Aberrant trafficking of NSCLC-associated EGFR mutants through the endocytic recycling pathway promotes interaction with Src

Byung M. Chung, Srikumar M. Raja, Robert J. Clubb, Chun Tu, Manju George, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Background: Epidermal growth factor receptor (EGFR) controls a wide range of cellular processes, and altered EGFR signaling contributes to human cancer. EGFR kinase domain mutants found in non-small cell lung cancer (NSCLC) are constitutively active, a trait critical for cell transformation through activation of downstream pathways. Endocytic trafficking of EGFR is a major regulatory mechanism as ligand-induced lysosomal degradation results in termination of signaling. While numerous studies have examined mutant EGFR signaling, the endocytic traffic of mutant EGFR within the NSCLC milieu remains less clear. Results: This study shows that mutant EGFRs in NSCLC cell lines are constitutively endocytosed as shown by their colocalization with the early/recycling endosomal marker transferrin and the late endosomal/lysosomal marker LAMP1. Notably, mutant EGFRs, but not the wild-type EGFR, show a perinuclear accumulation and colocalization with recycling endosomal markers such as Rab11 and EHD1 upon treatment of cells with endocytic recycling inhibitor monensin, suggesting that mutant EGFRs preferentially traffic through the endocytic recycling compartments. Importantly, monensin treatment enhanced the mutant EGFR association and colocalization with Src, indicating that aberrant transit through the endocytic recycling compartment promotes mutant EGFR-Src association. Conclusion: The findings presented in this study show that mutant EGFRs undergo aberrant traffic into the endocytic recycling compartment which allows mutant EGFRs to engage in a preferential interaction with Src, a critical partner for EGFR-mediated oncogenesis.

Original languageEnglish (US)
Article number84
JournalBMC Cell Biology
Volume10
DOIs
StatePublished - Nov 30 2009

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Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Monensin
Recycling
Transferrin
Endocytosis
Carcinogenesis
Ligands
Cell Line

ASJC Scopus subject areas

  • Cell Biology

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Aberrant trafficking of NSCLC-associated EGFR mutants through the endocytic recycling pathway promotes interaction with Src. / Chung, Byung M.; Raja, Srikumar M.; Clubb, Robert J.; Tu, Chun; George, Manju; Band, Vimla; Band, Hamid.

In: BMC Cell Biology, Vol. 10, 84, 30.11.2009.

Research output: Contribution to journalArticle

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