ROCK-dependent phosphorylation of NUP62 regulates p63 nuclear transport and squamous cell carcinoma proliferation

EMBO Rep. 2018 Jan;19(1):73-88. doi: 10.15252/embr.201744523. Epub 2017 Dec 7.

Abstract

p63, more specifically its ΔNp63α isoform, plays essential roles in squamous cell carcinomas (SCCs), yet the mechanisms controlling its nuclear transport remain unknown. Nucleoporins (NUPs) are a family of proteins building nuclear pore complexes (NPC) and mediating nuclear transport across the nuclear envelope. Recent evidence suggests a cell type-specific function for certain NUPs; however, the significance of NUPs in SCC biology remains unknown. In this study, we show that nucleoporin 62 (NUP62) is highly expressed in stratified squamous epithelia and is further elevated in SCCs. Depletion of NUP62 inhibits proliferation and augments differentiation of SCC cells. The impaired ability to maintain the undifferentiated status is associated with defects in ΔNp63α nuclear transport. We further find that differentiation-inducible Rho kinase reduces the interaction between NUP62 and ΔNp63α by phosphorylation of phenylalanine-glycine regions of NUP62, attenuating ΔNp63α nuclear import. Our results characterize NUP62 as a gatekeeper for ΔNp63α and uncover its role in the control of cell fate through regulation of ΔNp63α nuclear transport in SCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Amino Acid Sequence
  • Atlases as Topic
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Computational Biology
  • Cytosol / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Nuclear Pore Complex Proteins / genetics*
  • Nuclear Pore Complex Proteins / metabolism
  • Phosphorylation
  • Rho Guanine Nucleotide Exchange Factors / genetics
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Signal Transduction
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • rho-Associated Kinases / genetics*
  • rho-Associated Kinases / metabolism

Substances

  • CKAP4 protein, human
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nuclear Pore Complex Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • nuclear pore protein p62
  • rho-Associated Kinases