromes View Publications21
Stomach CancerProto-Oncogene Proteins c-cbl and Stomach Cancer View Publications22
Noonan SyndromeCBL mutation in Noonan Syndrome
Noonan Syndrome is an autosamal dominant multi-system disorder, characterised by facial anomalies, short stature, developmental delay, cardiac abnormalities and other symptoms. The syndrome pre-disposes to myeloproliferative disorders ( mainly chronic myeolomonocytic leukemia / juvenile myelomonocytic leukemia and acute lymphoblastic leukemia), with reports of neuroblastoma, rhabdomyosarcoma and a wide range of other tumors.
View Publications3
-Proto-Oncogene Proteins c-cbl and Noonan Syndrome View Publications3
von Hippel-Lindau DiseaseProto-Oncogene Proteins c-cbl and von Hippel-Lindau Disease View Publications1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CBL (cancer-related)

Blasco-Benito S, Moreno E, Seijo-Vila M, et al.
Therapeutic targeting of HER2-CB
Proc Natl Acad Sci U S A. 2019; 116(9):3863-3872 [PubMed] Free Access to Full Article Related Publications
Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB

Qi HY, Qu XJ, Liu J, et al.
Bufalin induces protective autophagy by Cbl-b regulating mTOR and ERK signaling pathways in gastric cancer cells.
Cell Biol Int. 2019; 43(1):33-43 [PubMed] Related Publications
Bufalin, a natural small-molecule compound derived from the traditional Chinese medicine Chan su, has shown promising anti-cancer effects against a broad variety of cancer cells through different mechanisms. It has been reported to induce autophagy in gastric cancer cells. However, the molecular mechanism involved is not fully elucidated. In the present study, we aimed to investigate the molecular mechanism by which bufalin induce autophagy in human gastric cancer cells. We found that bufalin induced apoptosis and autophagy in gastric cancer cells, and autophagy prevented human gastric cancer cells from undergoing apoptosis. Bufalin treatment changed the expression of autophagy-related proteins. Moreover, phosphorylated Akt, mTOR, and p70S6K were all significantly decreased, while phosphorylated ERK1/2 was increased by bufalin. Pretreatment of MGC803 cells with the ERK1/2-specific inhibitor PD98059 led to the down-regulation of LC3 II. Further study showed that Cbl-b positively regulated autophagy by suppressing mTOR and enhancing ERK1/2 activation. Therefore, our data provide evidence that bufalin induces autophagy in MGC803 cells via both Akt/mTOR/p70S6K and ERK signaling pathways, and Cbl-b-mediated suppression of mTOR and activation of ERK1/2 might play an important role.

Ishaque N, Abba ML, Hauser C, et al.
Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer.
Nat Commun. 2018; 9(1):4782 [PubMed] Free Access to Full Article Related Publications
Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3' UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3' UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy.

Wang M, Chen B, Ru Z, Cong L
CircRNA circ-ITCH suppresses papillary thyroid cancer progression through miR-22-3p/CBL/β-catenin pathway.
Biochem Biophys Res Commun. 2018; 504(1):283-288 [PubMed] Related Publications
While recent evidence has uncovered that circular RNAs (circRNAs) are vital regulators of carcinogenesis, their role in papillary thyroid cancer (PTC) is not clearly understood. In this study, we reveal that lower levels of circRNA circ-ITCH are expressed in PTC tissues than in normal adjacent tissues. Gain-of-functional assays show that circ-ITCH overexpression suppresses PTC cell proliferation and invasion and promotes apoptosis in vitro. Overexpression of circ-ITCH also leads to impaired tumor growth in vivo. Bioinformatics analysis and luciferase reporter assays demonstrate that circ-ITCH sponges miR-22-3p to upregulate the expression of CBL, an E3 ligase of nuclear β-catenin. Elevated levels of CBL suppress activation of the Wnt/β-catenin pathway and consequently attenuates PTC progression. In summary, our study reveals a novel signaling pathway of circ-ITCH/miR-22-3p/CBL/β-catenin involved in PTC development and progression.

Kumaradevan S, Lee SY, Richards S, et al.
c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/β-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation.
Am J Pathol. 2018; 188(8):1921-1933 [PubMed] Free Access to Full Article Related Publications
The proto-oncogene β-catenin drives colorectal cancer (CRC) tumorigenesis. Casitas B-lineage lymphoma (c-Cbl) inhibits CRC tumor growth through targeting nuclear β-catenin by a poorly understood mechanism. In addition, the role of c-Cbl in human CRC remains largely underexplored. Using a novel quantitative histopathologic technique, we demonstrate that patients with high c-Cbl-expressing tumors had significantly better median survival (3.7 years) compared with low c-Cbl-expressing tumors (1.8 years; P = 0.0026) and were more than twice as likely to be alive at 3 years compared with low c-Cbl tumors (P = 0.0171). Our data further demonstrate that c-Cbl regulation of nuclear β-catenin requires phosphorylation of c-Cbl Tyr371 because its mutation compromises its ability to target β-catenin. The tyrosine 371 (Y371H) mutant interacted with but failed to ubiquitinate nuclear β-catenin. The nuclear localization of the c-Cbl-Y371H mutant contributed to its dominant negative effect on nuclear β-catenin. The biological importance of c-Cbl-Y371H was demonstrated in various systems, including a transgenic Wnt-8 zebrafish model. c-Cbl-Y371H mutant showed augmented Wnt/β-catenin signaling, increased Wnt target genes, angiogenesis, and CRC tumor growth. This study demonstrates a strong link between c-Cbl and overall survival of patients with CRC and provides new insights into a possible role of Tyr371 phosphorylation in Wnt/β-catenin regulation, which has important implications in tumor growth and angiogenesis in CRC.

Zhang T, Zheng C, Hou K, et al.
Suppressed expression of Cbl-b by NF-κB mediates icotinib resistance in EGFR-mutant non-small-cell lung cancer.
Cell Biol Int. 2019; 43(2):98-107 [PubMed] Related Publications
Although epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) could greatly improve the prognosis of NSCLC patients harboring activating EGFR mutations, drug resistance still remains a major obstacle to successful treatment. Our previous study found that the EGFR-TKI icotinib could upregulate the expression of Casitas-B-lineage lymphoma protein-B (Cbl-b), an E3 ubiquitin ligase. In the present study, we aimed to clarify the potential role of Cbl-b in the resistance to icotinib, and the underlying mechanisms using EGFR-mutant cell lines. We found that icotinib inhibited the proliferation of mutant-EGFR NSCLC cells (PC9 and HCC827), and upregulated the expression of Cbl-b at both the protein and mRNA levels. Cbl-b knockdown decreased the sensitivity of PC9 and HCC827 cells to icotinib, and partially restored icotinib-inhibited AKT activation in PC9 cells. On the contrary, Cbl-b overexpression could partly reverse the drug resistance in PC9 icotinib-resistant cells (PC9/IcoR). Moreover, overexpressing p65, the main member of transcription factor NF-κB family, reversed the icotinib-mediated upregulation of Cbl-b. Collectively, these data suggest that icotinib could upregulate Cbl-b mediated by NF-κB inhibition, and Cbl-b contribute to the icotinib sensitivity in EGFR-mutant NSCLC cells. This study highlights that low expression of Cbl-b might be the key obstacles in the efficacy of icotinib therapy.

Li C, Dong Q, Che X, et al.
MicroRNA-29b-2-5p inhibits cell proliferation by directly targeting Cbl-b in pancreatic ductal adenocarcinoma.
BMC Cancer. 2018; 18(1):681 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs can be used in the prognosis of malignancies; however, their regulatory mechanisms are unknown, especially in pancreatic ductal adenocarcinoma (PDAC).
METHODS: In 120 PDAC specimens, miRNA levels were assessed by quantitative real time polymerase chain reaction (qRT-PCR). Then, the role of miR-29b-2-5p in cell proliferation was evaluated both in vitro (Trypan blue staining and cell cycle analysis in the two PDAC cell lines SW1990 and Capan-2) and in vivo using a xenograft mouse model. Next, bioinformatics methods, a luciferase reporter assay, Western blot, and immunohistochemistry (IHC) were applied to assess the biological effects of Cbl-b inhibition by miR-29b-2-5p. Moreover, the relationship between Cbl-b and p53 was evaluated by immunoprecipitation (IP), Western blot, and immunofluorescence.
RESULTS: From the 120 PDAC patients who underwent surgical resection, ten patients with longest survival and ten with shortest survival were selected. We found that high miR-29b-2-5p expression was associated with good prognosis (p = 0.02). The validation cohort confirmed miR-29b-2-5p as an independent prognostic factor in PDAC (n = 100, 95% CI = 0.305-0.756, p = 0.002). Furthermore, miR-29b-2-5p inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis both in vivo and in vitro. Interestingly, miR-29b-2-5p directly bound the Cbl-b gene, down-regulating its expression and reducing Cbl-b-mediated degradation of p53. Meanwhile, miR-29b-2-5p expression was negatively correlated with Cbl-b in PDAC tissues (r = - 0.33, p = 0.001).
CONCLUSIONS: Taken together, these findings indicated that miR-29b-2-5p improves prognosis in PDAC by targeting Cbl-b to promote p53 expression, and would constitute an important prognostic factor in PDAC.

Lee GW, Park JB, Park SY, et al.
The E3 ligase C-CBL inhibits cancer cell migration by neddylating the proto-oncogene c-Src.
Oncogene. 2018; 37(41):5552-5568 [PubMed] Related Publications
Neddylation is a cellular process that covalently conjugates substrate proteins with the small ubiquitin-like molecule NEDD8. As neddylation is required for fast turnover of proteins in proliferating cancer cells, the neddylation process is currently regarded as a potential target for cancer therapy. However, little is known about the role of neddylation in cancer invasion and metastasis. Unexpectedly, we here found that the neddylation blockade stimulates migration of lung cancer and glioblastoma cells. Mechanistically, C-CBL acts as the E3 ligase for neddylation of the proto-oncogene c-Src. After neddylation, c-Src is poly-ubiquitinated and degraded through the proteasome, which inhibits the PI3K-AKT pathway responsible for cell migration. In human lung cancer tissues, the downregulation of C-CBL was associated with c-Src/AKT, cancer metastasis, and poor survival in patients. Therefore, C-CBL is likely to play a tumor suppressive role by antagonizing a robust oncogenic signaling driven by c-Src. This study provides new insight about the role of neddylation in cancer metastasis. It also implies that the metastasis risk should be carefully evaluated before the clinical application of neddylation inhibitors as anticancer regimens.

Li W, Xu L, Che X, et al.
C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.
BMC Cancer. 2018; 18(1):507 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance.
METHODS: MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth.
RESULTS: MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression.
CONCLUSIONS: Our results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells by inhibiting the formation of the ER-c-Src-HER2 complex.

Alon M, Emmanuel R, Qutob N, et al.
Refinement of the endogenous epitope tagging technology allows the identification of a novel NRAS binding partner in melanoma.
Pigment Cell Melanoma Res. 2018; 31(5):641-648 [PubMed] Free Access to Full Article Related Publications
The NRAS oncoprotein is highly mutated in melanoma. However, to date, no comprehensive proteomic study has been reported for NRAS. Here, we utilized the endogenous epitope tagging (EET) approach for the identification of novel NRAS binding partners. Using EET, an epitope tag is added to the endogenously expressed protein, via modification of its genomic coding sequence. Existing EET systems are not robust, suffer from high background, and are labor-intensive. To this end, we present a polyadenylation signal-trap construct for N'-tagging that generates a polycistronic mRNA with the gene of interest. This system requires the integration of the tagging cassette in frame with the target gene to be expressed. Using this design, we demonstrate, for the first time, endogenous tagging of NRAS in melanoma cells allowing the identification of the E3 ubiquitin ligase c-CBL as a novel NRAS binding partner. Thus, our developed EET technology allows the characterization of new RAS effectors, which could be beneficial for the design of future drugs that inhibit constitutive signaling of RAS oncogenic mutants.

Shrestha N, Shrestha H, Ryu T, et al.
δ-Catenin Increases the Stability of EGFR by Decreasing c-Cbl Interaction and Enhances EGFR/Erk1/2 Signaling in Prostate Cancer.
Mol Cells. 2018; 41(4):320-330 [PubMed] Free Access to Full Article Related Publications
δ-Catenin, a member of the p120-catenin subfamily of armadillo proteins, reportedly increases during the late stage of prostate cancer. Our previous study demonstrates that δ-catenin increases the stability of EGFR in prostate cancer cell lines. However, the molecular mechanism behind δ-catenin-mediated enhanced stability of EGFR was not explored. In this study, we hypothesized that δ-catenin enhances the protein stability of EGFR by inhibiting its lysosomal degradation that is mediated by c-casitas b-lineage lymphoma (c-Cbl), a RING domain E3 ligase. c-Cbl monoubiquitinates EGFR and thus facilitates its internalization, followed by lysosomal degradation. We observed that δ-catenin plays a key role in EGFR stability and downstream signaling. δ-Catenin competes with c-Cbl for EGFR binding, which results in a reduction of binding between c-Cbl and EGFR and thus decreases the ubiquitination of EGFR. This in turn increases the expression of membrane bound EGFR and enhances EGFR/Erk1/2 signaling. Our findings add a new perspective on the role of δ-catenin in enhancing EGFR/Erk1/2 signaling-mediated prostate cancer.

Watanabe J, Sato K, Osawa Y, et al.
CBL mutation and MEFV single-nucleotide variant are important genetic predictors of tumor reduction in glucocorticoid-treated patients with chronic myelomonocytic leukemia.
Int J Hematol. 2018; 108(1):47-57 [PubMed] Related Publications
Glucocorticoid (GC) therapy occasionally relieves tumor-related fever and promotes tumor reduction in patients with chronic myelomonocytic leukemia (CMML). A mutation analysis of 24 patients with CMML revealed the relationship of GC effectiveness, defined as a monocyte reduction of > 50% within 3 days of methylprednisolone administration, with the MEFV single-nucleotide variant (SNV) and CBL mutation. Lipopolysaccharide-stimulated monocytes harboring MEFV E148Q produced greater amounts of IL-1β and TNF-α than did wild-type monocytes; this was effectively suppressed by GC. Primary CMML cells harboring the MEFV SNV and CBL mutation, and the myelomonocytic leukemia cell line GDM-1, harboring the CBL mutation, were both more significantly suppressed than non-mutated cells following GC treatment in the presence of GM-CSF. A loss-of-function CBL mutation prolonged STAT5 phosphorylation after GM-CSF stimulation, which was rapidly terminated in both patient samples and GDM-1 cells. In conclusion, GC therapy effectively treats CMML cells harboring the MEFV SNV and CBL mutation by reducing inflammatory cytokine production and terminating prolonged STAT5 phosphorylation in the GM-CSF signaling pathway.

Li P, Liu H, Zhang Z, et al.
Expression and Comparison of Cbl-b in Lung Squamous Cell Carcinoma and Adenocarcinoma.
Med Sci Monit. 2018; 24:623-635 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Non-small cell lung carcinoma (NSCLC) mainly includes lung squamous cell carcinoma and adenocarcinoma. This study aimed to investigate the difference between the expression of Cbl-b in lung squamous cell carcinoma and adenocarcinoma. MATERIAL AND METHODS The clinical features and survival data of NSCLC patients and Cbl-b mRNA (FPKM) were obtained from the TCGA database. Then, lung squamous cell carcinoma and adenocarcinoma cell lines were transfected with lentivirus-mediated RNA interference vector to knockdown the expression of Cbl-b. Next, a Transwell assay was performed to study the effect of Cbl-b shRNA on migration and invasion of lung squamous cell carcinoma and adenocarcinoma cells. Finally, Western blot analysis was performed to measure the expressions of PI3K, p-PI3K, AKT, p-AKT, ERK1/2, p-ERK1/2, GSK3β, p-GSK3β, mTOR, and p-mTOR protein in lung adenocarcinoma and squamous cell carcinoma cells. RESULTS The correlation of Cbl-b expression and OS was different between NSCLC adenocarcinoma and squamous carcinoma. After transfection, the expression of Cbl-b was inhibited in A549, H1975, and SW900 cells. Cbl-b shRNA promoted the migration and invasion of lung adenocarcinoma A549 and H1975 cells, but it inhibited the invasion of lung squamous cell carcinoma SW900 cells. In addition, Cbl-b regulated the expression of PI3K and ERK1/2-GSK3β pathway proteins in A549 and SW900 cells. CONCLUSIONS The OS of Cbl-b mRNA low expression in lung adenocarcinoma and squamous cell carcinoma was different. The difference in signal pathways may be one of the reasons for the difference in the correlation between Cbl-b expression and the survival rate of these 2 pathological types of lung cancer.

Wang S, Xu L, Che X, et al.
E3 ubiquitin ligases Cbl-b and c-Cbl downregulate PD-L1 in EGFR wild-type non-small cell lung cancer.
FEBS Lett. 2018; 592(4):621-630 [PubMed] Related Publications
Anti-PD-1/PD-L1 therapies have demonstrated prominent clinical effects in the treatment of non-small cell lung cancer (NSCLC). However, limited understanding of the regulatory mechanisms of PD-L1 has become one of the biggest challenges for further improving efficacy. In this study, we observed that in wild-type EFGR cell lines A549 and H460, the ubiquitin ligases Cbl-b and c-Cbl inhibit PD-L1 by inactivating STAT, AKT, and ERK signaling. MiR-181a and miR-940 were screened and validated to target Cbl-b and c-Cbl, respectively. Furthermore, in NSCLC tissues, the expression of Cbl-b/c-Cbl is negatively correlated with PD-L1 expression. Taken together, these findings indicated a new regulatory mechanism for PD-L1 in wild-type EGFR NSCLC cell lines by Cbl-b and c-Cbl.

Luo P, Wang X, Zhou J, et al.
C-Cbl and Cbl-b expression in skull base chordomas is associated with tumor progression and poor prognosis.
Hum Pathol. 2018; 74:129-134 [PubMed] Related Publications
Chordomas are rare, locally aggressive malignancies that are often difficult to eradicate. Surgery and radiotherapy are the first-line treatments, but the probability of local recurrence is high. According to our previous research, c-Cbl and Cbl-b have been linked to tumor progression and poor prognosis of glioma. However, their role in skull base chordomas is unclear. To clarify this issue, in the present study, we analyzed the expression of c-Cbl and Cbl-b in relation to the clinicopathological features and clinical outcome of skull base chordoma patients (n = 70). C-Cbl and Cbl-b expression was evaluated by immunohistochemistry, and a survival analysis was performed based on clinical data. We found that c-Cbl and Cbl-b were upregulated in 30 of 70 (42.9%) and 32 of 70 (45.7%) patients with skull base chordomas, respectively. A Kaplan-Meier analysis and log-rank test indicated that high c-Cbl and Cbl-b levels were significantly associated with overall survival (P = .003 and P = .008, respectively) and progression-free survival (P < .001 and P = .022, respectively). These data indicated that c-Cbl and Cbl-b expression in skull base chordomas can predict tumor invasion and poor prognosis and is therefore a potential therapeutic target for chordoma treatment.

Lipka DB, Witte T, Toth R, et al.
RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia.
Nat Commun. 2017; 8(1):2126 [PubMed] Free Access to Full Article Related Publications
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

Jack J, Small GW, Brown CC, et al.
Gene expression and linkage analysis implicate CBLB as a mediator of rituximab resistance.
Pharmacogenomics J. 2018; 18(3):467-473 [PubMed] Free Access to Full Article Related Publications
Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells. This study demonstrates the utility of genome-wide mapping to discover novel biological mechanisms of potential clinical advantage.

Wang J, Wang X, Chen T, et al.
Huaier Extract Inhibits Breast Cancer Progression Through a LncRNA-H19/MiR-675-5p Pathway.
Cell Physiol Biochem. 2017; 44(2):581-593 [PubMed] Related Publications
BACKGROUND/AIMS: Increasing evidence indicates that Huaier extract has promising therapeutic effects against cancer. However, the mechanisms that underlie its anti-tumor effects remain unclear. In recent years, various studies have shown that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cancer development and progression. Here, we explored the role of lncRNAs in Huaier-induced tumor suppression.
METHODS: Microarray profiling was performed to identify the candidate lncRNAs affected by Huaier extract. Quantitative realtime PCR (qPCR) was used to evaluate the transfection efficiency and the influence of Huaier extract on H19 expression. The effect of Huaier extract on the cell viability was examined by MTT. Moreover, the rates of apoptotic cells were detected using flow-cytometric analysis. Western blot analysis was applied to show the protein levels of CBL.
RESULTS: Microarray data derived from Huaier-treated breast cancer cells identified H19 as a potential target. Huaier extract reduced the expression of H19. The over-expression of H19 inhibited the cytotoxic effects of Huaier extract; in contrast, reduced H19 expression enhanced the function of Huaier extract. MiR-675-5p was identified as a mature product of H19. Moreover, Huaier extract reduced the miR-675-5p expression. Upregulating miR-675-5p reversed the inhibitory effects of Huaier extract, whereas downregulating miR-675-5p sensitized breast cancer cells to the effect of Huaier extract. In addition, Huaier extract increased the expression of CBL protein, a direct target of miR-675-5p.
CONCLUSION: Collectively, the data demonstrate that Huaier extract reduces viability and induces apoptosis in breast cancer cells via H19-miR-675-5p-CBL axis regulation.

Robles-Valero J, Lorenzo-Martín LF, Menacho-Márquez M, et al.
A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia.
Cancer Cell. 2017; 32(5):608-623.e9 [PubMed] Free Access to Full Article Related Publications
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX

Xu L, Zhang Y, Qu X, et al.
DR5-Cbl-b/c-Cbl-TRAF2 complex inhibits TRAIL-induced apoptosis by promoting TRAF2-mediated polyubiquitination of caspase-8 in gastric cancer cells.
Mol Oncol. 2017; 11(12):1733-1751 [PubMed] Free Access to Full Article Related Publications
Ubiquitination of caspase-8 regulates TNF-related apoptosis-inducing ligand (TRAIL) sensitivity in cancer cells, and the preligand assembly complex plays a role in caspase-8 polyubiquitination. However, whether such a complex exists in gastric cancer cells and its role in TRAIL-triggered apoptosis is unclear. In this study, DR5, casitas B-lineage lymphoma-b (Cbl-b)/c-Cbl, and TRAF2 formed a complex in TRAIL-resistant gastric cancer cells, and Cbl-b and c-Cbl were the critical adaptors linking DR5 and TRAF2. Treatment with TRAIL induced caspase-8 translocation into the DR5-Cbl-b/c-Cbl-TRAF2 complex to interact with TRAF2, which then mediated the K48-linked polyubiquitination of caspase-8. The proteasome inhibitor bortezomib markedly enriched the p43/41 products of caspase-8 activated by TRAIL, indicating proteasomal degradation of caspase-8. Moreover, TRAF2 knockdown prevented the polyubiquitination of caspase-8 and thus increased TRAIL sensitivity. In addition, the inhibition of Cbl-b or c-Cbl expression and overexpression of miR-141 targeting Cbl-b and c-Cbl partially reversed TRAIL resistance by inhibiting the interaction between TRAF2 and caspase-8 and the subsequent polyubiquitination of caspase-8. These results indicate that the DR5-Cbl-b/c-Cbl-TRAF2 complex inhibited TRAIL-induced apoptosis by promoting TRAF2-mediated polyubiquitination of caspase-8 in gastric cancer cells.

Märklin M, Heitmann JS, Fuchs AR, et al.
NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia.
Nat Commun. 2017; 8(1):755 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.

CHe X, Zhang Y, Qu X, et al.
The E3 ubiquitin ligase Cbl-b inhibits tumor growth in multidrug-resistant gastric and breast cancer cells.
Neoplasma. 2017; 64(6):887-892 [PubMed] Related Publications
Most receptor tyrosine kinases (RTKs) contribute to tumor growth, and their ubiquitination and degradation is related to the inhibition of tumor growth. Our previous study showed that the ubiquitin ligase Cbl-b was expressed at low levels in multidrug-resistant (MDR) gastric cancer cells compared with their parental cells. However, whether enhancement of Cbl-b expression in MDR cancer cells could prevent tumor proliferation via ubiquitination and degradation of RTK remains unclear. In the present study, Cbl-b overexpression reduced cell proliferation in MDR gastric and breast cancer cells, and effectively inhibited tumor growth in vivo. Additionally, Cbl-b overexpression reduced the total protein level of insulin-like growth factor 1 (IGF-1R), an important member of the RTK family. Moreover, Cbl-b overexpression promoted interaction of Cbl-b with IGF-1R, and induced ubiquitination and degradation of IGF-1R and inactivation of the IGF-1R pathway. These results suggest that the ubiquitin ligase Cbl-b inhibited tumor growth via ubiquitination and degradation of IGF-1R in MDR gastric and breast cancer cells.

Tan YC, Mirzapoiazova T, Won BM, et al.
Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL.
Sci Rep. 2017; 7(1):9192 [PubMed] Free Access to Full Article Related Publications
Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase and a molecule of adaptor that we have shown is important for non-small-cell lung cancer (NSCLC). We investigated if MET is a target of CBL and if enhanced in CBL-altered NSCLC. We showed that CBL wildtype cells have lower MET expression than CBL mutant cells. Ubiquitination of MET was also decreased in CBL mutant cells compared to wildtype cells. Mutant cells were also more sensitive to MET inhibitor SU11274 than wild-type cells. sh-RNA-mediated knockdown of CBL enhanced cell motility and colony formation in NSCLC cells, and these activities were inhibited by SU11274. Assessment of the phospho-kinome showed decreased phosphorylation of pathways involving MET, paxillin, EPHA2, and VEGFR. When CBL was knocked down in the mutant cell line H1975 (erlotinib-resistant), it became sensitive to MET inhibition. Our findings suggest that CBL status is a potential positive indicator for MET-targeted therapeutics in NSCLC.

Gainullin MR, Zhukov IY, Zhou X, et al.
Degradation of cofilin is regulated by Cbl, AIP4 and Syk resulting in increased migration of LMP2A positive nasopharyngeal carcinoma cells.
Sci Rep. 2017; 7(1):9012 [PubMed] Free Access to Full Article Related Publications
Expression of cofilin is directly associated with metastatic activity in many tumors. Here, we studied the role of Latent Membrane Protein 2 A (LMP2A) of Epstein-Barr Virus (EBV) in the accumulation of cofilin observed in nasopharyngeal cancer (NPC) tumor cells. We used LMP2A transformed NPC cell lines to analyze cofilin expression. We used mutation analysis, ectopic expression and down-regulation of Cbl, AIP4 and Syk in these cell lines to determine the effect of the LMP2A viral protein on cofilin degradation and its role in the assembly of a cofilin degrading protein complex. The LMP2A of EBV was found to interfer with cofilin degradation in NPC cells by accelerating the proteasomal degradation of Cbl and Syk. In line with this, we found significantly higher cofilin expression in NPC tumor samples as compared to the surrounding epithelial tissues. Cofilin, as an actin severing protein, influences cellular plasticity, and facilitates cellular movement in response to oncogenic stimuli. Thus, under relaxed cellular control, cofilin facilitates tumor cell movement and dissemination. Interference with its degradation may enhance the metastatic potential of NPC cells.

Wills MKB, Lau HR, Jones N
The ShcD phosphotyrosine adaptor subverts canonical EGF receptor trafficking.
J Cell Sci. 2017; 130(17):2808-2820 [PubMed] Related Publications
Shc family signalling adaptors connect activated transmembrane receptors to proximal effectors, and most also contain a sequence involved in clathrin-mediated receptor endocytosis. Notably, this AP2 adaptin-binding motif (AD) is absent from the ShcD (also known as Shc4) homolog, which also uniquely promotes ligand-independent phosphorylation of the epidermal growth factor receptor (EGFR). We now report that cultured cells expressing ShcD exhibit reduced EGF uptake, commensurate with a decrease in EGFR surface presentation. Under basal conditions, ShcD colocalises with the EGFR and facilitates its phosphorylation, ubiquitylation and accumulation in juxtanuclear vesicles identified as Rab11-positive endocytic recycling compartments. Accordingly, ShcD also functions as a constitutive binding partner for the E3 ubiquitin ligase Cbl. EGFR phosphorylation and focal accumulation likewise occur upon ShcD co-expression in U87 glioma cells. Loss of ShcD phosphotyrosine-binding function or insertion of the ShcA AD sequence each restore ligand acquisition through distinct mechanisms. The AD region also contains a nuclear export signal, indicating its multifunctionality. Overall, ShcD appears to possess several molecular permutations that actively govern the EGFR, which may have implications in development and disease.

Peer S, Baier G, Gruber T
Cblb-deficient T cells are less susceptible to PD-L1-mediated inhibition.
Oncotarget. 2017; 8(26):41841-41853 [PubMed] Free Access to Full Article Related Publications
Modulation of the immune system for the treatment of primary and metastatic tumors has been a goal of cancer research for many years. The E3 ubiquitin ligase Cbl-b has been established as an intracellular checkpoint that limits T cell activation, critically contributing to the maintenance of self-tolerance. Furthermore, it has been shown that Cblb deficiency enhances T cell effector functions towards tumors. Blockade of the immune checkpoints CTLA-4 and PD-1/PD-L1 has recently emerged as a promising strategy in the development of effective cancer immune therapies. Therefore, we explored the concept of targeting different checkpoints concomitantly. Interestingly, we observed that CTLA-4 but not PD-L1 based immunotherapy selectively enhanced the anti-tumor phenotype of Cblb-deficient mice. In agreement with the in vivo results, in vitro experiments showed that Cblb-/- T cells were less susceptible to PD-L1-mediated suppression of T cell proliferation and IFNγ secretion. Taken together, our findings reveal a so far unappreciated function of Cbl-b in the regulation of PD-1 signaling in murine T cells.

Lv K, Jiang J, Donaghy R, et al.
CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies.
Genes Dev. 2017; 31(10):1007-1023 [PubMed] Free Access to Full Article Related Publications
Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of

Jiang R, Tang J, Chen Y, et al.
The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion.
Nat Commun. 2017; 8:15129 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma (HCC). Here, we show that lnc-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumour size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models. Lnc-EGFR stimulates Treg differentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner. Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression. Lnc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potential therapeutic target for HCC.

Chang CH, Bijian K, Qiu D, et al.
Endosomal sorting and c-Cbl targeting of paxillin to autophagosomes regulate cell-matrix adhesion turnover in human breast cancer cells.
Oncotarget. 2017; 8(19):31199-31214 [PubMed] Free Access to Full Article Related Publications
Post-translational mechanisms regulating cell-matrix adhesion turnover during cell locomotion are not fully elucidated. In this study, we uncovered an essential role of Y118 site-specific tyrosine phosphorylation of paxillin, an adapter protein of focal adhesion complexes, in paxillin recruitment to autophagosomes to trigger turnover of peripheral focal adhesions in human breast cancer cells. We demonstrate that the Rab-7 GTPase is a key upstream regulator of late endosomal sorting of tyrosine118-phosphorylated paxillin, which is subsequently recruited to autophagosomes via the cargo receptor c-Cbl. Essentially, this recruitment involves a direct and selective interaction between Y118-phospho-paxillin, c-Cbl, and LC3 and is independent from c-Cbl E3 ubiquitin ligase activity. Interference with the Rab7-paxillin-autophagy regulatory network using genetic and pharmacological approaches greatly impacted focal adhesion stability, cell locomotion and progression to metastasis using a panel of human breast cancer cells. Together, these results provide novel insights into the requirement of phospho-site specific post-translational mechanism of paxillin for autophagy targeting to regulate cell-matrix adhesion turnover and cell locomotion in breast cancer cells.

Xu L, Zhang Y, Qu X, et al.
E3 Ubiquitin Ligase Cbl-b Prevents Tumor Metastasis by Maintaining the Epithelial Phenotype in Multiple Drug-Resistant Gastric and Breast Cancer Cells.
Neoplasia. 2017; 19(4):374-382 [PubMed] Free Access to Full Article Related Publications
Multiple drug resistance (MDR) and metastasis are two major factors that contribute to the failure of cancer treatment. However, the relationship between MDR and metastasis has not been characterized. Additionally, the role of the E3 ubiquitin ligase Cbl-b in metastasis of MDR gastric and breast cancer is not well known. In the present study, we found that MDR gastric and breast cancer cells possess a typical mesenchymal phenotype and enhanced cell migration capacity. Additionally, Cbl-b is poorly expressed in MDR gastric and breast cancer cells. In MDR gastric adenocarcinoma tissues, gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion (P=.016) and lymph node metastasis (P=.007). Moreover, overexpression of Cbl-b reduced cell migration in MDR cell cultures both in vitro and in vivo. Cbl-b overexpression also prevented EMT by inducing ubiquitination and degradation of EGFR, leading to inhibition of the EGFR-ERK/Akt-miR-200c-ZEB1 axis. However, further overexpression of EGFR on a background of Cbl-b overexpression restored both the mesenchymal phenotype and cell migration capacity of MDR gastric and breast cancer cells. These results suggest that Cbl-b is an important factor for maintenance of the epithelial phenotype and inhibition of cell migration in MDR gastric and breast cancer cells.

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