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.
Highlights
plakophilin 2 (PKP2) Is Required for Epidermal growth factor receptor (EGFR)-Induced nuclear factor-κB (NF-κB) Activation
As PKP2 interacts with HOIP, we examined the effects of ectopic expression of PKP2 on HOIP- and linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB reporter activities
We first demonstrate that PKP2 interacts with the kinase domain of EGFR, and PKP2 is required for EGFR-mediated NF-κB signaling and NF-κB-regulated gene expression
Summary
Epidermal growth factor receptor (EGFR) ( known as ErbB-1) is a member of the. ErbB family of plasma membrane receptor tyrosine kinases (RTKs), which includes. EGFR undergoes dimerization, autophosphorylation, and activation [1]. Overexpression and mutations result in EGFR constitutive activation, which has been shown in up to 30% of solid tumors, generally correlated with a poor prognosis [2,3,4]. Constitutive EGFR activation promotes cell survival, proliferation, and invasiveness by activating PI3K/AKT, signal transducer and activator of transcription (STAT), and nuclear factor-κB (NF-κB) pathways [4]. NF-κB activities are seen in multiple solid tumors and provide oncogenic signals to cancer cells. The mechanism of EGFR-mediated NF-κB activation is not well elucidated
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