Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling

K. Shtiegman, B. S. Kochupurakkal, Y. Zwang, G. Pines, A. Starr, A. Vexler, A. Citri, M. Katz, S. Lavi, Y. Ben-Basat, S. Benjamin, S. Corso, J. Gan, R. B. Yosef, S. Giordano, Y. Yarden

Research output: Contribution to journalArticle

Abstract

Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.

Original languageEnglish
Pages (from-to)6968-6978
Number of pages11
JournalOncogene
Volume26
Issue number49
DOIs
Publication statusPublished - Oct 25 2007

Fingerprint

Epidermal Growth Factor Receptor
Lung Neoplasms
Oncogene Proteins
Endocytosis
Lysosomes
Non-Small Cell Lung Carcinoma
Phosphotransferases
Down-Regulation
Ligands
Mutation

Keywords

  • Endocytosis
  • Gefitinib
  • Growth factor
  • NSCLC
  • Tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Shtiegman, K., Kochupurakkal, B. S., Zwang, Y., Pines, G., Starr, A., Vexler, A., ... Yarden, Y. (2007). Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. Oncogene, 26(49), 6968-6978. https://doi.org/10.1038/sj.onc.1210503

Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. / Shtiegman, K.; Kochupurakkal, B. S.; Zwang, Y.; Pines, G.; Starr, A.; Vexler, A.; Citri, A.; Katz, M.; Lavi, S.; Ben-Basat, Y.; Benjamin, S.; Corso, S.; Gan, J.; Yosef, R. B.; Giordano, S.; Yarden, Y.

In: Oncogene, Vol. 26, No. 49, 25.10.2007, p. 6968-6978.

Research output: Contribution to journalArticle

Shtiegman, K, Kochupurakkal, BS, Zwang, Y, Pines, G, Starr, A, Vexler, A, Citri, A, Katz, M, Lavi, S, Ben-Basat, Y, Benjamin, S, Corso, S, Gan, J, Yosef, RB, Giordano, S & Yarden, Y 2007, 'Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling', Oncogene, vol. 26, no. 49, pp. 6968-6978. https://doi.org/10.1038/sj.onc.1210503
Shtiegman K, Kochupurakkal BS, Zwang Y, Pines G, Starr A, Vexler A et al. Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. Oncogene. 2007 Oct 25;26(49):6968-6978. https://doi.org/10.1038/sj.onc.1210503
Shtiegman, K. ; Kochupurakkal, B. S. ; Zwang, Y. ; Pines, G. ; Starr, A. ; Vexler, A. ; Citri, A. ; Katz, M. ; Lavi, S. ; Ben-Basat, Y. ; Benjamin, S. ; Corso, S. ; Gan, J. ; Yosef, R. B. ; Giordano, S. ; Yarden, Y. / Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. In: Oncogene. 2007 ; Vol. 26, No. 49. pp. 6968-6978.
@article{26bfd981b3b647eca4324082213b4a19,
title = "Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling",
abstract = "Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.",
keywords = "Endocytosis, Gefitinib, Growth factor, NSCLC, Tyrosine kinase",
author = "K. Shtiegman and Kochupurakkal, {B. S.} and Y. Zwang and G. Pines and A. Starr and A. Vexler and A. Citri and M. Katz and S. Lavi and Y. Ben-Basat and S. Benjamin and S. Corso and J. Gan and Yosef, {R. B.} and S. Giordano and Y. Yarden",
year = "2007",
month = "10",
day = "25",
doi = "10.1038/sj.onc.1210503",
language = "English",
volume = "26",
pages = "6968--6978",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "49",

}

TY - JOUR

T1 - Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling

AU - Shtiegman, K.

AU - Kochupurakkal, B. S.

AU - Zwang, Y.

AU - Pines, G.

AU - Starr, A.

AU - Vexler, A.

AU - Citri, A.

AU - Katz, M.

AU - Lavi, S.

AU - Ben-Basat, Y.

AU - Benjamin, S.

AU - Corso, S.

AU - Gan, J.

AU - Yosef, R. B.

AU - Giordano, S.

AU - Yarden, Y.

PY - 2007/10/25

Y1 - 2007/10/25

N2 - Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.

AB - Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.

KW - Endocytosis

KW - Gefitinib

KW - Growth factor

KW - NSCLC

KW - Tyrosine kinase

UR - http://www.scopus.com/inward/record.url?scp=35549013373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35549013373&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1210503

DO - 10.1038/sj.onc.1210503

M3 - Article

C2 - 17486068

AN - SCOPUS:35549013373

VL - 26

SP - 6968

EP - 6978

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 49

ER -