Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation

Kim, Minsoo; Tezuka, T.; Tanaka, Keiji; Yamamoto, Tadashi

doi:10.1038/sj.onc.1207298

Cited by 58 publications

(60 citation statements)

References 33 publications

(37 reference statements)

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“…Cbl-3 is the least conserved member of the Cbl family of E3-ligases, and Cbl-3 lacks the entire C-terminal half present in c-Cbl and Cbl-b (Keane et al, 1999;Kim et al, 1999). Although Cbl-3 does not contain the ubiquitin binding-domain (UBA) that is located in this C-terminal region, Cbl-3 has a functional ring finger domain and can downregulate RTKs such as EGFR (Keane et al, 1999;Kim et al, 2004). The function of Cbl-3 in Ret downregulation, however, is more complex.…”

Section: Discussionmentioning

confidence: 99%

“…Immortalized mouse podocytes were maintained in vitro as described previously (Tsui et al, 2006). Flag-Cbl-3, Flag-Cbl-3 C351A, Flag-Cbl-3 G276E, and Flag-Cbl-3 TKB were kindly provided by Tadashi Yamamoto (University of Tokyo, Japan) (Kim et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

“…7 B, C), suggesting that CD2AP is required for Ret51 downregulation. The C351A point mutation within the ring finger domain of Cbl-3 abolishes its E3 ligase activity (Kim et al, 2004). This point mutation also eliminated the binding of Cbl-3 to Ret (Fig.…”

Section: Cd2ap Controls Whether Cbl-3 Inhibits or Promotes Ret Degradmentioning

confidence: 99%

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CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

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The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are critical for nervous system development and maintenance. GFLs promote survival and growth via activation of the receptor tyrosine kinase (RTK) Ret. In sympathetic neurons, the duration of Ret signaling is governed by how rapidly Ret is degraded after its activation. In an effort to elucidate mechanisms that control the half-life of Ret, we have identified two novel Ret interactors, CD2-associated protein (CD2AP) and Cbl-3. CD2AP, an adaptor molecule involved in the internalization of ubiquitinated RTKs, is associated with Ret under basal, unstimulated conditions in neurons. After Ret activation by GDNF, CD2AP dissociates. Similarly, the E3-ligase Cbl-3 interacts with unphosphorylated Ret and dissociates from Ret after Ret activation. In contrast to their dissociation from autophosphorylated Ret, an interaction between CD2AP and Cbl-3 is induced by GDNF stimulation of sympathetic neurons, suggesting that CD2AP and Cbl-3 dissociate from Ret as a complex. In neurons, the overexpression of CD2AP enhances the degradation of Ret and inhibits GDNF-dependent survival, and gene silencing of CD2AP blocks Ret degradation and promotes GDNF-mediated survival. Surprisingly, Cbl-3 overexpression dramatically stabilizes activated Ret and enhances neuronal survival, even though Cbl-family E3 ligases normally function to trigger RTK downregulation. In combination with CD2AP, however, Cbl-3 promotes Ret degradation rapidly and almost completely blocks survival promotion by GDNF, suggesting that Cbl-3 acts as a switch that is triggered by CD2AP and oscillates between inhibition and promotion of Ret degradation. Consistent with the hypothesis, Cbl-3 silencing in neurons only inhibited Ret degradation and enhanced neuronal survival in combination with CD2AP silencing. CD2AP and Cbl-3, therefore, constitute a checkpoint that controls the extent of Ret downregulation and, thereby, the sensitivity of neurons to GFLs.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Tsui¹,

Pierchala

2008

J. Neurosci.

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“…For instance, the malfunction of the Ub-proteasome pathway could either enhance the effect of oncoproteins or reduce the amount of tumor suppressor proteins. Indeed, the Ub system targets several positive growth regulators, for example, N-Myc, c-Myc, c-Fos, c-Jun and Src-like proteins, to proteasomal degradation (Kim et al, 2004;Nakayama and Nakayama, 2006;Weiss et al, 2007;Xia et al, 2007;Zhao et al, 2008). Similarly, enhanced Ub-proteasome-dependent degradation of tumor suppressor proteins, such as TP53, p27 or for mutated NF2, has also been implicated in the pathogenesis of malignancies (Gautreau et al, 2002;Sun, 2006).…”

Section: Introductionmentioning

confidence: 99%

Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumor

et al. 2009

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Protein ubiquitination is critical for many cellular processes, through its ability to regulate protein degradation and various signaling mechanisms. In the ubiquitin (Ub) system, substrate specificity is achieved through the E3 family of Ub ligases. Because alterations of the ubiquitination machinery have been reported in human cancers, the selective interference with Ub ligases might represent a powerful therapeutic tool. Here, we report the first wide survey of misregulation of Ub ligases in cancer. We analysed 82 Ub ligases in nine types of cancer by in situ hybridization on tissue microarrays. We found 27 instances in which an Ub ligase was altered in a given type of tumor, when compared with normal tissues: 21 cases of overexpression and 6 cases of underexpression. We further analysed selected Ub ligases in large cohorts of breast and non-small-cell lung carcinomas. In five, of six, of these extended analyses (HUWE1, CCNB1IP1, SIAH1 and SIAH2 in breast cancer and CCNB1IP1 in lung cancer), we found that the levels of Ub ligases correlated significantly with relevant prognostic factors, and with clinical outcome. Our findings show that the alteration of Ub ligases is a frequent event in cancer and identify candidate targets for molecular therapies.

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“…c-Src is ubiquitylated by the ubiquitin ligase Cbl-c (Yokouchi et al, 2001) and is reported to be degraded by the proteasome (Hakak and Martin, 1999;Harris et al, 1999). Likewise, v-Src is ubiquitylated by Cbl-c but is targeted for lysosomal degradation (Kim et al, 2004). Interestingly, the Srcfamily kinase Hck and the non-receptor tyrosine kinase Syk are degraded in part by the lysosome (Howlett and Robbins, 2002;Paolini et al, 2001), demonstrating the feasibility of lysosomal degradation of non-receptor tyrosine kinases.…”

Section: Integrin and Activated Src Accumulate On Early Endosomes In mentioning

confidence: 94%

The ESCRT machinery mediates polarization of fibroblasts through regulation of myosin light chain

Lobert

Stenmark

2012

Journal of Cell Science

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SummaryRecent evidence implicates the endosomal sorting complex required for transport (ESCRT) in the regulation of epithelial polarity in Drosophila melanogaster, but the mechanisms responsible for this action remain unclear. Here we show that ESCRTs determine cell orientation during directed migration in human fibroblasts. We find that endosomal retention of a5b1 integrin and its downstream signaling effector Src in ESCRT-depleted cells is accompanied by the failure to activate myosin light chain kinase (MLCK), which thereby cannot phosphorylate myosin regulatory light chain (MRLC). Using this mechanism, ESCRT-depleted fibroblasts fail to orient their Golgi complex to undergo directional migration and show impaired focal adhesion turnover and increased spreading on fibronectin. Consistent with these findings, expression of a phosphomimetic mutant of MRLC in ESCRT-depleted cells restores normal phenotypes during cell spreading and orientation of the Golgi. These results suggest that, through their role in regulating integrin trafficking, ESCRTs regulate phosphorylation of MRLC and, subsequently, Golgi orientation and cell spreading.

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Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation

Cited by 58 publications

References 33 publications

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

CD2AP and Cbl-3/Cbl-c Constitute a Critical Checkpoint in the Regulation of Ret Signal Transduction

Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumor

The ESCRT machinery mediates polarization of fibroblasts through regulation of myosin light chain

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