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

Abstract

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.

• Authors: Fang Hua, Wenzhuo Hao, Lingyan Wang, Shitao Li
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 21 (Nov 02 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34769306 (Publication Type: Journal Article)

Chemical References

• HOIPIN-8
• Hydrocarbons, Aromatic
• NF-kappa B
• PKP2 protein, human
• Plakophilins
• Ubiquitin
• RNF31 protein, human
• Ubiquitin-Protein Ligases
• ErbB Receptors

Topics

• Animals
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• ErbB Receptors (genetics, metabolism)
• Female
• Humans
• Hydrocarbons, Aromatic (pharmacology)
• Mice
• Mice, Nude
• NF-kappa B (genetics, metabolism)
• Phosphorylation
• Plakophilins (genetics, metabolism)
• Protein Processing, Post-Translational
• Signal Transduction
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination