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<p>FBXO42 is a poorly characterized F-box protein essential in 15% of cancer cell lines from diverse lineages. High-throughput approaches indicate that FBXO42 function correlates with that of coiled-coil protein CCDC6, and that the two proteins interact physically, but the relationship between them is not understood. We show that FBXO42 ubiquitinates PPP4C (protein phosphatase 4 catalytic subunit) and negatively regulates its expression. FBXO42 binds PPP4C independently of CCDC6. Similarly, we show that CCDC6 physically interacts with PPP4C independently of FBXO42, and identify a PPP4C binding site within CCDC6. However, mutation of CCDC6 does not reduce PPP4C ubiquitination, suggesting that FBXO42 and CCDC6 bind and regulate PPP4C through separate mechanisms. Viability of an FBXO42- and CCDC6-dependent glioblastoma cell line is rescued when PPP4C is knocked down along with FBXO42 or CCDC6, suggesting that aberrant activation of PPP4C is a driver of cell death when FBXO42 or CCDC6 activity is compromised. These findings tie together previous data suggesting that FBXO42 functions with CCDC6 by providing mechanistic insight into their independent regulation of PP4.</p>

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The regulation of protein phosphatase 4 by FBXO42 is required for cancer cell survival

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月14日

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  • Stephan H Spangenberg,
  • Nicholas Garaffo,
  • Enya Marie Catherine Alcindor,
  • Benjamin Lusk,
  • Vijaya Pandey,
  • Adam D Longhurst,
  • Emma Bolech,
  • Becky Xu Hua Fu,
  • Luke A Gilbert,
  • James A Wohlschlegel,
  • David P Toczyski

摘要

FBXO42 is a poorly characterized F-box protein essential in 15% of cancer cell lines from diverse lineages. High-throughput approaches indicate that FBXO42 function correlates with that of coiled-coil protein CCDC6, and that the two proteins interact physically, but the relationship between them is not understood. We show that FBXO42 ubiquitinates PPP4C (protein phosphatase 4 catalytic subunit) and negatively regulates its expression. FBXO42 binds PPP4C independently of CCDC6. Similarly, we show that CCDC6 physically interacts with PPP4C independently of FBXO42, and identify a PPP4C binding site within CCDC6. However, mutation of CCDC6 does not reduce PPP4C ubiquitination, suggesting that FBXO42 and CCDC6 bind and regulate PPP4C through separate mechanisms. Viability of an FBXO42- and CCDC6-dependent glioblastoma cell line is rescued when PPP4C is knocked down along with FBXO42 or CCDC6, suggesting that aberrant activation of PPP4C is a driver of cell death when FBXO42 or CCDC6 activity is compromised. These findings tie together previous data suggesting that FBXO42 functions with CCDC6 by providing mechanistic insight into their independent regulation of PP4.