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A novel epidermal growth factor receptor variant lacking multiple domains directly activates transcription and is overexpressed in tumors

Oncogene volume 31, pages 2953–2967 (2012)Cite this article

Abstract

The epidermal growth factor receptor (EGFR) is essential to multiple physiological and neoplastic processes via signaling by its tyrosine kinase domain and subsequent activation of transcription factors. EGFR overexpression and alteration, including point mutations and structural variants, contribute to oncogenesis in many tumor types. In this study, we identified an in-frame splice variant of the EGFR called mini-LEEK (mLEEK) that is more broadly expressed than the EGFR and is overexpressed in several cancers. Unlike previously characterized EGFR variants, mLEEK lacks the extracytoplasmic, transmembrane and tyrosine kinase domains. mLEEK localizes in the nucleus and functions as a transcription factor to regulate target genes involved in the cellular response to endoplasmic reticulum (ER) stress, including the master regulator of the unfolded protein response (UPR) pathways, molecular chaperone GRP78/Bip. We demonstrated that mLEEK regulates GRP78 transcription through direct interaction with a cis-regulatory element within the gene promoter. Several UPR pathways were interrogated and mLEEK expression was found to attenuate the induction of all pathways upon ER stress. Conversely, knockdown of mLEEK resulted in caspase-mediated cell death and sensitization to ER stress. These findings indicate that mLEEK levels determine cellular responses to unfavorable conditions that cause ER stress. This information, along with the overexpression of mLEEK in tumors, suggests unique strategies for therapeutic intervention. Furthermore, the identification of mLEEK expands the known mechanisms by which the EGFR gene contributes to oncogenesis and represents the first link between two previously disparate areas in cancer cell biology: EGFR signaling and the UPR.

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Acknowledgements

We thank R Nitta, G Li, S Mitra, C Del Vecchio and M Holgado-Madruga for comments. We thank K Mori, K Kokame, R Prywes and G Nolan for reagents. This work was supported by the NIH under Ruth L Kirschstein National Research Service Award F31 NS056581 from the NINDS to ECP, the Ovarian SPORE at FCCC (P50 CA083638) to AKG and AJW, NIH Grants R01 CA69495, R01 CA096539 and R01 CA124832, as well as a research grant from the National Brain Tumor Foundation and Grant 15IB-0080 from the California Breast Cancer Program to AJW.

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Authors and Affiliations

  1. Department of Neurosurgery and Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA

    E C Piccione, T J Lieu, C F Gentile, T R Williams & A J Wong

  2. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    A J Connolly

  3. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    A K Godwin

  4. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA

    A C Koong

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  1. E C Piccione
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Piccione, E., Lieu, T., Gentile, C. et al. A novel epidermal growth factor receptor variant lacking multiple domains directly activates transcription and is overexpressed in tumors. Oncogene 31, 2953–2967 (2012). https://doi.org/10.1038/onc.2011.465

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