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Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development
Fang Hua1, Wenzhuo Hao1, Lingyan Wang1
1Department of Microbiology and Immunology, Tulane University, New Orleans, LA 70112, USA.
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.
Insights
This study reveals a new signaling pathway where plakophilin 2 and the linear ubiquitin chain assembly complex activate NF-κB via epidermal growth factor receptor, crucial for tumor growth. Inhibiting HOIP shows promise for targeted cancer therapy.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Cancer Research
Background:
- Epidermal growth factor receptor (EGFR) signaling drives cell proliferation and differentiation.
- EGFR overexpression/mutations are common in solid tumors, correlating with poor prognosis.
- The precise signaling axis for EGFR-mediated NF-κB activation in tumors remains unclear.
Purpose of the Study:
- To elucidate the signaling axis responsible for EGFR-mediated NF-κB activation.
- To investigate the role of plakophilin 2 (PKP2) and the linear ubiquitin chain assembly complex (LUBAC) in this pathway.
- To evaluate the therapeutic potential of targeting this axis in cancer.
Main Methods:
- Investigated EGFR-mediated NF-κB activation using EGF stimulation.
- Utilized plakophilin 2 (PKP2) and LUBAC components, including HOIP.
- Employed gene knockout (HOIP) and pharmacological inhibition (HOIPIN-8) in cancer cell lines and xenograft models.
Main Results:
- PKP2 and LUBAC are essential for EGFR-mediated NF-κB activation.
- EGFR recruits PKP2, which activates LUBAC, leading to NEMO linear ubiquitination and NF-κB activation.
- HOIP knockout significantly reduced tumor cell proliferation and xenograft tumor growth (>70%).
- HOIPIN-8 inhibited NF-κB activation and proliferation in multiple cancer cell lines.
Conclusions:
- A novel linear ubiquitination signaling axis involving EGFR, PKP2, and LUBAC has been identified.
- This pathway is critical for EGF-induced NF-κB activation, cell proliferation, and tumor development.
- Targeting HOIP E3 ubiquitin ligase activity presents a potential therapeutic strategy for cancer treatment.
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