Beyond the RING: CBL proteins as multivalent adapters

Tsygankov, Alexander Y.; Teckchandani, Anjali; Feshchenko, Elena A; Swaminathan, Gayathri

doi:10.1038/sj.onc.1204781

Cited by 123 publications

(125 citation statements)

References 249 publications

(370 reference statements)

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“…In summary, the interaction between Sprouty and Cbl emerges as a focal point not only in Sprouty's role in restraining RTK signals but also in the life cycle of Sprouty proteins themselves. We speculate that Cbl plays a dual role in this web; along with ubiquitylating Sproutyassociated proteins and sorting them for lysosomal or proteasomal degradation, Cbl's function as a multivalent adaptor capable of engaging more than 50 different proteins [39] may underlie the ability of Sprouty to interfere with signaling pathways.…”

Section: Sprouty Proteins: Dual Regulators Of Rtk Signalingmentioning

confidence: 99%

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

2005

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Intracellular signals mediated by the family of receptor tyrosine kinases play pivotal roles in morphogenesis, cell fate determination and pathogenesis. Precise control of signal amplitude and duration is critical for the fidelity and robustness of these processes. Activation of receptor tyrosine kinases by their cognate growth factors not only leads to propagation of the signal through various biochemical cascades, but also sets in motion multiple attenuation mechanisms that ultimately terminate the active state. Early attenuators pre-exist prior to receptor activation and they act to limit signal propagation. Subsequently, late attenuators, such as Lrig and Sprouty, are transcriptionally induced and further act to dampen the signal. Central to the process of signaling attenuation is the role of the E3 ubiquitin ligase c-Cbl. While Cblmediated processes of receptor ubiquitylation and endocytosis are relatively well understood, the links of Cbl to other negative regulators are just now beginning to be appreciated. Here we review some emerging interfaces between Cbl and the transcriptionally induced negative regulators Lrig and Sprouty.

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Section: Sprouty Proteins: Dual Regulators Of Rtk Signalingmentioning

confidence: 99%

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

2005

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“…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.…”

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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.

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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...

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“…Previous studies have shown that c-Cbl and Cbl-b 2 function as adaptor proteins by interacting with other signaling molecules through their various protein-protein interacting motifs [3].…”

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confidence: 99%

Ruk is ubiquitinated but not degraded by the proteasome

Verdier

Valovka

Zhyvoloup

et al. 2002

European Journal of Biochemistry

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The regulator of ubiquitous kinase (Ruk) protein, also known as CIN85 or SETA, is an adaptor‐type protein belonging to the CD2AP/CMS family. It was found in complexes with many signaling proteins, including phosphoinositol (PtdIns) 3‐kinase (EC 2.7.1.137), Cbl, GRB2, p130Cas and Crk. Functional analysis of these interactions, implicated Ruk in the regulation of apoptosis, receptor endocytosis and cytoskeletal rearrangements. We have recently demonstrated that overexpression of Ruk induces apoptotic death in neurons, which could be reversed by activated forms of PtdIns 3‐kinase and PKB/Akt. Furthermore, Ruk was shown to be a negative regulator of PtdIns 3‐kinase activity through binding to its P85 regulatory subunit [Gout, I., Middleton, G., Adu, J., Ninkina, N. N., Drobot, L. B., Filonenko, V., Matsuka, G., Davies, A.M., Waterfield, M. & Buchman, V. L. (2000) Embo J.19, 4015–4025]. Here, we report for the first time, that all three isoforms of Ruk (L, M and S) are ubiquitinated. Specific interaction between the E3 ubiquitin ligase Cbl and all three Ruk isoforms was demonstrated by coexpression studies in Hek293 cells. The interaction of Ruk M and S isoforms with Cbl was found to be mediated via heterodimerization with Ruk L. The use of proteosomal and lysosomal inhibitors clearly indicated that ubiquitination of Ruk L does not lead to its degradation. Based on this study, we propose a possible mechanism for the regulation of Ruk function by ubiquitination.

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Beyond the RING: CBL proteins as multivalent adapters

Cited by 123 publications

References 249 publications

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

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

Ruk is ubiquitinated but not degraded by the proteasome

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