Nuclear FAM21 participates in NF-κB-dependent gene regulation in pancreatic cancer cells

Zhi Hui Deng, Timothy S. Gomez, Douglas G. Osborne, Christine A. Phillips-Krawczak, Jin San Zhang, Daniel D. Billadeau

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The pentameric WASH complex is best known for its role in regulating receptor trafficking from retromer-rich endosomal subdomains. FAM21 functions to stabilize the WASH complex through its N-terminal head domain and localizes it to endosomes by directly binding the retromer through its extended C-terminal tail. Herein, we used affinity purification combined with mass spectrometry to identify additional FAM21-interacting proteins. Surprisingly, multiple components of the nuclear factor κB (NF-κB) pathway were identified, including the p50 and p65 (RelA) NF-κB subunits. We show that FAM21 interacts with these components and regulates NF-κB-dependent gene transcription at the level of p65 chromatin binding. We further demonstrate that FAM21 contains a functional monopartite nuclear localization signal sequence (NLS) as well as a CRM1/exportin1-dependent nuclear export signal (NES), both of which work jointly with the N-terminal head domain and C-terminal retromer recruitment domain to regulate FAM21 cytosolic and nuclear subcellular localization. Finally, our findings indicate that FAM21 depletion sensitizes pancreatic cancer cells to gemcitabine and 5-fluorouracil. Thus, FAM21 not only functions as an integral component of the cytoplasmic WASH complex, but also modulates NF-κB gene transcription in the nucleus.

Original languageEnglish (US)
Pages (from-to)373-384
Number of pages12
JournalJournal of cell science
Volume128
Issue number2
DOIs
StatePublished - Jan 1 2015

Keywords

  • FAM21
  • NF-κB
  • Pancreatic cancer
  • Retromer
  • WASH complex

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Deng, Z. H., Gomez, T. S., Osborne, D. G., Phillips-Krawczak, C. A., Zhang, J. S., & Billadeau, D. D. (2015). Nuclear FAM21 participates in NF-κB-dependent gene regulation in pancreatic cancer cells. Journal of cell science, 128(2), 373-384. https://doi.org/10.1242/jcs.161513