c-Cbl Promotes T Cell Receptor-induced Thymocyte Apoptosis by Activating the Phosphatidylinositol 3-Kinase/Akt Pathway

Thien, Christine B.F.; Dagger, Samantha A.; Steer, James H.; Köentgen, Frank; Jansen, Elisa S.; Scott, Clare L.; Langdon, Wallace Y.

doi:10.1074/jbc.m109.094920

Cited by 19 publications

(33 citation statements)

References 44 publications

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“…Recently, it was demonstrated that in thymocytes, abrogation of Cbl-PI3K interaction in mice resulted in a significant decrease in AKT phosphorylation (51). Intriguingly, our results demonstrate that phosphorylation of AKT, both basal and RANKL-induced, was enhanced in Cbl YF/YF OCLs compared with WT cells, whereas the expression of AKT was similar in both cell types (Fig.…”

Section: Volume 285 • Number 47 • November 19 2010supporting

confidence: 45%

“…Indeed, AKT phosphorylation was previously linked to Cbl-PI3K interaction in thymocytes using a Cbl RING mutant (54). Recently, it was shown that the lack of Tyr 737 in Cbl, which prevents Cbl-PI3K interaction, renders activation of AKT in response to T-cell receptor stimulation weak and transient, in contrast to a normally robust and sustained AKT activation (51). Therefore, it appears that in osteoclasts, the role of Cbl in the PI3K-mediated binding is distinct from that in thymocytes.…”

Section: Discussionmentioning

confidence: 99%

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The Loss of Cbl-Phosphatidylinositol 3-Kinase Interaction Perturbs RANKL-mediated Signaling, Inhibiting Bone Resorption and Promoting Osteoclast Survival

Adapala

Barbe

Langdon

et al. 2010

Journal of Biological Chemistry

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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.Bone is a dynamic tissue that maintains both physical integrity and calcium homeostasis and is continuously remodeled throughout the lifetime of mammals. Bone integrity is maintained by the coordinated regulation of two cell types, osteoblasts and osteoclasts. Osteoblasts are of mesenchymal origin and are responsible for mineralizing the bone matrix. Osteoclasts are of hematopoietic origin and are highly specialized multinucleated cells capable of resorbing bone during the normal and pathological conditions (1). Cbl and Cbl-b are mammalian members of a family of adaptor proteins with E3 ubiquitin ligase activity that down-regulate signaling from tyrosine kinases by targeting the ubiquitylating machinery to the activated kinases and associated proteins (2, 3). Cbl proteins, being multivalent adaptors, also promote assembling of signaling complexes downstream of several receptors, including the macrophage colony-stimulating factor receptor (c-Fms), receptor activator of NFB (RANK), 2 and integrins (2). Tyrosine phosphorylation of Cbl upon receptor activation is one of the most common signaling phenomena shown to be crucial not only for its E3 ubiquitin ligase activity but also for its adaptor effects. All Cbl family members, including Cbl and Cbl-b, share a tyrosine kinase binding domain and RING domain that binds to ubiquitin-conjugating enzymes (E2s). The tyrosine kinase binding domain and the RING are highly conserved N-terminal halves of the Cbl family proteins. The C-terminal halves of Cbl and Cbl-b are much less conserved, with significant homology found primarily in short proline-rich motifs...

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Section: Volume 285 • Number 47 • November 19 2010supporting

confidence: 45%

Section: Discussionmentioning

confidence: 99%

The Loss of Cbl-Phosphatidylinositol 3-Kinase Interaction Perturbs RANKL-mediated Signaling, Inhibiting Bone Resorption and Promoting Osteoclast Survival

Adapala

Barbe

Langdon

et al. 2010

Journal of Biological Chemistry

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“…Interestingly, C379A mutant mice appear to develop MPD (13). A mutation in one of the key tyrosine residues in the C-terminal region (Y737F mutation) does not appear to lead to significant lymphoid/hematological phenotypes (32). Recently, Bandi and colleagues used retrovirus-mediated gene transfer to assess the consequences of introducing the 70Z Cbl (linker deNaramura et al…”

Section: Discussionmentioning

confidence: 99%

Rapidly fatal myeloproliferative disorders in mice with deletion of Casitas B-cell lymphoma (Cbl) and Cbl-b in hematopoietic stem cells

Naramura

Nandwani

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Casitas B-cell lymphoma (Cbl)-family E3 ubiquitin ligases are negative regulators of tyrosine kinase signaling. Recent work has revealed a critical role of Cbl in the maintenance of hematopoietic stem cell (HSC) homeostasis, and mutations in CBL have been identified in myeloid malignancies. Here we show that, in contrast to Cbl or Cbl-b single-deficient mice, concurrent loss of Cbl and Cbl-b in the HSC compartment leads to an early-onset lethal myeloproliferative disease in mice. Cbl, Cbl-b double-deficient bone marrow cells are hypersensitive to cytokines, and show altered biochemical response to thrombopoietin. Thus, Cbl and Cbl-b play redundant but essential roles in HSC regulation, whose breakdown leads to hematological abnormalities that phenocopy crucial aspects of mutant Cbl-driven human myeloid malignancies.ubiquitin ligase | leukemia M embers of the Casitas B-cell lymphoma (Cbl) protein family are critical negative regulators of protein tyrosine kinase (PTK)-mediated signal transduction pathways (1-3). An N-terminal tyrosine kinase binding (TKB) domain, composed of a four-helical bundle, a calcium-binding EF hand, and a variant SH2 domain, mediates specific docking of Cbl proteins on activated PTKs (and some nonkinase components of PTK signaling pathways) through cognate phosphotyrosine-containing motifs. A short linker region and a RING finger domain immediately C-terminal to the TKB domain mediate interaction with E2 ubiquitin-conjugating enzymes and are essential for E3 activity of Cbl proteins.In the past few years, several groups have reported mutations of the CBL gene in a subset of patients with myeloid neoplasms (4-13). A large proportion of CBL mutations is associated with myelodysplastic syndrome/myeloproliferative disorder (MDS/ MPD), a heterogeneous group of hematopoietic malignancies characterized by deregulated hematopoiesis and a high propensity to develop acute myeloid leukemia (AML). Strikingly, CBL mutations have been identified in more than 10% of patients with juvenile myelomonocytic leukemia (JMML), a pediatric subtype of MDS/MPD with excessive proliferation of myelomonocytic cells and hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). In both adult and pediatric cases, a majority of the CBL mutations cluster within the linker and RING finger domains. Interestingly, only rare CBLB mutations have been detected in these studies, although not all studies have looked for such mutations.Why mutations in CBL are specifically associated with MDS/ MPD and how these mutations produce the disease are of obvious interest. A recent study has demonstrated that Cbl protein functions to limit the size of the hematopoietic stem cell (HSC) compartment, and that Cbl-null mice show an expansion of HSCs with an enhanced ability to mediate long-term bone marrow repopulation (14). However, Cbl-null animals develop only mild, nonlethal MPD, indicating that other factors are involved. A unique feature of patient-derived CBL mutations is their frequent association with uniparenta...

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“…For example, c-Cbl and the ElonginB/C-Cullin2-CIS E3 ligase have been found to promote Bim degradation (Thien et al, 2010; Zhang et al, 2008). However, controversial results have been reported by different groups, thereby refuting a possible physiological role of either c-Cbl or CIS in Bim ubiquitination (Akiyama et al, 2003; Wiggins et al, 2007).…”

Section: Cdc20 Exerts Its Biological Functions Largely By Targetinmentioning

confidence: 99%

Targeting Cdc20 as a novel cancer therapeutic strategy

Wang

Zhang

Wan

et al. 2015

Pharmacology & Therapeutics

207

176

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The Anaphase Promoting Complex (APC, also called APC/C) regulates cell cycle progression by forming two closely related, but functionally distinct E3 ubiquitin ligase sub-complexes, APCCdc20 and APCCdh1, respectively. Emerging evidence has begun to reveal that Cdc20 and Cdh1 have opposing functions in tumorigenesis. Specifically, Cdh1 functions largely as a tumor suppressor, whereas Cdc20 exhibits an oncogenic function, suggesting that Cdc20 could be a promising therapeutic target for combating human cancer. However, the exact underlying molecular mechanisms accounting for their differences in tumorigenesis remain largely unknown. Therefore, in this review, we summarize the downstream substrates of Cdc20 and the critical functions of Cdc20 in cell cycle progression, apoptosis, ciliary disassembly and brain development. Moreover, we briefly describe the upstream regulators of Cdc20 and the oncogenic role of Cdc20 in a variety of human malignancies. Furthermore, we summarize multiple pharmacological Cdc20 inhibitors including TAME and Apcin, and their potential clinical benefits. Taken together, development of specific Cdc20 inhibitors could be a novel strategy for the treatment of human cancers with elevated Cdc20 expression.

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c-Cbl Promotes T Cell Receptor-induced Thymocyte Apoptosis by Activating the Phosphatidylinositol 3-Kinase/Akt Pathway

Cited by 19 publications

References 44 publications

The Loss of Cbl-Phosphatidylinositol 3-Kinase Interaction Perturbs RANKL-mediated Signaling, Inhibiting Bone Resorption and Promoting Osteoclast Survival

The Loss of Cbl-Phosphatidylinositol 3-Kinase Interaction Perturbs RANKL-mediated Signaling, Inhibiting Bone Resorption and Promoting Osteoclast Survival

Rapidly fatal myeloproliferative disorders in mice with deletion of Casitas B-cell lymphoma (Cbl) and Cbl-b in hematopoietic stem cells

Targeting Cdc20 as a novel cancer therapeutic strategy

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