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:	Fang Hua, Wenzhuo Hao, Lingyan Wang, Shitao Li
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	EGF LUBAC HOIP PKP2 linear ubiquitin NF-κB Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/663c777444d242aaa0f64d832fa99e9e
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spelling	oai:doaj.org-article:663c777444d242aaa0f64d832fa99e9e2021-11-11T17:17:51ZLinear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development10.3390/ijms2221118751422-00671661-6596https://doaj.org/article/663c777444d242aaa0f64d832fa99e9e2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11875https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Epidermal 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.Fang HuaWenzhuo HaoLingyan WangShitao LiMDPI AGarticleEGFLUBACHOIPPKP2linear ubiquitinNF-κBBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11875, p 11875 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	EGF LUBAC HOIP PKP2 linear ubiquitin NF-κB Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	EGF LUBAC HOIP PKP2 linear ubiquitin NF-κB Biology (General) QH301-705.5 Chemistry QD1-999 Fang Hua Wenzhuo Hao Lingyan Wang Shitao Li Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
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.
format	article
author	Fang Hua Wenzhuo Hao Lingyan Wang Shitao Li
author_facet	Fang Hua Wenzhuo Hao Lingyan Wang Shitao Li
author_sort	Fang Hua
title	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_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_sort	linear ubiquitination mediates egfr-induced nf-κb pathway and tumor development
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/663c777444d242aaa0f64d832fa99e9e
work_keys_str_mv	AT fanghua linearubiquitinationmediatesegfrinducednfkbpathwayandtumordevelopment AT wenzhuohao linearubiquitinationmediatesegfrinducednfkbpathwayandtumordevelopment AT lingyanwang linearubiquitinationmediatesegfrinducednfkbpathwayandtumordevelopment AT shitaoli linearubiquitinationmediatesegfrinducednfkbpathwayandtumordevelopment
_version_	1718432121055346688

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

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