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The scaffold protein PRR14L is linked to mitotic fidelity and sensitivity to MPS1 inhibition

Albert Z Liu1,2, Akshay Narkar1, Keming Li2

  • 1Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205.

Molecular Biology of the Cell
|May 20, 2026
PubMed

Insights

Researchers identified PRR14L as a key regulator of aneuploidy and mitosis. Loss of PRR14L causes mitotic errors when the spindle assembly checkpoint is inhibited, suggesting a new cancer vulnerability.

Area of Science:

  • Cell Biology
  • Genetics
  • Cancer Research

Background:

  • Aneuploidy, an abnormal chromosome number, is a common feature of cancer cells.
  • Targeting aneuploidy presents a potential strategy for cancer therapy.
  • The spindle assembly checkpoint (SAC) kinase MPS1/TTK is crucial for accurate chromosome segregation.

Purpose of the Study:

  • To identify genes influencing aneuploidy and the fitness of aneuploid cells.
  • To investigate the role of PRR14L in cell division and its interaction with mitotic regulators.
  • To explore therapeutic strategies targeting MPS1/TTK in cancers with altered PRR14L function.

Main Methods:

  • Genome-wide CRISPR/Cas9 screening using an MPS1/TTK inhibitor (NMS-P715).
  • Proximity labeling (TurboID) to identify PRR14L-interacting proteins.
  • Functional assays assessing mitotic progression and chromosome segregation.

Main Results:

  • Identified genes regulating aneuploidy and mitosis, including PRR14L.
  • PRR14L interacts with the PP2A-B56 phosphatase complex and TACC3.
  • Loss of PRR14L causes mitotic errors upon MPS1 inhibition, despite prolonging mitotic arrest under other conditions.

Conclusions:

  • PRR14L plays a paradoxical role in mitosis, promoting errors when the SAC is abrogated.
  • MPS1 inhibition represents a potential therapeutic vulnerability in cancers with PRR14L loss-of-function or FGFR-TACC3 fusions.

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