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

• Published in: EMBO reports 2018-01, Vol.19 (1), p.73-88
• Main Authors: Hazawa, Masaharu, Lin, De‐Chen, Kobayashi, Akiko, Jiang, Yan‐Yi, Xu, Liang, Dewi, Firli Rahmah Primula, Mohamed, Mahmoud Shaaban, Hartono, Nakada, Mitsutoshi, Meguro‐Horike, Makiko, Horike, Shin‐ichi, Koeffler, H Phillip, Wong, Richard W
• Format: Article
• Language: English
• Subjects: 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 fate; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Proliferation; Computational Biology; Cytosol - metabolism; Differentiation; EMBO03; EMBO20; Female; Gene Expression Regulation, Neoplastic; Glycine; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; HEK293 Cells; Humans; Imports; Kinases; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Nuclear transport; Nucleoporins; Phenylalanine; Phosphorylation; Proteins; Rho Guanine Nucleotide Exchange Factors - genetics; Rho Guanine Nucleotide Exchange Factors - metabolism; Rho-associated kinase; rho-Associated Kinases - genetics; rho-Associated Kinases - metabolism; Rocks; Signal Transduction; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Squamous cell carcinoma; Transport; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201744523

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. Synopsis Nucleoporin NUP62 promotes p63 nuclear import and SCC proliferation. Epidermal differentiation‐induced ROCK kinase phosphorylates NUP62 and limits p63 nuclear import. This study highlights NUP62 as a gatekeeper for p63 and regulator of SCC cell fate. High levels of NUP62 are required for proliferation and prevention of epidermal‐differentiation in squamous cell carcinoma (SCC) cells. NUP62 promotes p63 nuclear transport in SCC cells. ROCK‐dependent phosphorylation of FG domain of NUP62 limits p63 nuclear transport in SCC cells. Graphical Abstract Nucleoporin NUP62 promotes p63 nuclear import and SCC proliferation. Epidermal differentiation‐induced ROCK kinase phosphorylates NUP62 and limits p63 nuclear import. This study highlights NUP62 as a gatekeeper for p63 and regulator of SCC cell fate.