Regulating the regulator: negative regulation of Cbl ubiquitin ligases

Ryan, Philip; Davies, G C; Nau, Marion M.; Lipkowitz, Stanley

doi:10.1016/j.tibs.2005.12.004

Cited by 89 publications

(78 citation statements)

References 96 publications

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“…16 Consistent with the concept of intramolecular modification, it appears that the self-ubiquitinating activity of ITCH and other HECT ligases like NEDD4-1, NEDD4-2, SMURF2, and WWP1, is regulated through intramolecular interactions that are modulated by modifications such as phosphorylation, and that involve the HECT domain. [17][18][19] In an attempt to decipher the biological role of self-ubiquitination, it was proposed that it serves to target the ligase for degradation, 11 which has been observed indeed as a means of negative feedback for Mdm2, 6,20 E6-AP, 21 CBL ligases, 22 and the substrate receptor subunits of CRL complexes. 23 Self-ubiquitination can occur in substrateindependent 24 (Figure 2a) and -dependent modes 22 ( Figure 2b).…”

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

“…[17][18][19] In an attempt to decipher the biological role of self-ubiquitination, it was proposed that it serves to target the ligase for degradation, 11 which has been observed indeed as a means of negative feedback for Mdm2, 6,20 E6-AP, 21 CBL ligases, 22 and the substrate receptor subunits of CRL complexes. 23 Self-ubiquitination can occur in substrateindependent 24 (Figure 2a) and -dependent modes 22 ( Figure 2b). Also, binding to the substrate can protect the ligase from self-destruction 23 (Figure 2c).…”

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

“…In some cases, ligases have been reported to be degraded along with their substrates (Figure 2b proteins regulate a wide array of signal transduction pathways, many of which involve targeting of receptor and non-receptor tyrosine kinases (TKs). 22 Tyrosine phosphorylation of CBL proteins catalyzed by their TK substrates induces a conformational change, which results in activation of the ligase towards the substrate and itself. 3,22 Activation of the CBL substrate epidermal growth factor receptor (EGF-R) leads to a rapid decrease in the level of the EGF-R concomitant with a decrease in c-CBL, CBL-b, and CBL-c. 22,28 Similar decrease in CBL-b and c-CBL levels were observed after stimulation of the KIT receptor TK.…”

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

“…22 Tyrosine phosphorylation of CBL proteins catalyzed by their TK substrates induces a conformational change, which results in activation of the ligase towards the substrate and itself. 3,22 Activation of the CBL substrate epidermal growth factor receptor (EGF-R) leads to a rapid decrease in the level of the EGF-R concomitant with a decrease in c-CBL, CBL-b, and CBL-c. 22,28 Similar decrease in CBL-b and c-CBL levels were observed after stimulation of the KIT receptor TK. 29 In both cases, the degradation of the receptor and the CBL ligase was dependent on the RING domain of the E3.…”

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

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Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

2011

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Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of B1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed. Cell Death and Differentiation (2011) 18, 1393-1402 doi:10.1038/cdd.2011; published online 4 March 2011One of the major roles of the covalent modification of cellular proteins by ubiquitin is signaling them for proteasomal degradation ( Figure 1). The first step of the modification is catalyzed by the ubiquitin-activating enzyme, E1, which generates a high-energy thiol ester intermediate that is subsequently transferred to the second enzyme, a ubiquitinconjugating enzyme, E2. The third step ascertains substrate specificity, and is catalyzed by one of the numerous (B650) ubiquitin ligases, E3s. Typically, it results in the formation of an isopeptide bond between the C-terminal Gly of ubiquitin and an e-NH 2 group of an internal Lys of the substrate. Less frequently, it can generate a linear peptide bond with the a-NH 2 group, a thiol ester bond with an internal Cys, or an ester bond with a Thr or Ser. The three-step cascade of reactions is repeated, where additional ubiquitin moieties are attached sequentially to one another in an isopeptide bond involving one of the seven internal Lys residues in the ubiquitin moiety, thus generating a polyubiquitin chain. Lys48-based chains serve as a signal for proteasomal degradation, whereas chains based on other internal Lys residues, or modification by single moiety(ies) can serve non-proteolytic functions.Ligases fall into two main families: RING (really interesting new gene) and HECT (homologous to the E6-AP carboxy terminus) domain-containing E3s. RING ligases serve as scaffolds that facilitate direct transfer of ubiquitin from the E2 to the target protein. HECT E3s contain an active Cys residue to which ubiquitin binds prior to its transfer to the substrate (Figure 1). There are B600 RING finger and B30 HECT ligases in humans. Smaller families of ligases (U-box, plant homology domain, and zinc finger) have also been described.An important problem relates to regulation of the ubiquitin system components, and in particular to that of the ligases that are the specific substrate-recognizing elements. 1,2 Phosphorylation of an E3 can activate the protein, such as the ca...

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Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

Section: Degradation Of Ligases Via Self-catalyzed Ubiquitinationmentioning

confidence: 99%

See 2 more Smart Citations

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

2011

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“…Here we focused on the intracellular protein degradation system because it is a key mechanism involved in the regulation of various cellular processes including cell proliferation, differentiation, and survival [19]. Proteasome degradation involves a cascade of events requiring ubiquitin ligases that target proteins for ubiquitination and proteasome degradation [20][21][22]. Previous studies reported a positive effect of proteasome inhibition on osteoblast differentiation through prevention of proteasomal degradation of b-catenin [23], ATF4 [24] and RUNX2 by the E3 ubiquitin ligases Smurf-1 and Schnurri-3 [25][26][27], which supports an important role of E3 ubiquitin ligases in the control of bone metabolism [28].…”

Section: Introductionmentioning

confidence: 99%

Promotion of Osteoblast Differentiation in Mesenchymal Cells Through Cbl-Mediated Control of STAT5 Activity

et al. 2013

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The identification of the molecular mechanisms controlling the degradation of regulatory proteins in mesenchymal stromal cells (MSC) may provide clues to promote MSC osteogenic differentiation and bone regeneration. Ubiquitin ligase-dependent degradation of proteins is an important process governing cell fate. In this study, we investigated the role of the E3 ubiquitin ligase c-Cbl in MSC osteoblast differentiation and identified the mechanisms involved in this effect. Using distinct shRNA targeting c-Cbl, we showed that c-Cbl silencing promotes osteoblast differentiation in murine and human MSC, as demonstrated by increased alkaline phosphatase activity, expression of phenotypic osteoblast marker genes (RUNX2, ALP, type 1 collagen), and matrix mineralization in vitro. Coimmunoprecipitation analyses showed that c-Cbl interacts with the transcription factor STAT5, and that STAT5 forms a complex with RUNX2, a master transcription factor controlling osteoblastogenesis. Silencing c-Cbl decreased c-Cblmediated STAT5 ubiquitination, increased STAT5 protein level and phosphorylation, and enhanced STAT5 and RUNX2 transcriptional activity. The expression of insulin like growth factor-1 (IGF-1), a target gene of STAT5, was increased by c-Cbl silencing in MSC and in bone marrow stromal cells isolated from c-Cbl deficient mice, suggesting that IGF-1 contributes to osteoblast differentiation induced by c-Cbl silencing in MSC. Consistent with these findings, pharmacological inhibition of STAT5 activity, or neutralization of IGF-1 activity, abrogated the positive effect of c-Cbl knockdown on MSC osteogenic differentiation. Taken together, the data provide a novel functional mechanism by which the ubiquitin ligase c-Cbl regulates the osteoblastic differentiation program in mesenchymal cells by controlling Cbl-mediated STAT5 degradation and activity.

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