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Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to

Mickael Diallo1,2, Constança Pimenta1, Fernanda Murtinheira1,2

  • 1BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal.

Cellular Oncology (Dordrecht, Netherlands)
|December 27, 2023
PubMed

Insights

Asymmetric post-translational modifications (PTMs) on STAT3 affect its movement into the nucleus. These findings reveal a new regulatory mechanism for STAT3, a key factor in many cancers, suggesting novel therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is a crucial transcription factor frequently overactivated in solid tumors.
  • Post-translational modifications (PTMs) on STAT3 influence its function and cellular localization.
  • Previous studies indicated asymmetric PTMs affect STAT3 homodimer distribution.

Purpose of the Study:

  • To investigate the impact of asymmetric PTMs on STAT3 homodimer nuclear translocation under controlled conditions.
  • To provide further evidence for asymmetric PTMs as a regulatory mechanism for STAT3.

Main Methods:

  • Utilized STAT3-/- HeLa cells to eliminate interference from endogenous STAT3.
  • Applied Leukemia Inhibitory Factor (LIF) as a defined cytokine stimulus.
  • Employed time-lapse microscopy to observe STAT3 homodimer nuclear translocation dynamics.

Main Results:

  • S727 dephosphorylation (S727A) and K685 inactivation (K685R) mutations slightly enhanced STAT3 nuclear translocation.
  • K49 inactivation (K49R) mutation demonstrated a delay in STAT3 nuclear translocation.
  • Asymmetric PTMs significantly influence the kinetics of STAT3 homodimer nuclear entry.

Conclusions:

  • Asymmetrically modified STAT3 homodimers represent a novel regulatory layer for STAT3.
  • Targeting these asymmetric modifications could offer new therapeutic strategies for STAT3-driven cancers.
Keywords:
HomodimerizationLeukemia inhibitory factorPost-translational modificationsSTAT3

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