The Cbl Family and Other Ubiquitin Ligases

Duan, Lei; Reddi, Alagarsamy Lakku; Ghosh, Amiya K.; Dimri, Manjari; Band, Hamid

doi:10.1016/j.immuni.2004.06.012

Cited by 121 publications

(29 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, if the ERK → SHP1 connection is not considered, the number of loops is reduced dramatically from 172 to 13 (with only 11 being negative), all located in the upper part of the network. c-Cbl is involved in ∼85% of them, thus underscoring the importance of c-Cbl in the regulation of signaling processes [25,26]. …”

Section: Resultsmentioning

confidence: 99%

A Logical Model Provides Insights into T Cell Receptor Signaling

et al. 2007

View full text Add to dashboard Cite

Cellular decisions are determined by complex molecular interaction networks. Large-scale signaling networks are currently being reconstructed, but the kinetic parameters and quantitative data that would allow for dynamic modeling are still scarce. Therefore, computational studies based upon the structure of these networks are of great interest. Here, a methodology relying on a logical formalism is applied to the functional analysis of the complex signaling network governing the activation of T cells via the T cell receptor, the CD4/CD8 co-receptors, and the accessory signaling receptor CD28. Our large-scale Boolean model, which comprises 94 nodes and 123 interactions and is based upon well-established qualitative knowledge from primary T cells, reveals important structural features (e.g., feedback loops and network-wide dependencies) and recapitulates the global behavior of this network for an array of published data on T cell activation in wild-type and knock-out conditions. More importantly, the model predicted unexpected signaling events after antibody-mediated perturbation of CD28 and after genetic knockout of the kinase Fyn that were subsequently experimentally validated. Finally, we show that the logical model reveals key elements and potential failure modes in network functioning and provides candidates for missing links. In summary, our large-scale logical model for T cell activation proved to be a promising in silico tool, and it inspires immunologists to ask new questions. We think that it holds valuable potential in foreseeing the effects of drugs and network modifications.

show abstract

Section: Resultsmentioning

confidence: 99%

A Logical Model Provides Insights into T Cell Receptor Signaling

et al. 2007

View full text Add to dashboard Cite

show abstract

“…c-Cbl is a E3 ubiquitin ligase that usually plays an inhibitory role during T cell activation (33). However, c-Cbl was also postulated to function as an adaptor molecule that, upon tyrosine phosphorylation, may catalyze the formation of signaling complexes and facilitate cell activation.…”

Section: Discussionmentioning

confidence: 99%

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Zhong

Veillette

2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The signaling lymphocytic activation molecule family of receptors has been implicated in the pathophysiology of autoimmunity in humans and mice. One member of the family, Ly108, was strongly linked to lupus susceptibility in mice. High expression of a Ly108 isoform, Ly108-1, was observed in lymphocytes of lupus-prone mice. Herein, we examined the molecular basis for the influence of Ly108 on lupus susceptibility by studying Ly108 signal transduction in T cells. We observed that Ly108 was able to mediate a tyrosine phosphorylation signal implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on engagement of the extracellular domain of Ly108 and co-expression of the Src homology 2 (SH2) domain-containing adaptor signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). Evaluation of T cells from mice carrying mutations in the SAP-FynT pathway indicated that Ly108-triggered protein tyrosine phosphorylation was due to the capacity of SAP to recruit FynT. Importantly, Ly108-1 was more apt at triggering tyrosine phosphorylation signals in T cells when compared with the predominant Ly108 isoform found in non-lupus-prone mice, Ly108-2. This difference was due in part to the presence in Ly108-1 of a unique intra-cytoplasmic tyrosine-based motif that promoted Ly108 signal transduction. Together these data provided a molecular explanation for the involvement of Ly108 in lupus susceptibility in mice.

show abstract

“…Recent reports show that c-cbl protein acts as a ubiquitin ligase (E3 enzyme) that binds and forms a complex with the RTKs and then facilitates the transfer of ubiquitin from ubiquitinconjugating enzymes to the RTKs (12,13). This E3 enzyme activity results in the monoubiquitylation or multiubiquitylation and further degradation of RTKs in the lysosome or proteasome.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of long-term memory retention and short-term synaptic plasticity in cbl-b null mice

Tan

Liu²,

Koshiya³

et al. 2006

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

View full text Add to dashboard Cite

The cbl-b gene is a member of the cbl protooncogene family. It encodes a protein with multiple domains, which can interact with other proteins in a variety of signaling pathways. The functions of cbl family genes in the brain are unknown. In this report, we used genetic, immunohistochemical, behavioral, and electrophysiological approaches to study the role of cbl-b in learning and memory. Cbl-b null mice developed normally and had no abnormalities in their locomotor performance. In spatial learning and memory studies, cbl-b null and WT mice performed similarly during training. To test memory retention, two probe trials were used. cbl-b null mice performed slightly better 1 day after training. However, in the probe trial 45 days after training, the cbl-b null group showed significantly higher memory retention than WT mice, suggesting an enhancement of long-term memory. Using electrophysiological approaches, we found there was enhanced paired-pulse facilitation in the Schaffer Collateral-CA1 glutamatergic synapses of the cbl-b null mice. On the other hand, there was no difference in long-term potentiation between the two groups of mice. In summary, we provide evidence that (i) cbl-b protein is concentrated in the synaptic regions of CA1, CA3, and the dentate gyrus of the hippocampus; (ii) cbl-b null mice have enhanced long-term memory; and (iii) cbl-b null mice show an enhancement in short-term plasticity. These results indicate that cbl-b is a negative regulator of long-term memory, and its neuronal mechanism regulates synaptic transmission in the hippocampus.cbl-b knockout mice ͉ hippocampus ͉ paired-pulse facilitation W ith the human and mouse genomes fully sequenced, many candidate genes that may be related to the process of learning and memory are available for gene targeting and other mutagenesis studies. Analysis of the behavioral, physiological, and biochemical consequences of these mutations will help implicate molecular pathways important for learning and memory, as well as their underlying synaptic mechanisms.Cbl-b belongs to the cbl-protooncogene family. It contains multiple functional domains, including a tyrosine kinase-binding (TKB) domain, a RING-finger domain, and a proline-rich region, as well as an ubiquitin-associated domain. The TKB domain has been shown to recognize specific phosphotyrosine residues on activated tyrosine kinases (1, 2). The RING-finger domain is the site whereby cbl family proteins recruit ubiquitinconjugating enzymes, which add ubiquitin to targeted proteins. These domains are required for cbl family proteins to regulate signaling transduction and protein degradation. C-cbl and cbl-b genes are strongly expressed in thymus, testes, and other tissues (3). Gene targeting in mice has shown that cbl-b is involved in pivotal events of lymphocyte activation (4, 5).Although earlier Northern hybridization demonstrated that cbl-b mRNAs are expressed in many tissues, including the brain (3), the distribution of the cbl-b protein and its function in the brain are still unknown.To unders...

show abstract

The Cbl Family and Other Ubiquitin Ligases

Cited by 121 publications

References 94 publications

A Logical Model Provides Insights into T Cell Receptor Signaling

A Logical Model Provides Insights into T Cell Receptor Signaling

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Enhancement of long-term memory retention and short-term synaptic plasticity in cbl-b null mice

Contact Info

Product

Resources

About