Ras-independent oncogenic transformation by an EGF-receptor mutant

Julie L. Boerner, Michael J. McManus, G. Steven Martin, Nita Jane Maihle

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Mutations in the ligand-binding domain of the epidermal growth factor receptor have been identified in several types of human cancers, including malignant gliomas. These mutations render signaling by this receptor to be constitutively ligand-independent. In fibroblasts transformed with ligand-independent epidermal growth factor receptor mutants, there is a correlation between the formation of a unique phosphotyrosine protein complex and oncogenic transformation. This phosphoprotein complex includes Grb2, Shc, Sos, tyrosine-phosphorylated form of caldesmon, and two, as yet, unidentified proteins. The presence of Grb2, Shc, and Sos in this complex implicates Ras in ligand-independent signaling by these oncogenic epidermal growth factor receptor mutants. We, therefore, have used retroviral co-infections of cultured primary fibroblasts to determine if Ras activation is required for phosphoprotein complex formation, stress fiber loss, or transformation. As predicted, expression of a dominant-negative Ras mutant (N17Ras) completely abrogates ligand-stimulated soft agar colony growth of primary fibroblasts. In contrast, N17Ras expression has no effect on v-ErbB mediated stress fiber disassembly, soft agar colony growth, or phosphoprotein complex assembly. In addition, our data suggest that ligand-dependent Ras activation may be suppressed by oncogenic v-ErbB expression. Together these observations suggest that oncogenic signaling by v-ErbB does not require Ras activation, and implicate an alternative signal transduction pathway in ligand-independent epidermal growth factor receptor oncogenic signaling.

Original languageEnglish (US)
Pages (from-to)935-942
Number of pages8
JournalJournal of Cell Science
Volume113
Issue number6
StatePublished - Apr 12 2000
Externally publishedYes

Fingerprint

Epidermal Growth Factor Receptor
Ligands
Phosphoproteins
Stress Fibers
Fibroblasts
Agar
Calmodulin-Binding Proteins
Mutation
Phosphotyrosine
Growth
Coinfection
Glioma
Tyrosine
Signal Transduction
Proteins
Neoplasms

Keywords

  • Chicken embryo fibroblast
  • Dominant-negative Ras
  • Stress fiber
  • V-ErbB

ASJC Scopus subject areas

  • Cell Biology

Cite this

Boerner, J. L., McManus, M. J., Martin, G. S., & Maihle, N. J. (2000). Ras-independent oncogenic transformation by an EGF-receptor mutant. Journal of Cell Science, 113(6), 935-942.

Ras-independent oncogenic transformation by an EGF-receptor mutant. / Boerner, Julie L.; McManus, Michael J.; Martin, G. Steven; Maihle, Nita Jane.

In: Journal of Cell Science, Vol. 113, No. 6, 12.04.2000, p. 935-942.

Research output: Contribution to journalArticle

Boerner, JL, McManus, MJ, Martin, GS & Maihle, NJ 2000, 'Ras-independent oncogenic transformation by an EGF-receptor mutant', Journal of Cell Science, vol. 113, no. 6, pp. 935-942.
Boerner JL, McManus MJ, Martin GS, Maihle NJ. Ras-independent oncogenic transformation by an EGF-receptor mutant. Journal of Cell Science. 2000 Apr 12;113(6):935-942.
Boerner, Julie L. ; McManus, Michael J. ; Martin, G. Steven ; Maihle, Nita Jane. / Ras-independent oncogenic transformation by an EGF-receptor mutant. In: Journal of Cell Science. 2000 ; Vol. 113, No. 6. pp. 935-942.
@article{62b3fcfea01e4274b1368f5c4aed1df9,
title = "Ras-independent oncogenic transformation by an EGF-receptor mutant",
abstract = "Mutations in the ligand-binding domain of the epidermal growth factor receptor have been identified in several types of human cancers, including malignant gliomas. These mutations render signaling by this receptor to be constitutively ligand-independent. In fibroblasts transformed with ligand-independent epidermal growth factor receptor mutants, there is a correlation between the formation of a unique phosphotyrosine protein complex and oncogenic transformation. This phosphoprotein complex includes Grb2, Shc, Sos, tyrosine-phosphorylated form of caldesmon, and two, as yet, unidentified proteins. The presence of Grb2, Shc, and Sos in this complex implicates Ras in ligand-independent signaling by these oncogenic epidermal growth factor receptor mutants. We, therefore, have used retroviral co-infections of cultured primary fibroblasts to determine if Ras activation is required for phosphoprotein complex formation, stress fiber loss, or transformation. As predicted, expression of a dominant-negative Ras mutant (N17Ras) completely abrogates ligand-stimulated soft agar colony growth of primary fibroblasts. In contrast, N17Ras expression has no effect on v-ErbB mediated stress fiber disassembly, soft agar colony growth, or phosphoprotein complex assembly. In addition, our data suggest that ligand-dependent Ras activation may be suppressed by oncogenic v-ErbB expression. Together these observations suggest that oncogenic signaling by v-ErbB does not require Ras activation, and implicate an alternative signal transduction pathway in ligand-independent epidermal growth factor receptor oncogenic signaling.",
keywords = "Chicken embryo fibroblast, Dominant-negative Ras, Stress fiber, V-ErbB",
author = "Boerner, {Julie L.} and McManus, {Michael J.} and Martin, {G. Steven} and Maihle, {Nita Jane}",
year = "2000",
month = "4",
day = "12",
language = "English (US)",
volume = "113",
pages = "935--942",
journal = "Journal of Cell Science",
issn = "0021-9533",
publisher = "Company of Biologists Ltd",
number = "6",

}

TY - JOUR

T1 - Ras-independent oncogenic transformation by an EGF-receptor mutant

AU - Boerner, Julie L.

AU - McManus, Michael J.

AU - Martin, G. Steven

AU - Maihle, Nita Jane

PY - 2000/4/12

Y1 - 2000/4/12

N2 - Mutations in the ligand-binding domain of the epidermal growth factor receptor have been identified in several types of human cancers, including malignant gliomas. These mutations render signaling by this receptor to be constitutively ligand-independent. In fibroblasts transformed with ligand-independent epidermal growth factor receptor mutants, there is a correlation between the formation of a unique phosphotyrosine protein complex and oncogenic transformation. This phosphoprotein complex includes Grb2, Shc, Sos, tyrosine-phosphorylated form of caldesmon, and two, as yet, unidentified proteins. The presence of Grb2, Shc, and Sos in this complex implicates Ras in ligand-independent signaling by these oncogenic epidermal growth factor receptor mutants. We, therefore, have used retroviral co-infections of cultured primary fibroblasts to determine if Ras activation is required for phosphoprotein complex formation, stress fiber loss, or transformation. As predicted, expression of a dominant-negative Ras mutant (N17Ras) completely abrogates ligand-stimulated soft agar colony growth of primary fibroblasts. In contrast, N17Ras expression has no effect on v-ErbB mediated stress fiber disassembly, soft agar colony growth, or phosphoprotein complex assembly. In addition, our data suggest that ligand-dependent Ras activation may be suppressed by oncogenic v-ErbB expression. Together these observations suggest that oncogenic signaling by v-ErbB does not require Ras activation, and implicate an alternative signal transduction pathway in ligand-independent epidermal growth factor receptor oncogenic signaling.

AB - Mutations in the ligand-binding domain of the epidermal growth factor receptor have been identified in several types of human cancers, including malignant gliomas. These mutations render signaling by this receptor to be constitutively ligand-independent. In fibroblasts transformed with ligand-independent epidermal growth factor receptor mutants, there is a correlation between the formation of a unique phosphotyrosine protein complex and oncogenic transformation. This phosphoprotein complex includes Grb2, Shc, Sos, tyrosine-phosphorylated form of caldesmon, and two, as yet, unidentified proteins. The presence of Grb2, Shc, and Sos in this complex implicates Ras in ligand-independent signaling by these oncogenic epidermal growth factor receptor mutants. We, therefore, have used retroviral co-infections of cultured primary fibroblasts to determine if Ras activation is required for phosphoprotein complex formation, stress fiber loss, or transformation. As predicted, expression of a dominant-negative Ras mutant (N17Ras) completely abrogates ligand-stimulated soft agar colony growth of primary fibroblasts. In contrast, N17Ras expression has no effect on v-ErbB mediated stress fiber disassembly, soft agar colony growth, or phosphoprotein complex assembly. In addition, our data suggest that ligand-dependent Ras activation may be suppressed by oncogenic v-ErbB expression. Together these observations suggest that oncogenic signaling by v-ErbB does not require Ras activation, and implicate an alternative signal transduction pathway in ligand-independent epidermal growth factor receptor oncogenic signaling.

KW - Chicken embryo fibroblast

KW - Dominant-negative Ras

KW - Stress fiber

KW - V-ErbB

UR - http://www.scopus.com/inward/record.url?scp=0034071737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034071737&partnerID=8YFLogxK

M3 - Article

VL - 113

SP - 935

EP - 942

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 6

ER -