Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR

X. Li, Y. Lu, K. Liang, J. M. Hsu, C. Albarracin, Gordon Mills, M. C. Hung, Z. Fan

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Epidermal growth factor receptor (EGFR)-mediated cell signaling is critical for mammary epithelial cell growth and survival; however, targeting EGFR has shown no or only minimal therapeutic benefit in patients with breast cancer. Here, we report a novel regulatory mechanism of EGFR signaling that may explain the low response rates. We found that breast tumor kinase (Brk)/protein-tyrosine kinase 6 (PTK6), a nonreceptor protein-tyrosine kinase highly expressed in most human breast tumors, interacted with EGFR and sustained ligand-induced EGFR signaling. We demonstrate that Brk inhibits ligand-induced EGFR degradation through uncoupling activated EGFR from casitas B-lineage lymphoma-mediated EGFR ubiquitination. In addition, upon activation by EGFR, Brk directly phosphorylated Y845 in the EGFR kinase domain, thereby further potentiating EGFR kinase activity. Experimental elevation of Brk conferred resistance of breast cancer cells to cetuximab (an EGFR-blocking antibody)-induced inhibition of cell signaling and proliferation, whereas knockdown of Brk sensitized the cells to cetuximab by inducing apoptosis. Our findings reveal a previously unknown role of Brk in EGFR-targeted therapy.

Original languageEnglish (US)
Pages (from-to)4372-4383
Number of pages12
JournalOncogene
Volume31
Issue number40
DOIs
StatePublished - Oct 4 2012
Externally publishedYes

Fingerprint

Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Phosphotransferases
Breast Neoplasms
Ligands
Blocking Antibodies
Ubiquitination
Lymphoma
Cell Survival
Breast
Epithelial Cells
Cell Proliferation
Apoptosis

Keywords

  • breast cancer
  • Brk
  • Cbl
  • EGFR
  • Src

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR. / Li, X.; Lu, Y.; Liang, K.; Hsu, J. M.; Albarracin, C.; Mills, Gordon; Hung, M. C.; Fan, Z.

In: Oncogene, Vol. 31, No. 40, 04.10.2012, p. 4372-4383.

Research output: Contribution to journalArticle

Li, X, Lu, Y, Liang, K, Hsu, JM, Albarracin, C, Mills, G, Hung, MC & Fan, Z 2012, 'Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR', Oncogene, vol. 31, no. 40, pp. 4372-4383. https://doi.org/10.1038/onc.2011.608
Li, X. ; Lu, Y. ; Liang, K. ; Hsu, J. M. ; Albarracin, C. ; Mills, Gordon ; Hung, M. C. ; Fan, Z. / Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR. In: Oncogene. 2012 ; Vol. 31, No. 40. pp. 4372-4383.
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