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Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a...

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Autores principales: Hua, Fang, Hao, Wenzhuo, Wang, Lingyan, Li, Shitao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585052/
https://www.ncbi.nlm.nih.gov/pubmed/34769306
http://dx.doi.org/10.3390/ijms222111875
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author Hua, Fang
Hao, Wenzhuo
Wang, Lingyan
Li, Shitao
author_facet Hua, Fang
Hao, Wenzhuo
Wang, Lingyan
Li, Shitao
author_sort Hua, Fang
collection PubMed
description Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-κB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) were required for EGFR-mediated NF-κB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IκB phosphorylation and subsequent NF-κB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-κB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-κB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR and that perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy.
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spelling pubmed-85850522021-11-12 Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development Hua, Fang Hao, Wenzhuo Wang, Lingyan Li, Shitao Int J Mol Sci Article Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-κB signaling pathway, to induce cell differentiation and proliferation. Overexpression and mutations of EGFR are found in up to 30% of solid tumors and correlate with a poor prognosis. Although it is known that EGFR-mediated NF-κB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) were required for EGFR-mediated NF-κB activation. Upon EGF stimulation, EGFR recruited PKP2 to the plasma membrane, and PKP2 bridged HOIP, the catalytic E3 ubiquitin ligase in the LUBAC, to the EGFR complex. The recruitment activated the LUBAC complex and the linear ubiquitination of NEMO, leading to IκB phosphorylation and subsequent NF-κB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-κB activity and reduced cell proliferation. HOIP knockout also abrogated the growth of A431 epidermal xenograft tumors in nude mice by more than 70%. More importantly, the HOIP inhibitor, HOIPIN-8, inhibited EGFR-mediated NF-κB activation and cell proliferation of A431, MCF-7, and MDA-MB-231 cancer cells. Overall, our study reveals a novel linear ubiquitination signaling axis of EGFR and that perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy. MDPI 2021-11-02 /pmc/articles/PMC8585052/ /pubmed/34769306 http://dx.doi.org/10.3390/ijms222111875 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hua, Fang
Hao, Wenzhuo
Wang, Lingyan
Li, Shitao
Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
title Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
title_full Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
title_fullStr Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
title_full_unstemmed Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
title_short Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
title_sort linear ubiquitination mediates egfr-induced nf-κb pathway and tumor development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585052/
https://www.ncbi.nlm.nih.gov/pubmed/34769306
http://dx.doi.org/10.3390/ijms222111875
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AT haowenzhuo linearubiquitinationmediatesegfrinducednfkbpathwayandtumordevelopment
AT wanglingyan linearubiquitinationmediatesegfrinducednfkbpathwayandtumordevelopment
AT lishitao linearubiquitinationmediatesegfrinducednfkbpathwayandtumordevelopment