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Aberrant MET activation impairs perinuclear actin cap organization with YAP1 cytosolic relocation

Michela Sgarzi1,2, Martina Mazzeschi1, Spartaco Santi3,4

  • 1IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Communications Biology
|October 14, 2023
PubMed

Insights

Oncogenic MET signaling disrupts the perinuclear actin cap and YAP1 activity, altering cell shape and motility. Restoring MET or YAP1 function reestablishes normal nuclear structure and directed cell movement.

Area of Science:

  • Cell biology
  • Cancer research
  • Mechanotransduction

Background:

  • The perinuclear actin cap regulates nuclear shape and cell directionality.
  • Its underlying signaling network remains largely unknown.
  • Dysregulation of nuclear organization is implicated in cancer progression.

Purpose of the Study:

  • To investigate the role of MET signaling in organizing the perinuclear actin cap.
  • To elucidate the connection between MET, YAP1, and nuclear morphology.
  • To understand how these changes impact cell motility.

Main Methods:

  • Studied cancer cells with constitutively active MET.
  • Utilized MET ablation and introduction of hyperactive MET in normal cells.
  • Employed Transmission Electron Microscopy (TEM) analysis.
  • Investigated the YAP1 pathway and its interaction with MET.

Main Results:

  • Active MET causes actin cap rearrangement, spherical nuclei, and impaired YAP1 activity.
  • MET ablation restores YAP1, enhances cell directionality, and flattens nuclei.
  • Hyperactive MET in normal cells alters nuclear height and actin cap organization.
  • A constitutively active YAP1 mutant (YAP5SA) counteracted MET's effects.

Conclusions:

  • A signaling axis links MET, YAP1 inactivation, and actin cap misalignment.
  • This axis impacts nuclear shape and cell motility.
  • Targeting this pathway may offer therapeutic strategies for cancers with MET alterations.

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