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Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling

Zehua Zhu1, Kristina Todorova, Kevin K Lee

  • 1Authors' Affiliations: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown; Broad Institute of Harvard and MIT, Cambridge Center, Massachusetts; Institute of Immunology, Sofia, Bulgaria; and Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

Cancer Research
|February 15, 2014
PubMed

Insights

Small GTPase RhoE mediates Notch signaling in skin cancers. RhoE is essential for Notch1

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Notch signaling aberrations are linked to various cancers.
  • NOTCH1 mutations are common in leukemia/lymphoma, but loss-of-function suggests tumor suppressor roles in solid tumors.
  • Understanding Notch signaling in epithelial cancers is crucial.

Purpose of the Study:

  • To identify downstream mediators of Notch signaling in squamous cell carcinomas (SCC).
  • To elucidate the role of RhoE/Rnd3 in Notch1 signaling within skin epithelia.

Main Methods:

  • Investigated RhoE as a transcriptional target of activated Notch1.
  • Assessed the impact of RhoE depletion on Notch1 signaling and keratinocyte differentiation.
  • Examined RhoE's role in the nuclear translocation of Notch1 intracellular domain (N1IC) via importin interactions.

Main Results:

  • RhoE is a downstream mediator of Notch signaling in skin SCC.
  • Activated Notch1 targets RhoE transcriptionally; RhoE is attenuated in SCC cells.
  • RhoE depletion impairs Notch1-mediated differentiation, promoting proliferation and N1IC nuclear translocation.
  • RhoE facilitates N1IC recruitment to target gene promoters, establishing a feedback loop.

Conclusions:

  • RhoE is a critical Notch1 target essential for mediating Notch1 signaling in SCC.
  • RhoE's function in N1IC nuclear translocation and target gene recruitment is vital for cell fate decisions.
  • This regulatory circuit involving RhoE and Notch1 is important in epithelial carcinogenesis.

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