Expression of a naturally occurring constitutively active variant of the epidermal growth factor receptor in mouse fibroblasts increases motility

Pedersen, Mikkel W.; Tkach, Vadim; Pedersen, Nina Marie; Berezin, Vladimir; Poulsen, Hans Skovgaard

doi:10.1002/ijc.11566

Cited by 71 publications

(64 citation statements)

References 35 publications

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“…The constitutive TK activity of the EGFRvIII results in the malignant transformation of cells (Han et al, 1996;Nagane et al, 1996;Huang et al, 1997;Antonyak et al, 1998;Montgomery, 2002;Johns et al, 2003;Abulrob et al, 2004;Luwor et al, 2004;Pedersen et al, 2004). In this study, we found that the EGFRvIII is regulated by the Cbl proteins in an identical manner to the WT EGFR.…”

Section: Discussionsupporting

confidence: 58%

“…Unlike the wild-type (WT) EGFR, the EGFRvIII is unable to bind to EGF or transforming growth factor-α (Ekstrand et al, 1994;Nishikawa et al, 1994;Moscatello et al, 1996) but, instead, it can dimerize spontaneously (Moscatello et al, 1996;Fernandes et al, 2001;Montgomery, 2002). The spontaneous dimerization and ensuing TK activation of the EGFRvIII is necessary to transform cells (Han et al, 1996;Nagane et al, 1996;Huang et al, 1997;Antonyak et al, 1998;O'Rourke et al, 1998;Montgomery, 2002;Johns et al, 2003;Abulrob et al, 2004;Luwor et al, 2004;Pedersen et al, 2004).…”

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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Section: Discussionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

et al. 2006

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“…We tested whether the observed time delay in the motility response of L929 fibroblasts to serum could be reproduced in another fibroblasts cell line, the NR6wtEGFR cell line, which previously has been used to study the molecular mechanisms underlying EGFinduced cell motility [Chen et al, 1994;Pedersen et al, 2004]. From Figure 8, it appears that the motility response of NR6wtEGFR cells to serum was delayed to the same extent as the motility response of L929 cells, indicating that this probably is a general phenomenon.…”

Section: Serum-induced Changes In Fibroblast Motility Require Proteinmentioning

confidence: 97%

The role of RhoA in the regulation of cell morphology and motility

Tkach¹,

Bock²,

Berezin³

2005

Cell Motil. Cytoskeleton

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Members of the Rho family of small GTPases are key regulators of the actin cytoskeleton, particularly in relation to the cell shape changes and the adhesion dynamic that drive cell migration. Here, we report the effect of activation or inhibition of the function of RhoA on cell motility and morphology. Both in the presence and the absence of serum, expression of constitutively active RhoA dramatically inhibited L929 fibroblasts' cell motility, and induced a rounding of the cells and a decrease in the number of processes per cell. In contrast, expression of a dominant negative mutant of RhoA had no effect on cell motility or morphology in steady-state conditions with or without serum in the medium. Inhibition of p160ROCK, a kinase effector of RhoA, only partially inhibited cell migration. Conversely, when cells were submitted to a period of serum deprivation followed by addition of serum, inhibition of endogenous RhoA by expression of the dominant negative mutant of RhoA impeded cell motility after serum stimulation. Thus, RhoA activity is required for stimulation of cell locomotion by serum factors. It was also observed that the addition of serum factors to quiescent L929 and NR6wtEGFR fibroblasts resulted in a delayed motility response of several hours compared to the immediately induced morphological changes, indicating the absence of a previously assumed direct correlation between changes in cell motility and cell morphology in response to serum addition. The motility response of L929 and NR6wtEGFR fibroblasts to serum stimulation required protein synthesis. Cell Motil.

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“…The epidermal growth factor (EGF) and its receptor (EGFR) constitute a well-characterized receptor-ligand system that plays an important role in the regulation of cell growth, proliferation, survival, and motility (1)(2)(3)(4). EGFR is involved in oncogenic transformation, which can be caused by receptor overexpression, autocrine ligand loops, gene amplification, or activating mutations such as the EGFR type III deletion mutant (EGFRvIII; refs.…”

Section: Introductionmentioning

confidence: 99%

Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor–Induced Cancer Cell Motility

Larsen

Pedersen

Stockhausen

et al. 2007

Molecular Cancer Research

126

118

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EphA2 overexpression has been reported in many cancers and is believed to play an important role in tumor metastasis and angiogenesis. We show that the activated epidermal growth factor receptor (EGFR) and the cancer-specific constitutively active EGFR type III deletion mutant (EGFRvIII) induce the expression of EphA2 in mammalian cell lines, including the human cancer cell lines A431 and HN5. The regulation is partially dependent on downstream activation of mitogen-activated protein kinase/extracellular signal -regulated kinase kinase and is a direct effect on the EphA2 promoter. Furthermore, EGFR and EphA2 both localize to the plasma membrane and EphA2 coimmunoprecipitates with activated EGFR and EGFRvIII. Ligand activation of EphA2 and EphA2 knockdown by small interfering RNA inhibit EGF-induced cell motility of EGFR-overexpressing human cancer cells, indicating a functional role of EphA2 in EGFR-expressing cancer cells. (Mol Cancer Res 2007;5(3):283 -93)

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Expression of a naturally occurring constitutively active variant of the epidermal growth factor receptor in mouse fibroblasts increases motility

Cited by 71 publications

References 35 publications

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

The role of RhoA in the regulation of cell morphology and motility

Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor–Induced Cancer Cell Motility

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