Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis.

Julie L. Boerner, Andrew J. Danielsen, Courtney A. Lovejoy, Z. Wang, Subhash C. Juneja, Jessica M. Faupel-Badger, Jaime R. Darce, Nita J. Maihle

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Mutations within members of the EGF/ErbB receptor family frequently release the oncogenic potential of these receptors, resulting in the activation of downstream signaling events independent of ligand regulatory constraints. We previously have demonstrated that the signal transduction events originating from S3-v-ErbB, a ligand-independent, oncogenic EGF receptor mutant, are qualitatively distinct from the ligand-dependent mitogenic signaling pathways associated with the wild-type EGF receptor. Specifically, expression of S3-v-ErbB in primary fibroblasts results in anchorage-independent growth, increased invasive potential, and the formation of a transformation-specific phosphoprotein signaling complex, all in a Ras-independent manner. Here we demonstrate the transformation-specific interaction between two components of this complex: the adaptor protein Grb2 and the cytoskeletal regulatory protein caldesmon. This interaction is mediated via both the amino-terminal SH3 and central SH2 domains of Grb2, and the amino-terminal (myosin-binding) domain of caldesmon. Expression of a dominant-negative Grb2 deletion mutant, which lacks the carboxy-terminal SH3 domain, in fibroblasts expressing S3-v-ErbB results in a reduction in phosphoprotein complex formation, the loss of anchorage-independent growth, and a reduction in invasive potential. Together, these results demonstrate a Ras-independent role for Grb2 in modulating cytoskeletal function during ligand-independent EGF receptor-mediated transformation, and provide further support for the hypothesis that ligand-independent oncogenic signaling is qualitatively distinct from ligand-dependent mitogenic signaling by the EGF receptor.

Original languageEnglish (US)
Pages (from-to)6679-6689
Number of pages11
JournalOncogene
Volume22
Issue number43
StatePublished - Oct 2 2003

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Actin Cytoskeleton
Carcinogenesis
Epidermal Growth Factor Receptor
Ligands
Calmodulin-Binding Proteins
src Homology Domains
Phosphoproteins
Fibroblasts
Cytoskeletal Proteins
Myosins
Growth
Signal Transduction
EGF Family of Proteins
Mutation
Proteins

Keywords

  • Caldesmon
  • EGFR/ErbB
  • Grb2
  • v-ErbB

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Boerner, J. L., Danielsen, A. J., Lovejoy, C. A., Wang, Z., Juneja, S. C., Faupel-Badger, J. M., ... Maihle, N. J. (2003). Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis. Oncogene, 22(43), 6679-6689.

Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis. / Boerner, Julie L.; Danielsen, Andrew J.; Lovejoy, Courtney A.; Wang, Z.; Juneja, Subhash C.; Faupel-Badger, Jessica M.; Darce, Jaime R.; Maihle, Nita J.

In: Oncogene, Vol. 22, No. 43, 02.10.2003, p. 6679-6689.

Research output: Contribution to journalArticle

Boerner, JL, Danielsen, AJ, Lovejoy, CA, Wang, Z, Juneja, SC, Faupel-Badger, JM, Darce, JR & Maihle, NJ 2003, 'Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis.', Oncogene, vol. 22, no. 43, pp. 6679-6689.
Boerner JL, Danielsen AJ, Lovejoy CA, Wang Z, Juneja SC, Faupel-Badger JM et al. Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis. Oncogene. 2003 Oct 2;22(43):6679-6689.
Boerner, Julie L. ; Danielsen, Andrew J. ; Lovejoy, Courtney A. ; Wang, Z. ; Juneja, Subhash C. ; Faupel-Badger, Jessica M. ; Darce, Jaime R. ; Maihle, Nita J. / Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis. In: Oncogene. 2003 ; Vol. 22, No. 43. pp. 6679-6689.
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