Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival

Dayde, D.; Guerard, M.; Perron, Pascal; As, Hatat; Barrial, C.; Eymin, Béatrice; Gazzéri, Sylvie

doi:10.1038/onc.2015.480

Cited by 26 publications

(20 citation statements)

References 53 publications

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“…Immunoprecipitation revealed that binding of MUC1 and phosphorylated EGFR was considerably increased by PTX treatment and effectively blocked by erlotinib ( Supplementary Figure S5E ). Given that multiple lines of studies have implicated MUC1 26 , 28 , 39 and EGFR 40 in transcription regulation as coactivators, we next investigated whether PTX-induced interaction between MUC1 and EGFR in the nucleus could contribute to transcriptional of ABCB1. To this end, ChIP assay was carried out in both HeLa229 and HeLa229/TR cells.…”

Section: Resultsmentioning

confidence: 99%

MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner

Jin

Liao

et al. 2017

Cell Death Dis

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Chemoresistance contributes to cancer relapse and increased mortality in a variety of cancer types, raising a pressing need to better understand the underlying mechanism. MUC1 is abnormally overexpressed in numerous carcinomas and associated with poor prognosis. However, the functional significance of MUC1 in chemoresistance has not been fully elucidated. Here, we showed that MUC1 expression was considerably induced in cells that had acquired chemoresistance at both transcriptional and post-translational levels. Using gain- and loss-of function approaches, we demonstrated a critical role of MUC1 in induction of drug resistance. Through stimulation of EGFR activation and nuclear translocation, MUC1 increased the expression of ATP-binding cassette transporter B1 (ABCB1). Remarkably, targeted suppression of EGFR or ABCB1 by both shRNAs and inhibitors effectively reversed chemoresistance. Moreover, co-administration of the inhibitors of MUC1–EGFR–ABCB1 with paclitaxel significantly blocked not only tumor growth but also relapse in xenograft mouse model. Our data collectively support a model in which MUC1 induces acquired chemotherapy resistance by upregulating ABCB1 in an EGFR-dependent manner, providing a novel molecular basis of using the EGFR inhibitor in MUC1-positive cancers to prevent chemotherapy resistance.

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Section: Resultsmentioning

confidence: 99%

MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner

Jin

Liao

et al. 2017

Cell Death Dis

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“…To fully understand the signaling pathways associated with nEGFR in cancer evolution, the protein-protein interaction maps of membrane EGFR and nEGFR were compared. STRING software and previous studies on EGFR pathways were used to construct interaction maps of membrane EGFR and nEGFR 40 - 44 . The results show that common frequent interaction nodes for both nEGFR and membrane EGFR are STAT 3, GRB 2, BCAR1, and STAT 1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Analysis of origin and protein-protein interaction maps suggests distinct oncogenic role of nuclear EGFR during cancer evolution

et al. 2017

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Receptor tyrosine kinase EGFR usually is localized on plasma membrane to induce progression of many cancers including cancers in children (Bodey et al. In Vivo. 2005, 19:931-41), but it contains a nuclear localization signal (NLS) that mediates EGFR nuclear translocation (Lin et al. Nat Cell Biol. 2001, 3:802-8). Here we report that NLS of EGFR has its old evolutionary origin. Protein-protein interaction maps suggests that nEGFR pathways are different from membrane EGFR and EGF is not found in nEGFR network while androgen receptor (AR) is found, which suggests the evolution of prostate cancer, a well-known AR driven cancer, through changes in androgen- or EGF-dependence. Database analysis suggests that nEGFR correlates with the tumor grades especially in prostate cancer patients. Structural predication analysis suggests that NLS can compromise the differential protein binding to EGFR through stretch linkers with evolutionary mutation from N to V. In experiment, elevation of nEGFR but not membrane EGFR was found in castration resistant prostate cancer cells. Finally, systems analysis of NLS and transmembrane domain (TM) suggests that NLS has old origin while NLS neighboring domain of TM has been undergone accelerated evolution. Thus nEGFR has an old origin resembling the cancer evolution but TM may interfere with NLS driven signaling for natural selection of survival to evade NLS induced aggressive cancers. Our data suggest NLS is a dynamic inducer of EGFR oncogenesis during evolution for advanced cancers. Our model provides novel insights into the evolutionary role of NLS of oncogenic kinases in cancers.

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“…Nuclear EGFR is known to play an important role in tumours. Nuclear transport of EGFR is mediated by vesicular trafficking protein Vps34, and EGFR is recruited to the Arf promoter to repress the transcription of Arf tumour suppressor [ 38 ]. Moreover, in renal cell carcinoma, recent evidence indicates that the membranous expression of EGFR has a correlation with poorly differentiated and high nuclear grade tumours, while nuclear EGFR expression is high in well differentiated and low nuclear grade tumours [ 39 ].…”

Section: The Nuclear Transportation Routes Of Plasma Membrane-bound Pmentioning

confidence: 99%

The nuclear transportation routes of membrane-bound transcription factors

Liu

Fan

et al. 2018

Cell Commun Signal

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Membrane-bound transcription factors (MTFs) are transcription factors (TFs) that are anchored in membranes in a dormant state. Activated by external or internal stimuli, MTFs are released from parent membranes and are transported to the nucleus. Existing research indicates that some plasma membrane (PM)-bound proteins and some endoplasmic reticulum (ER) membrane-bound proteins have the ability to enter the nucleus. Upon specific signal recognition cues, some PM-bound TFs undergo proteolytic cleavage to liberate the intracellular fragments that enter the nucleus to control gene transcription. However, lipid-anchored PM-bound proteins enter the nucleus in their full length for depalmitoylation. In addition, some PM-bound TFs exist as full-length proteins in cell nucleus via trafficking to the Golgi and the ER, where membrane-releasing mechanisms rely on endocytosis. In contrast, the ER membrane-bound TFs relocate to the nucleus directly or by trafficking to the Golgi. In both of these pathways, only the fragments of the ER membrane-bound TFs transit to the nucleus. Several different nuclear trafficking modes of MTFs are summarized in this review, providing an effective supplement to the mechanisms of signal transduction and gene regulation. Moreover, targeting intracellular movement pathways of disease-associated MTFs may significantly improve the survival of patients.

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Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival

Cited by 26 publications

References 53 publications

MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner

MUC1 induces acquired chemoresistance by upregulating ABCB1 in EGFR-dependent manner

Analysis of origin and protein-protein interaction maps suggests distinct oncogenic role of nuclear EGFR during cancer evolution

The nuclear transportation routes of membrane-bound transcription factors

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