Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival

Lo, Hui-Wen; Hung, Mien‐Chie

doi:10.1038/sj.bjc.6602941

Cited by 274 publications

(267 citation statements)

References 50 publications

(125 reference statements)

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“…[73][74][75] This localization has been most extensively studied for EGFR and has been proposed to involve routing from endosomes or direct extraction from cell membrane. Suggested functions for EGFR in the nucleus have included action as a transcription factor, a chromatin re-modeling agent, an agent in DNA repair and/or a signal transducer by means of its tyrosine kinase activity.…”

Section: Turnover Localization and Traffickingmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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Section: Turnover Localization and Traffickingmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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“…This is because many receptor tyrosine kinases are detected in the cell nucleus and function as transcription cofactors to activate gene promoters, such as the EGFR family (Lo and Hung, 2006). Nuclear translocation of EGFRs has been reported to play a critical role in cancer progression (Lo and Hung, 2006).…”

Section: Gastric Cancermentioning

confidence: 99%

The role of the VEGF-C/VEGFR-3 axis in cancer progression

et al. 2006

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Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) (also called VEGFR-3) is activated by its specific ligand, VEGF-C, which promotes cancer progression. The VEGF-C/VEGFR-3 axis is expressed not only by lymphatic endothelial cells but also by a variety of human tumour cells. Activation of the VEGF-C/VEGFR-3 axis in lymphatic endothelial cells can facilitate metastasis by increasing the formation of lymphatic vessels (lymphangiogenesis) within and around tumours. The VEGF-C/VEGFR-3 axis plays a critical role in leukaemic cell proliferation, survival, and resistance to chemotherapy. Moreover, activation of the VEGF-C/VEGFR-3 axis in several types of solid tumours enhances cancer cell mobility and invasion capabilities, promoting cancer cell metastasis. In this review, we discuss the novel function and molecular mechanism of the VEGF-C/VEGFR-3 axis in cancer progression.

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“…C ell surface EGF receptor (EGFR) has been shown to be localized in the nucleus (1)(2)(3)(4). Nuclear EGFR has been demonstrated to contribute to cancer cell resistance to cetuximab and radiation treatment (5,6) and to be negatively correlated with overall survival of patients with multiple cancer types (7)(8)(9)(10)(11).…”

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confidence: 99%

RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus

Huo

Wang

Xia

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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EGF induces the translocation of EGF receptor (EGFR) from the cell surface to the nucleus where EGFR activates gene transcription through its binding to an AT-rich sequence (ATRS) of the target gene promoter. However, how EGFR, without a DNA-binding domain, can bind to the gene promoter is unclear. In the present study, we show that RNA helicase A (RHA) is an important mediator for EGFRinduced gene transactivation. EGF stimulates the interaction of EGFR with RHA in the nucleus of cancer cells. The EGFR/RHA complex then associates with the target gene promoter through binding of RHA to the ATRS of the target gene promoter to activate its transcription. Knockdown of RHA expression in cancer cells abrogates the binding of EGFR to the target gene promoter, thereby reducing EGF/EGFR-induced gene expression. In addition, interruption of EGFR-RHA interaction decreases the EGFR-induced promoter activity. Consistently, we observed a positive correlation of the nuclear expression of EGFR, RHA, and cyclin D1 in human breast cancer samples. These results indicate that RHA is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus.cyclin D1 | nuclear translocation | inducible nitric oxide synthase | transcription C ell surface EGF receptor (EGFR) has been shown to be localized in the nucleus (1-4). Nuclear EGFR has been demonstrated to contribute to cancer cell resistance to cetuximab and radiation treatment (5, 6) and to be negatively correlated with overall survival of patients with multiple cancer types (7-11). Moreover, nuclear EGFR interacts with signal transducer and activator of transcription 3 (STAT3), signal transducer and activator of transcription 5A (STAT5A), E2F1, DNA-dependent protein kinase (DNA-PK), and proliferating cell nuclear antigen (PCNA) and plays important roles in cell transformation, proliferation, and DNA repair and replication (12-16). Nuclear EGFR regulates gene expression by binding to an AT-rich sequence (ATRS) of the gene's promoter (13,16,17). Additionally, a recent unbiased protein-DNA interactome study indicates that EGFR is a DNAbinding protein (18). However, EGFR does not contain a DNAbinding domain, and evidence supporting direct binding of EGFR to the specific DNA sequence is lacking. Thus, identifying the DNA-binding partner for EGFR is crucial for understanding how EGFR regulates gene transcription in the nucleus.RNA helicase A (RHA), the human homolog of Drosophila maleless (MLE) that increases the transcription of male X-linked genes (19), is a multifunctional protein and is conserved in Drosophila and mammals (20)(21)(22). RHA belongs to the aspartateglutamate-alanine-aspartate (DEAD) box family of proteins and has the ability to bind to RNA and DNA (23,24). RHA regulates gene transcription by interacting with transcription factors (22) or by binding directly to the target gene promoter (25). Moreover, Drosophila MLE activates rox2 transcription by binding to an ATrich region of the gene promoter (26). Interestingly, this AT-rich region contains the previo...

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Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival

Cited by 274 publications

References 50 publications

The ERBB3 receptor in cancer and cancer gene therapy

The ERBB3 receptor in cancer and cancer gene therapy

The role of the VEGF-C/VEGFR-3 axis in cancer progression

RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus

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