title: Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling.
abstract: 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.
authors: 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.
authors: Zehua
authors: Z
authors: Zhu
authors: Kristina
authors: K
authors: Todorova
authors: Kevin K
authors: KK
authors: Lee
authors: Jun
authors: J
authors: Wang
authors: Eunjeong
authors: E
authors: Kwon
authors: Ivan
authors: I
authors: Kehayov
authors: Hyung-Gu
authors: HG
authors: Kim
authors: Vihren
authors: V
authors: Kolev
authors: G Paolo
authors: GP
authors: Dotto
authors: Sam W
authors: SW
authors: Lee
authors: Anna
authors: A
authors: Mandinova
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D051881:Receptor, Notch1 / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000473:pathology; D020741:rho GTP-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: D051881:Receptor, Notch1; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins