Send to

Choose Destination
Cancer Res. 2014 Apr 1;74(7):2082-93. doi: 10.1158/0008-5472.CAN-12-0452. Epub 2014 Feb 13.

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

Author information

Authors' 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.


Aberrations of Notch signaling have been implicated in a variety of human cancers. Oncogenic mutations in NOTCH1 are common in human T-cell leukemia and lymphomas. However, loss-of-function somatic mutations in NOTCH1 arising in solid tumors imply a tumor suppressor function, which highlights the need to understand Notch signaling more completely. Here, we describe the small GTPase RhoE/Rnd3 as a downstream mediator of Notch signaling in squamous cell carcinomas (SCC) that arise in skin epithelia. RhoE is a transcriptional target of activated Notch1, which is attenuated broadly in SCC cells. RhoE depletion suppresses Notch1-mediated signaling in vitro, rendering primary keratinocytes resistant to Notch1-mediated differentiation and thereby favoring a proliferative cell fate. Mechanistic investigations indicated that RhoE controls a key step in Notch1 signaling by mediating nuclear translocation of the activated portion of Notch1 (N1IC) through interaction with importins. Our results define RhoE as a Notch1 target that is essential for recruitment of N1IC to the promoters of Notch1 target genes, establishing a regulatory feedback loop in Notch1 signaling. This molecular circuitry may inform distinct cell fate decisions to Notch1 in epithelial tissues, where carcinomas such as SCC arise.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center