NF-κB-induced KIAA1199 promotes survival through EGFR signalling

Nat Commun. 2014 Nov 4;5:5232. doi: 10.1038/ncomms6232.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Cell Lymphoma 3 Protein
  • Cell Survival
  • Cervical Intraepithelial Neoplasia / metabolism
  • Epidermal Growth Factor / metabolism
  • Epithelial-Mesenchymal Transition
  • ErbB Receptors / metabolism*
  • HeLa Cells
  • Humans
  • Hyaluronoglucosaminidase
  • Keratinocytes / metabolism
  • Lysosomes / metabolism
  • MCF-7 Cells
  • Papillomavirus Infections / metabolism*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Semaphorin-3A / metabolism
  • Transcription Factor RelA / metabolism*
  • Transcription Factors / metabolism*

Substances

  • B-Cell Lymphoma 3 Protein
  • BCL3 protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • SEMA3A protein, human
  • Semaphorin-3A
  • Transcription Factor RelA
  • Transcription Factors
  • Epidermal Growth Factor
  • ErbB Receptors
  • CEMIP protein, human
  • Hyaluronoglucosaminidase

Associated data

  • GEO/GSE60551