NF-κB-induced KIAA1199 promotes survival through EGFR signalling

Abstract

Constitutive activation of EGFR- and NF-κB-dependent pathways is a hallmark of cancer, yet signalling proteins that connect both oncogenic cascades are poorly characterized. Here we define KIAA1199 as a BCL-3- and p65-dependent gene in transformed keratinocytes. KIAA1199 expression is enhanced on human papillomavirus (HPV) infection and is aberrantly expressed in clinical cases of cervical (pre)neoplastic lesions. Mechanistically, KIAA1199 binds Plexin A2 and protects from Semaphorin 3A-mediated cell death by promoting EGFR stability and signalling. Moreover, KIAA1199 is an EGFR-binding protein and KIAA1199 deficiency impairs EGF-dependent Src, MEK1 and ERK1/2 phosphorylations. Therefore, EGFR stability and signalling to downstream kinases requires KIAA1199. As such, KIAA1199 promotes EGF-mediated epithelial–mesenchymal transition (EMT). Taken together, our data define KIAA1199 as an oncogenic protein induced by HPV infection and constitutive NF-κB activity that transmits pro-survival and invasive signals through EGFR signalling.

EGFR and NF-κB: partners in cancer

“…In this context, KIAA1199 is transcriptionally induced by NF-kB proteins in transformed keratinocytes as well as in breast cancerderived cells (Figure 3) [41,42]. The oncogenic human papillomavirus (HPV) also positively regulates KIAA1199 gene transcription through BCL-3 in cervical cancer cells [41]. KIAA1199 promotes EGFR stability by limiting its EGFdependent degradation in lysosomes, and therefore positively regulates EGFR signaling [41].…”

“…The oncogenic human papillomavirus (HPV) also positively regulates KIAA1199 gene transcription through BCL-3 in cervical cancer cells [41]. KIAA1199 promotes EGFR stability by limiting its EGFdependent degradation in lysosomes, and therefore positively regulates EGFR signaling [41]. KIAA1199 actually limits semaphorin 3A-dependent cell death by promoting EGFR phosphorylation and as well as EGF-dependent epithelialmesenchymal transition (EMT) in cervical cancer cells [41].…”

“…KIAA1199 promotes EGFR stability by limiting its EGFdependent degradation in lysosomes, and therefore positively regulates EGFR signaling [41]. KIAA1199 actually limits semaphorin 3A-dependent cell death by promoting EGFR phosphorylation and as well as EGF-dependent epithelialmesenchymal transition (EMT) in cervical cancer cells [41]. As such, KIAA1199 links NF-kB-dependent gene transcription to EGFR signaling to sustain cell survival and invasion [41].…”

“…KIAA1199 actually limits semaphorin 3A-dependent cell death by promoting EGFR phosphorylation and as well as EGF-dependent epithelialmesenchymal transition (EMT) in cervical cancer cells [41]. As such, KIAA1199 links NF-kB-dependent gene transcription to EGFR signaling to sustain cell survival and invasion [41]. Another example of positive correlation between NF-kB and EGFR activities has been described in head and neck squamous cell carcinomas (HNSCCs) in which IKKa and/or b knockdown significantly decreased Figure 2.…”

“…Nuclear BCL-3 drives KIAA1199 gene transcription. KIAA1199 binds to plexin A2 to limit semaphorin 3A-dependent cell death, and also stabilizes EGFR to promote EGF-dependent SRC and ERK1/2 activation, and subsequent epithelial-mesenchymal transition (EMT) [41].…”