The Tyrosine Kinase Negative Regulator c-Cbl as a RING-Type, E2-Dependent Ubiquitin-Protein Ligase

Joazeiro, Claudio A.P.; Wing, Simon S.; Huang, Han-kuei; Leverson, Joel D.; Hunter, Tony; Liu, Yun‐Cai

doi:10.1126/science.286.5438.309

Cited by 951 publications

(815 citation statements)

References 27 publications

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“…Ubiquitylation of EGFR and subsequent degradation controls the intensity of downstream signals after receptor activation. c-Cbl, a ubiquitin E3 ligase, is recruited to EGFR upon ligand stimulation, and then initiates the ubiquitylation of the activated receptor (Joazeiro et al, 1999;Levkowitz et al, 1999). The ubiquitylated EGFR is internalized into early endosomes, from where it is either recycled to plasma membrane, or delivered to multivesicular bodies and late endosomes for degradation (Waterman and Yarden, 2001;Ravid et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

et al. 2009

Oncogene

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Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands play important roles in nervous system development. Recently, they have been implicated in tumorigenesis of different cancers. In this study, we showed that the expression of ephrinA5 was dramatically downregulated in primary gliomas compared with normal tissues. Forced expression of ephrinA5 reduced tumorigenicity of human glioma U373 cells. Epidermal growth factor receptor (EGFR), which frequently acts as an oncoprotein in glioma, was greatly decreased in ephrinA5-transfected glioma cells, and the two molecules exhibited a mutually exclusive expression pattern in primary glioma samples. We found that ephrinA5 enhanced c-Cbl binding to EGFR, thus promoted ubiquitylation and degradation of the receptor. Either ephrinA5-Fc or EphA2-Fc treatment simulating bidirectional signaling of Eph/ephrin system resulted in EGFR decrease. This study discovered that ephrinA5 acted as a tumor suppressor in glioma, and its negative regulation of EGFR contributed to the suppressive effects. In addition to identifying a novel mechanism underlying tumor suppressor activity of ephrinA5, we also showed cross-talk between different receptor tyrosine kinase families in glioma. These findings may improve therapeutic strategies for glioma.

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Section: Discussionmentioning

confidence: 99%

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

et al. 2009

Oncogene

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“…To investigate whether IAP protein Livin, like other RING finger proteins, can regulate itself through auto-ubiquitination, 11,23,24 we compared the endogenous Livin in the presence or absence of proteasome inhibitor MG132 or ALLN. We found that Livin is regulated by self-ubiquitination, and as a result, Livin undergoes proteasome-mediated degradation.…”

Section: Discussionmentioning

confidence: 99%

Livin promotes Smac/DIABLO degradation by ubiquitin–proteasome pathway

Huang

Song

et al. 2006

Cell Death Differ

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Livin, a member of the inhibitor of apoptosis protein (IAP) family, encodes a protein containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. It has been reported that Livin directly interacts with caspase-3 and -7 in vitro and caspase-9 in vivo via its BIR domain and is negatively regulated by Smac/DIABLO. Nonetheless, the detailed mechanism underlying its antiapoptotic function has not yet been fully characterized. In this report, we provide, for the first time, the evidence that Livin can act as an E3 ubiquitin ligase for targeting the degradation of Smac/ DIABLO. Both BIR domain and RING finger domain of Livin are required for this degradation in vitro and in vivo. We also demonstrate that Livin is an unstable protein with a half-life of less than 4 h in living cells. The RING domain of Livin promotes its auto-ubiquitination, whereas the BIR domain is likely to display degradation-inhibitory activity. Mutation in the Livin BIR domain greatly enhances its instability and nullifies its binding to Smac/DIABLO, resulting in a reduced antiapoptosis inhibition. Our findings provide a novel function of Livin: it exhibits E3 ubiquitin ligase activity to degrade the pivotal apoptotic regulator Smac/DIABLO through the ubiquitin-proteasome pathway.

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“…The ERK pathway affects EGFR trafficking by threonine phosphorylation of EGFR Consequent to EGF stimulation, activated EGFR is rapidly ubiquitinated by c-Cbl, an SH2 domain-containing ubiquitin ligase that itself becomes phosphorylated and binds to EGFR, which promotes postinternalization of EGFR and sorting to endosomes and lysosomes for degradation (Levkowitz et al, 1998;Joazeiro et al, 1999;Waterman et al, 1999). In DU145 cells, EGF stimulation led to EGFR ubiquitination (Figure 3a, upper panel, lane 2), which was enhanced by PD98059 (lane 4 vs 2), but not by LY294002 (lane 6 vs 2).…”

Section: Inhibition Of the Erk Pathway Enhances Egf-induced Egfr Actimentioning

confidence: 99%

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

et al. 2010

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Upregulation of epidermal growth factor receptor (EGFR) and subsequent increases in extracellular-regulated kinase (ERK) and Akt signaling are implicated in prostate cancer progression. Impaired endocytic downregulation of EGFR also contributes to oncogenic phenotypes such as metastasis. Thus, understanding the roles of divergent signaling pathways in the regulation of EGFR trafficking and EGFRdriven invasive migration may enable the development of more effective therapies. In this study, we use the human prostate cancer cell lines, DU145 and PC3, to investigate the effects of both the ERK and Akt pathways on epidermal growth factor (EGF)-mediated EGFR signaling, trafficking and cell motility. We show that DU145 and PC3 cells overexpress EGFR and migrate in a ligand (EGF)-dependent manner. Next, we show that pharmacological inhibition of ERK (but not Akt) signaling enhances EGFinduced EGFR activation, ubiquitination and downregulation, and may lead to enhanced receptor turnover. These findings negatively correlate with ERK-mediated threonine phosphorylation of EGFR, implicating it as a possible mechanism. Further, we uncover that EGF promotes disassembly of cell-cell junctions, downregulation of E-cadherin and upregulation of the transcriptional repressor, Snail, typical characteristics of epithelial-mesenchymal transition (EMT). These effects are dependent on activation of Akt, as inhibition of Akt signaling abolishes EGF/EGFR-driven cell migration and EMT. Knockdown of endogenous Snail also prevents EGFR-mediated downregulation of E-cadherin, EMT and cell migration. Surprisingly, inhibition of the ERK pathway augments EGFR-dependent motility, occurring concomitantly with elevation of EGF-induced Akt activity. Collectively, our results suggest that EGF-triggered ERK activation has profound feedback on EGFR signaling and trafficking by EGFR threonine phosphorylation, and Akt has a pivotal role in EGFR-mediated cell migration by activating EMT. More important, our results also suggest that therapeutic targeting of ERK signaling may have undesirable outcomes (for example, augmenting EGFR-driven motility).

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The Tyrosine Kinase Negative Regulator c-Cbl as a RING-Type, E2-Dependent Ubiquitin-Protein Ligase

Cited by 951 publications

References 27 publications

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

Livin promotes Smac/DIABLO degradation by ubiquitin–proteasome pathway

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

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