PMC:5541714 / 1222-4635 JSONTXT

{"project":"2_test","denotations":[{"id":"28714950-18815398-79090972","span":{"begin":149,"end":150},"obj":"18815398"},{"id":"28714950-21125677-79090973","span":{"begin":392,"end":393},"obj":"21125677"},{"id":"28714950-22261334-79090974","span":{"begin":744,"end":745},"obj":"22261334"},{"id":"28714950-22261334-79090975","span":{"begin":828,"end":829},"obj":"22261334"},{"id":"28714950-11533659-79090976","span":{"begin":905,"end":906},"obj":"11533659"},{"id":"28714950-19840943-79090977","span":{"begin":1120,"end":1121},"obj":"19840943"},{"id":"28714950-26497368-79090978","span":{"begin":1259,"end":1260},"obj":"26497368"},{"id":"28714950-23232401-79090979","span":{"begin":1414,"end":1415},"obj":"23232401"},{"id":"28714950-9683573-79090980","span":{"begin":1853,"end":1854},"obj":"9683573"},{"id":"28714950-11707338-79090981","span":{"begin":1974,"end":1975},"obj":"11707338"},{"id":"28714950-10411904-79090982","span":{"begin":2151,"end":2153},"obj":"10411904"},{"id":"28714950-16531398-79090983","span":{"begin":2311,"end":2313},"obj":"16531398"},{"id":"28714950-19935715-79090984","span":{"begin":2532,"end":2534},"obj":"19935715"},{"id":"28714950-19900451-79090985","span":{"begin":2690,"end":2692},"obj":"19900451"},{"id":"28714950-15520177-79090986","span":{"begin":2966,"end":2968},"obj":"15520177"},{"id":"28714950-19681071-79090987","span":{"begin":2970,"end":2972},"obj":"19681071"},{"id":"28714950-21242965-79090988","span":{"begin":2974,"end":2976},"obj":"21242965"},{"id":"28714950-23698466-79090989","span":{"begin":3168,"end":3170},"obj":"23698466"}],"text":"Introduction\nLung cancer is the leading cause of cancer death worldwide, and non-small cell lung cancer (NSCLC) is the dominant type of this disease.1 Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that acts as the major driver of NSCLC; it regulates important tumorigenic processes, including proliferation, apoptosis, angiogenesis, invasion and drug resistance.2 EGFR is well known to localize to the plasma membrane, where it phosphorylates downstream substrates on their tyrosine residues in response to extracellular stimulation. Activated EGFR normally undergoes endocytosis and subsequent transportation to various organelles for degradation, recycling, or to perform functions that remain poorly understood.3 Recent studies showed that EGFR can translocate into the nucleus and mitochondria,3 but although nuclear EGFR is thought to function as a transcription factor,4 relatively little is known about the translocation/function of mitochondrial EGFR. We do know that EGF stimulation enhances the mitochondrial localization of EGFR and decreases cellular ATP in breast cancer cells,5 and that the mitochondrial translocation of EGFR enhances NSCLC cancer cell invasion and metastasis by regulating mitochondrial dynamics.6 Moreover, ErbB2, another member of the EGFR protein family, reportedly translocated into mitochondria and regulates cellular metabolism in breast cancer.7 These studies suggest that the localization of EGFR to mitochondria can affect cellular metabolism related to tumorigenesis. To date, however, little is known about how the mitochondrial localization of EGFR is regulated.\nTid1, which is also known as mitochondrial heat shock protein 40 (mtHSP40), contains a conserved DnaJ domain through which it interacts with members of the heat shock protein 70 (HSP70) family of chaperone proteins.8 Two alternatively spliced isoforms, Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S), are expressed in human cells.9 The N-terminus of Tid1 bears a mitochondrial signal sequence, and a major fraction of endogenous or ectopically expressed Tid1 was found to reside in the mitochondrial matrix.10 Tid1-L has a greater cytosolic stability and a lower rate of mitochondrial import compared with Tid1-S, meaning that Tid1-S predominates in the mitochondria.11 Tid1 has been shown to form a complex with p53 under hypoxic conditions; this complex directs the mitochondrial translocation of p53 and the subsequent initiation of the mitochondrial apoptosis pathway in breast cells.12 Mitochondrial Tid1 has been shown to interact with the amino-terminal segment of adenomatous polyposis cell (APC) tumor suppressor to facilitate apoptosis.13 Therefore, Tid1 appears to participate in transporting candidate proteins to mitochondria and regulating the function of mitochondrial proteins.\nSeveral studies have indicated that Tid1 is involved in regulating RTK-mediated signaling, such as through EGFR, ErbB2 and cMet.14, 15, 16 Our group has recently shown that Tid1-L can interact with EGFR through the HSP90/HSP70 complex, and that it inhibits EGFR signaling by enhancing the ubiquitinylation and degradation of EGFR.17 However, it is not yet known whether Tid1 can participate in the mitochondrial translocation of EGFR and/or regulate its functions in mitochondria. In this work, we examined the role of Tid1 in the mitochondrial localization of EGFR in NSCLC."}