Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism

Abstract

It is well known that ErbB2, a receptor tyrosine kinase, localizes on the plasma membrane. Here we describe a novel observation that ErbB2 also localizes in mitochondria of cancer cells and patient samples. We found that ErbB2 translocates into mitochondria through the association with mtHSP70. Additionally, mitochondrial ErbB2 (mtErbB2) negatively regulates mitochondrial respiratory functions. Oxygen consumption and activities of complexes of the mitochondrial electron transport chain were decreased in mtErbB2-overexpressing cells. Mitochondrial membrane potential and the cellular ATP level also were decreased. In contrast, mtErbB2 enhanced cellular glycolysis. The translocation of ErbB2 and its impact on mitochondrial function are kinase dependent. Interestingly, cancer cells with higher levels of mtErbB2 were more resistant to ErbB2 targeting antibody trastuzumab. Our study provides a novel perspective on the metabolic regulatory function of ErbB2 and reveals that mtErbB2 plays an important role in the regulation of cellular metabolism and cancer cell resistance to therapeutics.

Journey to the Center of the Mitochondria Guided by the Tail Anchor of Protein Tyrosine Phosphatase 1B

“…regulation of mitochondrial EGFR signaling [41][42][43] ) and in the mitochondrial interior (e.g. regulation of activities of Src 33,36-40 and SHP2 33,40,44 , regulation of electron transport chain enzymes 34,35 ).…”

“…In particular, our library of PTP1B D/A chimeras that localize to each submitochondrial region (OMM, IMS, matrix) should provide a useful set of tools for future FLIM-based examination of its locally restricted engagement with substrates. Its potential regulation of basic mitochondrial functioning could be revealed using assays for cellular oxygen consumption, electron transport chain activity, glucose uptake, lactate production, or the ATP/ADP ratio 43 . Finally, methods for detecting different post-translationally modified isoforms of PTP1B (phosphorylated, oxidized, sumoylated, cleaved) would be useful to develop and employ for discerning any potential differences (that may have functional consequences) of mitochondrial PTP1B subfractions from its more distributed pool along the ER.…”

“…PTB-mCherry displayed a basal recruitment to the mitochondria that significantly increased upon EGF stimulation. The PTB-mCherry probe may be detecting important Shc substrates like the receptor tyrosine kinases ErbB1 and ErbB2, for which mitochondrial pools have recently been claimed [41][42][43] .…”

“…As previous studies reporting the localization of ErbB1 or ErbB2 to mitochondria were performed using cells that either naturally overexpressed c-Src (breast cancer cells 43 ) or were cotransfected with a c-Src construct (10T1/2 cells 41,42 ), we undertook a separate set of experiments in which COS-7 cells were transfected with ErbB1-mCitrine, c-Src-mTurquoise, and Tom20-mTagBFP. In these experiments, we also observed no detectable mitochondrial presence of the fluorescently labeled c-Src or ErbB1 (data not shown).…”

“…PTP1B's potential presence at the mitochondria could be important for regulation of the mitochondrial phosphotyrosine proteome 34 , with important targets including several enzymes in the electron transport chain 35 , Src family kinases that localize to the mitochondria 33,[36][37][38][39][40] , or other well-established substrates of PTP1B that also have been detected at the mitochondria like the EGF receptors ErbB1 41,42 and ErbB2 43 and the tyrosine phosphatase SHP2 33,40,44 . PTP1B's mitochondrial localization, though, should be confirmed first (in particular, for more general cell lines), before further speculating on how it may reach this organelle or how its interaction there with putative as well as known substrates might affect basic mitochondrial functions.…”