Tandem duplication of the epidermal growth factor receptor tyrosine kinase and calcium internalization domains in A-172 glioma cells

Fenstermaker, Robert A.; Ciesielski, Michael; Castiglia, Gregory J

doi:10.1038/sj.onc.1202156

Cited by 28 publications

(43 citation statements)

References 26 publications

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“…Size dierences between deglycosylated wild type and mutant EGFR protein cores in KE cells suggest that approximately one kilobase of additional mRNA sequence would be required, beyond that present in the wild type EGFR transcript, to encode the EGFR-like protein present in A-172 cells (Steck et al, 1988). In addition to the 11.5 kb species present in A-172 cells, we and others have identi®ed similar mRNA species in KE and A-1235 cells (Figure 1c; Steck et al, 1988;Fenstermaker et al, 1998). We have not detected any transcripts larger than 10.5 kb in A-431 carcinoma cells or in any other cell line that does not express either 185 kDa or 190 kDa EGFR-reactive species.…”

Section: Glioma Cells Produce Large Egfr-like Transcriptssupporting

confidence: 77%

“…Other large EGFR forms are found in KE and A-1235 human glioma cell lines (Panneerselvam et al, 1995;Steck et al, 1988). The A-172 mutant contains tandem duplication of sequences that encode the tyrosine kinase and calcium internalization domains of the molecule (Fenstermaker et al, 1998). Together with the mutant receptor found in both A-172 cells and glioma biopsy specimens, and evidence presented here regarding the related KE and A-1235 mutants, results suggest the existence of a distinct class of oncogenic EGFR tandem duplication mutants (TDM) present in some human gliomas.…”

mentioning

confidence: 52%

“…The tandem duplication of EGFR exons 18 through 25 present in KE and A-1235 cells contains one fewer exon than the mutant EGFR transcript in A-172 cells (i.e. exon 26; Fenstermaker et al, 1998). Sequencing of RT ± PCR fragments from RPG-77 gave results identical to those obtained with fragments from A-172 cells (i.e.…”

Section: Nucleotide Sequences Of the Mutant Egfr Transcriptsmentioning

confidence: 66%

“…One such 190 kDa protein is recognized in A-172 cells by antibodies to both intracellular and extracellular regions of the EGFR, but not by antibodies to HER2, HER3 or HER4 (Panneerselvam et al, 1995;Fenstermaker et al, 1998). In addition to the wild type 170 kDa EGFR molecule, KE and A-1235 human glioma cells express EGFR-reactive species of approximately 185 kDa (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

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Oncogenic epidermal growth factor receptor mutants with tandem duplication: gene structure and effects on receptor function

Ciesielski

Fenstermaker

2000

Oncogene

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A number of epidermal growth factor receptor (EGFR) deletion mutants have been identi®ed in gliomas, in which the EGFR gene is frequently ampli®ed and rearranged. We have previously characterized the structure of a gene in A-172 human glioma cells that encodes a 190-kDa EGFR mutant with tandem duplication of the tyrosine kinase (TK) and calcium-mediated internalization (CAIN) domains. Here we describe a 185-kDa tandem duplication mutant (TDM) that is expressed in KE and A-1235 glioma cells, along with certain functional characteristics of the mutants. The corresponding transcripts in KE and A-1235 cells contain 1053 additional nucleotides representing an in-frame duplication of exons 18 through 25 which encode the entire TK region and a portion of the CAIN domain. As with duplication of the entire TK/CAIN region (exons 18 ± 26) in A-172 cells, duplication of exons 18 ± 25 is associated with a speci®c genomic rearrangement between¯anking introns. Involved introns contain homology to recombination signal sequence (RSS) heptamers present in the V(D)J region of the T lymphocyte receptor gene. In de®ned medium, both oncogenic TDM are constitutively autophosphorylated and ineciently downregulated. High-anity binding is reduced in EGFR.TDM/18 ± 26, although the t I P of receptor internalization is not prolonged. Oncogene (2000) 19, 810 ± 820.

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Section: Glioma Cells Produce Large Egfr-like Transcriptssupporting

confidence: 77%

mentioning

confidence: 52%

Section: Nucleotide Sequences Of the Mutant Egfr Transcriptsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

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Oncogenic epidermal growth factor receptor mutants with tandem duplication: gene structure and effects on receptor function

Ciesielski

Fenstermaker

2000

Oncogene

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“…The most commonly found mutation (EGFRvIII) involves a deletion in the NH 2 -terminal portion of EGFR, from residues 6 to 273 (5)(6)(7). Several other types of rearrangements have been found, however, including even a tandem duplication of the tyrosine kinase and calcium internalization domains (4,5,8). Half of all glioblastomas exhibit EGFR amplification, and of these, 15% possess COOH-terminal truncated EGFR (at residue 958) (5).…”

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confidence: 99%

A Carboxyl-terminal Mutation of the Epidermal Growth Factor Receptor Alters Tyrosine Kinase Activity and Substrate Specificity as Measured by a Fluorescence Polarization Assay

Beebe¹,

Wiepz

Guadarrama

et al. 2003

Journal of Biological Chemistry

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The expression of certain COOH-terminal truncation mutants of the epidermal growth factor receptor (EGFR) can lead to cell transformation, and with ligand stimulation, a broader spectrum of phosphorylated proteins appears compared with EGF-treated cells expressing wild-type EGFR. Accordingly, it has been proposed that elements within the COOH terminus may determine substrate specificity of the EGFR tyrosine kinase (Decker, S. J., Alexander, C., and Habib, T. Our data demonstrate that the steady-state kinetic parameters for the ct1022 mutant differ from those of the wild-type enzyme, and the differences are substrate-dependent. These results support the concept that this oncogenic truncation/mutation alters EGFR substrate specificity, rather than causing a general alteration of activity. We performed the experiments using a non-radioactive fluorescence polarization assay that quantifies the degree of phosphorylation of peptide as well as natural substrates. The results are consistent with those from the traditional [␥-32 P]ATP/filtration assay.Binding of EGF 1 and other ligands to EGFR and its relatives (ErbB2, ErbB3, and ErbB4) triggers a highly complicated signaling network (1, 2). Overexpression as well as oncogenic deletions and truncations of EGFR have been observed in many cancer types, including glioblastomas and non-small cell lung, pancreatic, breast, head and neck, colon, prostate, ovarian, and cervical tumors (3-5). The most commonly found mutation (EGFRvIII) involves a deletion in the NH 2 -terminal portion of EGFR, from residues 6 to 273 (5-7). Several other types of rearrangements have been found, however, including even a tandem duplication of the tyrosine kinase and calcium internalization domains (4,5,8). Half of all glioblastomas exhibit EGFR amplification, and of these, 15% possess COOH-terminal truncated EGFR (at residue 958) (5). Furthermore, expressing certain COOH-terminal truncation mutants in cell culture results in dramatic EGF-induced increases in the variety of phosphorylated proteins present compared with those observed in cells expressing wild-type EGFR (9 -12).The cause of this increase in the assortment of phosphorylated proteins has not yet been completely explored; however, EGF-induced receptor internalization and degradation occurred at a slower rate with an oncogenic EGFR mutant possessing a COOH-terminal truncation at residue 973 rather than with wild-type EGFR (10, 13). Cells expressing this mutant develop a transformed phenotype when grown in the presence of low EGF concentrations (13). Moreover, data suggest that ⌬973-EGFR and ErbB2 heterodimers form in cells expressing this mutant. The ErbB2 in these cells is tyrosyl phosphorylated in the absence of added ligand (12). Interestingly, the oncogene product of the avian erythroblastosis virus (verbB) is an NH 2 -and COOH-terminal truncated version of EGFR (ErbB1) (14,15).Cellular changes in phosphotyrosine levels may occur not only as a result of changes in the catalytic properties of the enzyme, but may also reflect alteratio...

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Tyrosine kinase‐altered spindle cell neoplasms with EGFR internal tandem duplications

Kao

Pinto

Trobaugh‐Lotrario

et al. 2022

Genes Chromosomes & Cancer

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In this study, we present two extra‐renal pediatric spindle cell neoplasms with epidermal growth factor receptor (EGFR) internal tandem duplications (ITD). Histologically, these tumors demonstrated the same histologic features seen in other tyrosine kinase‐altered spindle cell neoplasms, with one case showing abundant adipose tissue with cellular fibrous septae resembling lipofibromatosis and the other case showing fascicles of spindled cells resembling infantile fibrosarcoma. There was variable expression of CD34, S100, and SMA, and all cases were negative for panTRK. This case series adds to our molecular understanding of the spectrum of tyrosine kinase‐altered spindle cell neoplasms and represents the first reported examples of EGFR ITDs in extra‐renal tumors. The presence of EGFR alterations in the absence of gene fusions represents a potential therapeutic target and necessitates a broader testing panel for this group of tumors.

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Tandem duplication of the epidermal growth factor receptor tyrosine kinase and calcium internalization domains in A-172 glioma cells

Cited by 28 publications

References 26 publications

Oncogenic epidermal growth factor receptor mutants with tandem duplication: gene structure and effects on receptor function

Oncogenic epidermal growth factor receptor mutants with tandem duplication: gene structure and effects on receptor function

A Carboxyl-terminal Mutation of the Epidermal Growth Factor Receptor Alters Tyrosine Kinase Activity and Substrate Specificity as Measured by a Fluorescence Polarization Assay

Tyrosine kinase‐altered spindle cell neoplasms with EGFR internal tandem duplications

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