Tid1-S regulates the mitochondrial localization of EGFR in non-small cell lung carcinoma

Abstract

The epidermal growth factor receptor (EGFR) is the major driver of non-small cell lung carcinoma (NSCLC). Mitochondrial accumulation of EGFR has been shown to promote metastasis in NSCLC, yet little is known about how the mitochondrial localization of EGFR is regulated. In this work, we show that Tid1 (also known as mitochondrial HSP40) is involved in the mitochondrial localization of EGFR, and that the DnaJ domain of Tid1-S is essential for the Tid1-S-mediated transportation of EGFR into mitochondria. Overexpression of Tid1-S increased the migration and invasion of NSCLC cells cultured in vitro. High levels of EGFR and Tid1-S were detected in the mitochondria of cancerous lesions from stage IV NSCLC patients, and high levels of mitochondrial Tid1-S/EGFR were correlated with lymph node metastasis and poor overall survival of NSCLC patients. We thus conclude that Tid1-S critically governs the mitochondrial localization of EGFR through the mtHSP70 transportation pathway, and that the mitochondrial accumulation of EGFR appears to promote metastasis in NSCLC.

Profiling of subcellular EGFR interactome reveals hnRNP A3 modulates nuclear EGFR localization

“…The EGFR-interacting proteins in mitochondria were found to correlate with precursor metabolite generation, energy production, and mitochondrion organization ( Table 1). The mitochondrial EGFR-interactome included Dnaja3 ( Table 1, also known as Tid-1); this protein has been shown to govern the mitochondrial localization of EGFR, and the mitochondrial accumulation of EGFR has been shown to promote metastasis in NSCLC 33 . While the functions of mitochondrial EGFR remain poorly understood, our pathway analyses revealed that many of the mitochondrial EGFR-interacting proteins are involved in the metabolism of propanoate, fatty acids, and degradation of valine, leucine, and isoleucine ( Table 2).…”

“…Nuclear, cytoplasmic, and mitochondrial fractions were obtained from lung cancer cells using a Qproteome mitochondria isolation kit (Qiagen, Venlo, Netherlands) according to the manufacturer's protocol 33 . Cells were suspended in a lysis buffer, which selectively disrupts the cell membrane without solubilizing it, resulting in the isolation of cytosolic proteins.…”

“…Western blotting, immunoprecipitation, and immunofluorescence (IF) were performed as described previously 24,33 . The distributions of hnRNP A3 and EGFR in NSCLC tissues and cells were determined by IF staining as described previously 33 .…”

“…Western blotting, immunoprecipitation, and immunofluorescence (IF) were performed as described previously 24,33 . The distributions of hnRNP A3 and EGFR in NSCLC tissues and cells were determined by IF staining as described previously 33 . Cells or tissues were visualized under confocal microscopy (LSM 700; Carl Zeiss, Jena, Germany) and the MetaMorph software was used to examine colocalization (MetaMorph Inc., Nashville, TN, USA).…”

Hydroxygenkwanin Suppresses Non-Small Cell Lung Cancer Progression by Enhancing EGFR Degradation

“…IHC was performed, as described previously [29]. The primary antibodies used for staining were targeted against EGFR and pEGFR [32].…”