Role of conformational alteration in the epidermal growth factor receptor (EGFR) function

Bishayee, Subal

doi:10.1016/s0006-2952(00)00425-1

Cited by 55 publications

(42 citation statements)

References 22 publications

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“…Due to the potential for mevalonate metabolite depletion to functionally alter the EGFR signaling pathway, HMG-CoA reductase and EGFR-targeted therapies may be associated (15,32,33). This study has shown that the combination of lovastatin and gefitinib induced significant cooperative cytotoicity in all 16 squamous cell carcinomas, NSCLC, and colon carcinomas that were tested irrespective of their EGFR expression levels.…”

Section: Discussionmentioning

confidence: 82%

Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor

Mantha

Hanson²,

Goss³

et al. 2005

Clinical Cancer Research

103

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Purpose: The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutations within the ATP binding site confers increased susceptibility to gefitinib, a potent tyrosine kinase inhibitor of EGFR. Agents that can inhibit EGFR function through different mechanisms may enhance gefitinib activity in patients lacking these mutations. Mevalonate metabolites play significant roles in the function of the EGFR; therefore, mevalonate pathway inhibitors may potentiate EGFRtargeted therapies.Experimental Design: In this study, we evaluated the effect of lovastatin on EGFR function and on gefitinib activity. Effects on EGFR function were analyzed by Western blot analysis using phosphospecific antibodies to EGFR, AKT, and extracellular signal-regulated kinase. Cytotoxic effects of lovastatin and/or gefitinib were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry.Results: Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation by 24 hours that was reversed by the coadministration of mevalonate. Combining lovastatin and gefitinib treatments showed enhanced inhibition of AKT activation by EGF in SCC9 cells. The combination of 10 Mmol/L lovastatin and 10 Mmol/L gefitinib treatments showed cooperative cytotoxicity in all 8 squamous cell carcinomas, 4 of 4 non -small cell lung carcinoma and 4 of 4 colon carcinoma cell lines tested. Isobologram and flow cytometric analyses of three representative cell lines with wild-type EGFR ATP binding sites confirmed that this combination was synergistic inducing a potent apoptotic response.Conclusions: Taken together, these results show that targeting the mevalonate pathway can inhibit EGFR function. They also suggest the potential utility of combining these clinically relevant therapeutic approaches.

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Section: Discussionmentioning

confidence: 82%

Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor

Mantha

Hanson²,

Goss³

et al. 2005

Clinical Cancer Research

103

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“…Various gangliosides were shown to interact with the extracellular domain of EGFR and either inhibit or stimulate ligand-induced activation of the receptor . This association is dependent on glycosylation of EGFR (Wang et al, 2001b), which in turn, regulates the conformation of the extracellular domain and ligand-induced dimerization of the receptor (Bishayee, 2000;Tsuda et al, 2000;Fernandes et al, 2001). In this regard, we found that expression of CD82 had a marked effect on surface expression of gangliosides GM1 and GD1a (Table 1 and Fig.…”

Section: Discussionmentioning

confidence: 99%

Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR

Odintsova

Voortman

Gilbert

et al. 2003

Journal of Cell Science

121

122

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We have previously shown that CD82, a transmembrane protein of the tetraspanin superfamily is associated with EGFR and has a negative effect on EGF-induced signalling (Odintsova, E., Sugiura, T. and Berditchevski, F. (2000) Curr. Biol. 10, 1009-1012). Here we demonstrate that CD82 specifically attenuates ligand-induced dimerization of EGFR. The recombinant soluble large extracellular loop of CD82 has no effect on the dimerization thereby suggesting that other parts of the protein are required. Although CD82 is also associated with ErbB2 and ErbB3, ligand-induced assembly of the ErbB2-ErbB3 complexes is not affected in CD82-expressing cells. Furthermore, in contrast to the CD82-EGFR association, CD82-ErbB2 and CD82-ErbB3 complexes are stable in the presence of ErbB3 ligand. The effect of CD82 on the formation of EGFR dimers correlates with changes in compartmentalisation of the ErbB receptors on the plasma membrane. Expression of CD82 causes a significant increase in the amount of EGFR and ErbB2 in the light fractions of the sucrose gradient. This correlates with the increased surface expression of gangliosides GD1a and GM1 and redistribution of GD1a and EGFR on the plasma membrane. Furthermore, in CD82-expressing cells GD1a is co-localised with EGFR and the tetraspanin. Taken together our results offer a molecular mechanism of the attenuating activity of CD82 towards EGFR, whereby GD1a functions as a mediator of CD82-dependent compartmentalisation of the receptor.

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“…GnT-V glycosylation of Ncadherin reduces N-cadherin clustering at the cell membrane, resulting in reduced adhesion (18). GnT-V -catalyzed glycosylation of EGFR enhances ligand binding, autophosphorylation, and subsequent downstream signaling, thus promoting cell proliferation (15,16,48).…”

Section: Discussionmentioning

confidence: 99%

Coexpression of β1,6-N-Acetylglucosaminyltransferase V Glycoprotein Substrates Defines Aggressive Breast Cancers with Poor Outcome

Siddiqui

Pawelek

Handerson

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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B1,6-N-Acetylglucosaminyltransferase-V (GnT-V) catalyzes the addition of complex oligosaccharide side chains to glycoproteins, regulating the expression and function of several proteins involved in tumor metastasis. We analyzed the expression of five cell-surface glycoprotein substrates of GnT-V, matriptase, B1-integrin, epidermal growth factor receptor, lamp-1, and N-cadherin, on a tissue microarray cohort of 670 breast carcinomas with 30-year follow-up. Phaseolus vulgaris leukocytic phytohemagglutinin (LPHA), a lectin specific for B1,6-branched oligosaccharides, was used to assay GnT-V activity. Our results show a high degree of correlation of the LPHA staining with matriptase, lamp-1, and N-cadherin expressions, but not with epidermal growth factor receptor or B1-integrin expressions. In addition, many of the GnT-V substrate proteins exhibited strong coassociations. Elevated levels of GnT-V substrates were correlated with various markers of tumor progression, including positive node status, large tumor size, estrogen receptor negativity, HER2/neu overexpression, and high nuclear grade. Furthermore, LPHA and matriptase showed significant association with disease-related survival. Unsupervised hierarchical clustering of the GnT-V substrate protein expression and LPHA revealed two distinct clusters: one with higher expression of all markers and poor patient outcome and one with lower expression and good outcome. These clusters showed independent prognostic value for disease-related survival when compared with traditional markers of tumor progression. Our results indicate that GnT-V substrate proteins represent a unique subset of coexpressed tumor markers associated with aggressive disease. (Cancer Epidemiol Biomarkers Prev 2005;14(11):2517 -23)

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Role of conformational alteration in the epidermal growth factor receptor (EGFR) function

Cited by 55 publications

References 22 publications

Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor

Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor

Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR

Coexpression of β1,6-N-Acetylglucosaminyltransferase V Glycoprotein Substrates Defines Aggressive Breast Cancers with Poor Outcome

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