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  2. 14-3-3ε inhibits premature centriole disengagement by inhibiting the activity of Plk1 and separase

14-3-3ε inhibits premature centriole disengagement by inhibiting the activity of Plk1 and separase

  • J Cell Sci. 2025 Jul 15;138(14):jcs263808. doi: 10.1242/jcs.263808.
Monika A Jaiswal 1 2 Akshay Karn 1 Aparna Das 1 Anisha Kumari 1 Shilu Tiwari 1 Sorab N Dalal 1 2
Affiliations

Affiliations

  • 1 Cell and Tumour Biology , Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar Node, Navi Mumbai 410210, India.
  • 2 Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India.
Abstract

The 14-3-3 protein family regulates several pathways in mammalian cells, including centrosome duplication. However, the precise mechanisms by which 14-3-3 paralogs regulate the centrosome cycle remain unclear. To identify the mechanisms by which 14-3-3ε regulates centrosome duplication, we altered two conserved acidic residues in the 14-3-3ε phospho-peptide-binding pocket that regulate complex formation and dissociation with the associated ligands, D127 and E134, to alanine. Altering these residues to alanine led to opposing effects on centrosome duplication; the D127A mutant inhibited centrosome duplication, whereas cells expressing the E134A mutant showed the presence of supernumerary centrosomes. We demonstrate that 14-3-3ε does not inhibit centriole duplication, as reported for 14-3-3γ, but inhibits centriole disengagement. Using a combination of pharmacological and genetic approaches, we demonstrate that 14-3-3ε inhibits the activity of PLK1 and Separase [also known as separin (ESPL1)], leading to disengagement defects that ultimately lead to decreased proliferation and cell death. Our work demonstrates that different 14-3-3 paralogs regulate different steps in the centrosome cycle and that disrupting complex formation between 14-3-3ε and PLK1 or Separase could be a novel therapeutic strategy in tumor cells.

Keywords

14-3-3ε; Centriole disengagement; Centrosome cycle; Plk1; Separase.

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