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EphA2 phosphorylation at Ser897 by the Cdk1/MEK/ERK/RSK pathway regulates M-phase progression via maintenance of

Yuichiro Kaibori1, Youhei Saito1, Yuji Nakayama1

  • 1Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto, Japan.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|January 23, 2019
PubMed

Insights

EphA2 phosphorylation at Ser897 is crucial for cell division, regulating mitotic spindle formation and cortical rigidity through the Cdk1/MEK/ERK/RSK pathway and Ephexin4/RhoG. This ensures proper M-phase progression, preventing errors like spindle mispositioning.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Successful cell division relies on accurate mitotic spindle formation.
  • EphA2, a receptor tyrosine kinase, plays a role in cell division, with known phosphorylation sites at Tyr588 and Ser897.
  • Mitotic errors can arise from disruptions in spindle formation and cell cycle progression.

Purpose of the Study:

  • To investigate the role of EphA2 phosphorylation at Ser897 in regulating M-phase progression and mitotic spindle formation.
  • To elucidate the signaling pathways and molecular interactions involved in EphA2-mediated mitotic regulation.

Main Methods:

  • EphA2 knockdown and expression of wild-type and mutant EphA2.
  • Inhibition of MEK/ERK and RSK kinases.
  • Introduction of active cyclin-dependent kinase 1 (Cdk1) and cyclin B1.
  • Knockdown of Ephexin4 and RhoG, and expression of constitutively active RhoG mutant.

Main Results:

  • EphA2 knockdown induced mitotic errors, including M-phase delay, asymmetric spindle positioning, multipolar spindles, and cell blebs.
  • EphA2 phosphorylation at Ser897, regulated by Cdk1/cyclin B1 and MEK/ERK/RSK pathways, was critical for M-phase progression.
  • Interaction with Ephexin4 and RhoG was dependent on EphA2 Ser897 phosphorylation, impacting cortical rigidity and spindle formation.
  • Rescue experiments confirmed the essential role of Ser897 phosphorylation in EphA2 function during mitosis.

Conclusions:

  • EphA2 phosphorylation at Ser897 is a key regulator of M-phase progression.
  • This phosphorylation event is controlled by the Cdk1/MEK/ERK/RSK signaling cascade.
  • EphA2, via Ephexin4 and RhoG, maintains cortical rigidity, which is essential for proper mitotic spindle assembly and function.
Keywords:
Ephexin4RhoGblebbingmitosismitotic spindle formation

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