title: The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases.
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.
authors.affiliation: From the Cancer Center, the Departments of Radiation Oncology, cbergom@mcw.edu.
authors.forename: Carmen
authors.initials: C
authors.lastname: Bergom
authors.affiliation: From the Cancer Center, the Departments of Radiation Oncology, Pharmacology and Toxicology, and the Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, and.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hauser
authors.affiliation: From the Cancer Center, Pharmacology and Toxicology, and.
authors.forename: Amy
authors.initials: A
authors.lastname: Rymaszewski
authors.affiliation: From the Cancer Center, Pharmacology and Toxicology, and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gonyo
authors.affiliation: the Human and Molecular Genetics Center, and.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Prokop
authors.affiliation: the Department of Chemistry.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Jennings
authors.affiliation: the Department of Chemistry, Biochemistry Undergraduate Program, and.
authors.forename: Alexis J
authors.initials: AJ
authors.lastname: Lawton
authors.affiliation: From the Cancer Center, the Departments of Radiation Oncology.
authors.forename: Anne
authors.initials: A
authors.lastname: Frei
authors.affiliation: From the Cancer Center, Pharmacology and Toxicology, and.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Lorimer
authors.affiliation: Pathology.
authors.forename: Irene
authors.initials: I
authors.lastname: Aguilera-Barrantes
authors.affiliation: From the Cancer Center, Pathology.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Mackinnon
authors.affiliation: the Mass Spectroscopy Facility for Proteomics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Noon
authors.affiliation: the Department of Chemistry, Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Fierke
authors.affiliation: From the Cancer Center, Pharmacology and Toxicology, and.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
mesh_terms: D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000201:enzymology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C117307:KRAS protein, human; D016328:NF-kappa B; C115955:RAP1GDS1 protein, human; D025521:Tumor Suppressor Proteins; C066737:RHOA protein, human; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; C468772:DIRAS1 protein, human; D020558:GTP Phosphohydrolases; D016283:Proto-Oncogene Proteins p21(ras); D020742:rhoA GTP-Binding Protein
keywords: Di-Ras1; GTPase Kras (KRAS); NF-kappaB (NF-KB); Rap1GDS1; Ras homolog gene family, member A (RhoA); Ras-related protein 1 (Rap1); Rig; SmgGDS; breast cancer; glioblastoma
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