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Ha-RasV12-Induced Multilayer Cellular Aggregates Is Mediated by Rac1 Activation Rather Than YAP Activation

Li-Ying Wu1, Chia-Lin Han1, Hsi-Hui Lin1,2

  • 1Department of Physiology, College of Medicine, National Cheng Kung University, Tainan City 70101, Taiwan.

Biomedicines
|May 28, 2022
PubMed

Insights

Ha-Ras V12 overexpression causes nuclear YAP translocation by downregulating Caveolin-1 and disrupting cell junctions via the ERK pathway. Rac activity, not YAP, drives Ha-Ras-induced cellular aggregation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Ras proteins are key regulators of cell signaling pathways.
  • The Hippo-YAP pathway controls organ size and tissue homeostasis.
  • Caveolin-1 (Cav1) plays roles in cell adhesion and signaling.

Purpose of the Study:

  • To investigate the mechanism by which Ha-Ras V12 overexpression induces nuclear Yes-associated protein (YAP) translocation in MDCK cells.
  • To elucidate the role of Caveolin-1 (Cav1) in Ha-Ras-mediated cell junction disruption and YAP localization.
  • To determine the contribution of YAP activation versus other pathways in Ha-Ras-induced cellular aggregation.

Main Methods:

  • Overexpression of Ha-Ras V12 in Madin-Darby Canine Kidney (MDCK) cells.
  • Analysis of YAP nuclear translocation using immunofluorescence.
  • Assessment of cell junction integrity and Caveolin-1 expression.
  • Investigation of the involvement of ERK and Rac pathways via Western blotting and pathway inhibitors.

Main Results:

  • Ha-Ras V12 overexpression induced YAP nuclear translocation independently of the Hippo pathway at cell confluence.
  • Ha-Ras V12 downregulated Cav1 expression, leading to disrupted cell junction integrity and subsequent YAP nuclear localization.
  • Cav1 downregulation by Ha-Ras V12 occurred via the ERK pathway.
  • Ha-Ras V12-induced cellular aggregation was independent of YAP activation but dependent on the ERK-Rac pathway.

Conclusions:

  • Ha-Ras V12 disrupts epithelial cell polarity and promotes YAP nuclear translocation by downregulating Cav1 through the ERK pathway.
  • Cell junction integrity is crucial for regulating YAP localization in Ras-transformed cells.
  • Rac pathway activation, downstream of ERK, is essential for Ha-Ras-induced cellular aggregation, independent of YAP.
Keywords:
Caveolin-1Ha-RasV12RacYAPcell aggregatesmyosin IIB

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