期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 12, 页码 6534-6545出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.696831
关键词
breast cancer; glioblastoma; GTPase Kras (KRAS); Ras homolog gene family; member A (RhoA); Ras-related protein 1 (Rap1); Di-Ras1; NF-kappaB (NF-KB); Rap1GDS1; Rig; SmgGDS
资金
- Medical College of Wisconsin Cancer Center and Research Affairs Committee, Advancing a Healthier Wisconsin
- Radiological Society of North America
- Robert D. and Patricia E. Kern Family Foundation
- National Center for Research Resources
- National Center for Advancing Translational Sciences
- Office of the Director of the National Institutes of Health [8KL2TR000056]
- Nancy Laning Sobczak
- Breast Cancer Research Award
- Institutional Research from the American Cancer Society [86-004-26]
- National Institutes of Health [RO1CA188871, F32GM112317, RO1GM040602]
The small GTPase DiRas1 has tumor-suppressive activities, unlike the oncogenic properties more common to small GTPases such as K-Ras and RhoA. Although DiRas1 has been found to be a tumor suppressor in gliomas and esophageal squamous cell carcinomas, the mechanisms by which it inhibits malignant phenotypes have not been fully determined. In this study, we demonstrate that DiRas1 binds to SmgGDS, a protein that promotes the activation of several oncogenic GTPases. In silico docking studies predict that DiRas1 binds to SmgGDS in a manner similar to other small GTPases. SmgGDS is a guanine nucleotide exchange factor for RhoA, but we report here that SmgGDS does not mediate GDP/GTP exchange on DiRas1. Intriguingly, DiRas1 acts similarly to a dominant-negative small GTPase, binding to SmgGDS and inhibiting SmgGDS binding to other small GTPases, including K-Ras4B, RhoA, and Rap1A. DiRas1 is expressed in normal breast tissue, but its expression is decreased in most breast cancers, similar to its family member DiRas3 (ARHI). DiRas1 inhibits RhoA- and SmgGDS-mediated NF-B transcriptional activity in HEK293T cells. We also report that DiRas1 suppresses basal NF-B activation in breast cancer and glioblastoma cell lines. Taken together, our data support a model in which DiRas1 expression inhibits malignant features of cancers in part by nonproductively binding to SmgGDS and inhibiting the binding of other small GTPases to SmgGDS.
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