Ubiquitin Ligase Activity and Tyrosine Phosphorylation Underlie Suppression of Growth Factor Signaling by c-Cbl/Sli-1

Levkowitz, Gil; Waterman, Hadassa; Ettenberg, Seth A.; Katz, Mark N.; Tsygankov, Alexander Y.; Alroy, Iris; Lavi, Sara; Iwaï, Kazuhiro; Reiss, Yuval; Ciechanover, Aaron; Lipkowitz, Stanley; Yarden, Yosef

doi:10.1016/s1097-2765(00)80231-2

Cited by 904 publications

(989 citation statements)

References 39 publications

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“…First, autophosphorylation of EGFR can have either a positive or a negative role in the regulation of EGFR activity depending upon the site and temporal–spatial balance. We hypothesized that absence of two major negative regulatory phosphorylation sites at Y1016 and Y1069, in the L858R/CYF10, Ex19Del/CYF10 or Ex20Ins/CYF10 EGFR mutants are sufficient to induce oncogenic signaling cascades through aberrant activation of the Ras‐ERK signaling and loss of EGFR ubiquitination and subsequent receptor degradation, respectively 31, 32. However, this is not the case in wild‐type EGFR/CYF10 mutants, suggesting that ligand induced multiple autophosphorylation is required for cellular transformation in wild‐type EGFR.…”

Section: Discussionmentioning

confidence: 99%

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

Cho

Kim

et al. 2018

Intl Journal of Cancer

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Aberrant activation of cancer‐derived mutants of the epidermal growth factor receptor (EGFR) is closely associated with cancer pathogenesis and is thought to be mediated through multiple tyrosine phosphorylations within the C‐terminal domain. Here, we examined the consequences of the loss of these C‐terminal phosphorylation sites on cellular transformation in the context of lung‐cancer‐derived L858R, exon 19 deletion and exon 20 insertion mutant EGFR. Oncogenic EGFR mutants with substitution of the 10 potential C‐terminal tyrosine autophosphorylation sites for phenylalanine (CYF10) were still able to promote anchorage‐independent growth in soft agar at levels comparable to the parental L858R or exon19 deletion or exon 20 insertion mutants with intact autophosphorylation sites. Furthermore, these CYF10 mutants retained the ability to transform Ba/F3 cells in the absence of IL‐3. Bead‐based phosphorylation and immunoprecipitation analyses demonstrated that key EGFR‐associated proteins—including Grb2 and PLC‐γ—are neither phosphorylated nor bound to CYF10 mutants in transformed cells. Taken together, we conclude that tyrosine phosphorylation is not required for oncogenic activity of lung‐cancer‐derived mutant EGFR, suggesting these mutants can lead to cellular transformation by an alternative mechanism independent of EGFR phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

Cho

Kim

et al. 2018

Intl Journal of Cancer

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“…However, the intracellular domain of the EGFRvIII is not mutated and thus the Cbl protein-binding sites are intact. The Cbl proteins bind the phosphorylated EGFR (Levkowitz et al, 1999) and the phosphorylation pattern of active EGFRvIII is similar to that of the activated WT EGFR (Fernandes et al, 2001). The inability of the Cbl proteins to interact with or downregulate the EGFRvIII suggested a novel mechanism regulating the interaction between the EGFRvIII and the Cbl proteins.…”

Section: Introductionmentioning

confidence: 98%

“…The Cbl proteins (Cbl, Cbl-b, and Cbl-c) are negative regulators of WT EGFR signaling (Ettenberg et al, 1999a(Ettenberg et al, , b, 2001Keane et al, 1999;Levkowitz et al, 1999;Waterman et al, 1999a;Yokouchi et al, 1999;Duan et al, 2003). The Cbl proteins all contain an aminoterminal TK-binding (TKB) domain, a RING finger domain, and a region of proline-rich sequences in their carboxy-terminus (Nau and Lipkowitz, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…They are recruited to the activated EGFR either by the direct binding of their TKB domain to the phosphotyrosine residue at position 1045 in the EGFR (Levkowitz et al, 1999) or by an indirect mechanism mediated by Grb2 -the SH3 domains of Grb2 bind the proline-rich region of the Cbl proteins and the SH2 domain of Grb2 binds the phosphorylated EGFR (Waterman et al, 2002;Jiang et al, 2003). The RING finger domain of the Cbl proteins allows them to function as ubiquitin ligases (E3s) and so to target the EGFR signaling complex for internalization and subsequent degradation in the lysosome (Ettenberg et al, 1999b(Ettenberg et al, , 2001Levkowitz et al, 1999;Waterman et al, 1999a;Yokouchi et al, 1999;Duan et al, 2003). Thus, the Cbl proteins mediate the downregulation of the EGFR following stimulation with EGF.…”

Section: Introductionmentioning

confidence: 99%

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EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

et al. 2006

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The overexpression or mutation of tyrosine kinases (TKs), such as the epidermal growth factor receptor (EGFR), can lead to the development of cancer. The most common mutation of the EGFR in glioblastomas is the deletion of exons 2-7 known as the EGFRvIII. This mutant receptor cannot bind EGF but, instead, is constitutively active. The Cbl family of ubiquitin ligases (Cbl, Cbl-b, and Cbl-c) targets the activated EGFR for degradation. As the EGFRvIII is transforming, we investigated whether it could be downregulated by the Cbl proteins. The over-expression of all three Cbl proteins resulted in the ubiquitination and degradation of the EGFRvIII. As with the wild-type EGFR, the TK-binding domain and the RING finger of Cbl-b are sufficient for the downregulation of the EGFRvIII. Also, we found that Cbl-b is recruited to the EGFRvIII and inhibits the transformation of NIH 3T3 cells by the EGFRvIII. Mutation of the Cbl-binding site (Y1045F) in the EGFRvIII inhibits its ubiquitination and downregulation by Cbl-b and enhances its ability to transform. Furthermore, the EGFR TK inhibitor, AG 1478, prevents the downregulation of the EGFRvIII by the Cbl proteins and antagonizes the ability of an immunotoxin directed against the EGFRvIII to kill cells expressing this receptor. In conclusion, the EGFR-vIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRvIII immunotoxins.

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“…Unlike most other membrane receptors, ErbB3 does not undergo degradation by lysosomes 9, 10, but is degraded by proteasomes catalysed by Nrdp1 5, 11. The overexpression of ErbB3 has been reported to contribute to tumour malignancy and therapeutic resistance in cancers 12, 13, 14, 15.…”

Section: Introductionmentioning

confidence: 99%

Nrdp1S, short variant of Nrdp1, inhibits human glioma progression by increasing Nrdp1‐mediated ErbB3 ubiquitination and degradation

Wang

Bao

et al. 2015

J Cellular Molecular Medi

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The ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp1) is involved in the induction of apoptosis and suppression of tumour formation. We previously showed that it was expressed at lower levels in human glioma tissues compared with normal brain tissues. However, the mechanism underlying this is unclear. Here, we reported that a novel short variant (Nrdp1S), lacking 71 amino acids at the N‐terminal, was expressed in normal human brain tissue, but absent from glioma tissues. Similar to Nrdp1, Nrdp1S could be degraded by the proteasomal pathway, but exhibited an even longer half‐life than Nrdp1. Nrdp1S was also shown to form a heterodimer with Nrdp1, which increased its stability, thereby augmenting the Nrdp1‐mediated ubiquitination and degradation of ErbB3. EdU incorporation, MTT assay and in vitro colony formation demonstrated that Nrdp1S significantly inhibited the cell tumourigenicity. These results together suggest that Nrdp1S is a tumour suppressor that which potentiates the Nrdp1‐mediated ubiquitination and degradation of ErbB3. An Nrdp1S deficiency may also be an important factor in the loss of Nrdp1.

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Ubiquitin Ligase Activity and Tyrosine Phosphorylation Underlie Suppression of Growth Factor Signaling by c-Cbl/Sli-1

Cited by 904 publications

References 39 publications

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

Autophosphorylation of the carboxyl‐terminal domain is not required for oncogenic transformation by lung‐cancer derived EGFR mutants

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

Nrdp1S, short variant of Nrdp1, inhibits human glioma progression by increasing Nrdp1‐mediated ErbB3 ubiquitination and degradation

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