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Front-biased activation of the Ras-Rab5-Rac1 loop coordinates collective cell migration.

Yuya Jikko1, Eriko Deguchi1, Kimiya Matsuda2

  • 1Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-Cho, Sakyo-ku, Kyoto 606-8501, Japan.

Journal of Cell Science
|July 16, 2025
PubMed
Summary
This summary is machine-generated.

Scientists discovered a front-to-rear signaling loop involving Ras, Rab5, and Rac1 in collectively migrating cells. This pathway is crucial for specifying the cell front, guiding cell movement and orientation.

Keywords:
Cell migrationCell polarityCollective cell migrationEGFRERM family proteinEpidermal growth factor receptorRabRac1Ras protein

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biophysics

Background:

  • Collective cell migration relies on intercellular signaling.
  • The epidermal growth factor receptor (EGFR)-Ras-ERK pathway is key to this process.
  • Mechanisms for front-rear information integration and cell front specification are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying front-rear information processing in collective cell migration.
  • To identify the determinants of cellular front-side specification.
  • To elucidate the role of EGFR, Ras, Rac1, and Rab5A in this process.

Main Methods:

  • Utilized Förster resonance energy transfer (FRET) biosensors to visualize protein activity.
  • Employed chemogenetic tools for precise control and observation.
  • Analyzed the spatial activation patterns of EGFR, Ras, Rac1, and Rab5A.

Main Results:

  • EGFR activation was uniform across cells, but Ras activation was front-biased.
  • Front-biased activation of Ras depended on Merlin and Rac1.
  • Rab5A (Rab5) also showed front-biased activation, functioning downstream of Ras and upstream of Rac1.
  • A positive feedback loop involving Ras, Rab5, and Rac1 was identified at the cell front.

Conclusions:

  • A novel feedback loop (Ras-Rab5-Rac1) is established at the front of migrating cells.
  • This loop is critical for processing front-rear information and specifying cell polarity.
  • Findings provide new spatio-temporal insights into collective cell migration dynamics.