Mitochondrially localized EGFR is independent of its endocytosis and associates with cell viability

Abstract

The molecular mechanism underlying epidermal growth factor receptor (EGFR) localization in mitochondria remains largely unknown. Using immune electron microscopy, we validated that EGFR could be localized on either the outer or the inner membrane of mitochondria. Mutant receptor lacked amino acids 646-660 was flawed in migration onto the organelles, whereas the mutated receptor with a defective endocytosis showed a greater capability of moving onto mitochondria upon stimulation of epidermal growth factor (EGF). Gefitinib, an inhibitor of EGFR kinase, inhibited the receptor endocytosis after short time of treatment, yet, only reduced cell viability as well as the amount of mitochondrial EGFR after longer time of exposure. Moreover, the content of mitochondrial EGFR transfer was decreased when the cells were exposed to the apoptotic inducer etoposide. EGF-induced programmed cell death usually coincided with a decline in mitochondrial EGFR. These data indicated that the mitochondrial-localized EGFR is independent of its internalization and may be correlated with cell survival and participate in the ligand-induced programmed cell death.

Involvement of de novo synthesized palmitate and mitochondrial EGFR in EGF induced mitochondrial fusion of cancer cells

“…Recent years have witnessed expansions of understanding of EGFR and HER2 functions from the plasma membrane to the nucleus 19 and to the mitochondria. [21][22][23]25,48 Our data reveal that cancer tissues contain mtEGFR and that mtEGFR play important roles in cancer cells. One of the questions that need to be addressed regarding the non-plasma membranous intracellular EGFRs is that what intracellular signal(s) is (are) involved in regulating their tyrosine kinase activity.…”

“…Besides the plasma membrane, EGFR can also exist in the nucleus 19,20 and in the mitochondrion. [21][22][23] In the nucleus, EGFR participates in transcriptional regulation. 24 The function of mitochondrial EGFR (mtEGFR) of cancer cells is largely unknown.…”

“…21,23 The localization of EGFR to the mitochondria is regulated by the activity of Src, 21,22,26 which is likely independent of the endocytosis of plasma membranous EGFR (pmEGFR). 23 Signals that can activate the mtEGFR and the role of mtEGFR activation in survival of cancer cells remain to be investigated.…”

Cetuximab induces mitochondrial translocalization of EGFRvIII, but not EGFR: involvement of mitochondria in tumor drug resistance?

“…Because we observed an increased AlamarBlue reduction after incubation with cetuximab, but no changes in cell number or BrdU labeling, we concluded that cetuximab might be directly modulating the mitochondrial activity. This is interesting in the context of recent reports that EGFR and EGFRvIII interact with mitochondria after their translocation from the cell surface [38][39][40]. However, the molecular mechanisms underlying the mitochondrial localization of EGFR or EGFRvIII remains largely [41].…”

Signaling of Receptor Tyrosine Kinases in the Nucleus

“…EGFR phosphorylated at Y845 was found in the mitochondria and interacted with cytochrome c oxidase subunit II (CoxII) to possibly regulate cell survival. The method by which EGFR is translocated to the mitochondria is unknown, but was not related to endocytotsis of the EGFR protein and did not involve the function of Shc adaptor proteins (Yao et al, 2010). Furthermore, deletion studies showed that a putative mitochondrial-targeting signal between amino acids 646 and 660 was only partially responsible for migration (Boerner et al, 2004).…”