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The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases. J Biol Chem 2016 Mar 18;291(12):6534-45

Date

01/28/2016

Pubmed ID

26814130

Pubmed Central ID

PMC4813585

DOI

10.1074/jbc.M115.696831

Scopus ID

2-s2.0-84964859354 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

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-κB transcriptional activity in HEK293T cells. We also report that DiRas1 suppresses basal NF-κB 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.

Author List

Bergom C, Hauser AD, Rymaszewski A, Gonyo P, Prokop JW, Jennings BC, Lawton AJ, Frei A, Lorimer EL, Aguilera-Barrantes I, Mackinnon AC, Noon K, Fierke CA, Williams CL

Authors

Amy Rymaszewski PhD Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Breast Neoplasms
Carcinoma, Ductal, Breast
GTP Phosphohydrolases
Guanine Nucleotide Exchange Factors
Guanosine Diphosphate
Guanosine Triphosphate
HEK293 Cells
Humans
MCF-7 Cells
Molecular Docking Simulation
NF-kappa B
Protein Binding
Protein Structure, Secondary
Proto-Oncogene Proteins p21(ras)
Tumor Suppressor Proteins
rhoA GTP-Binding Protein