Hua, F.; Hap, W.; Wang, L.; Li, S. Linear Ubiquitination Mediates EGFR-Induced NF-kB Pathway and Tumor Development. Preprints2021, 2021090394. https://doi.org/10.20944/preprints202109.0394.v1
APA Style
Hua, F., Hap, W., Wang, L., & Li, S. (2021). Linear Ubiquitination Mediates EGFR-Induced NF-kB Pathway and Tumor Development. Preprints. https://doi.org/10.20944/preprints202109.0394.v1
Chicago/Turabian Style
Hua, F., Lingyan Wang and Shitao Li. 2021 "Linear Ubiquitination Mediates EGFR-Induced NF-kB Pathway and Tumor Development" Preprints. https://doi.org/10.20944/preprints202109.0394.v1
Abstract
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that instigates several signaling cascades, including the NF-kB 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-kB activation is involved in tumor development, the signaling axis is not well elucidated. Here, we found that PKP2 and the LUBAC complex were required for EGFR-mediated NF-kB 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 IkB phosphorylation and subsequent NF-kB activation. Furthermore, EGF-induced linear ubiquitination was critical for tumor cell proliferation and tumor development. Knockout of HOIP impaired EGF-induced NF-kB 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-kB 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 perturbation of HOIP E3 ubiquitin ligase activity is potential targeted cancer therapy.
Keywords
EGF; LUBAC; HOIP; PKP2; linear ubiquitin; NF-kB; tumorigenesis
Subject
Biology and Life Sciences, Immunology and Microbiology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
