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An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering. Sci Signal 2013 May 28;6(277):ra39

Date

05/30/2013

Pubmed ID

23716716

Pubmed Central ID

PMC4278376

DOI

10.1126/scisignal.2003374

Scopus ID

2-s2.0-84878725519   70 Citations

Abstract

During metastasis, cancer cells acquire the ability to dissociate from each other and migrate, which is recapitulated in vitro as cell scattering. The small guanosine triphosphatase (GTPase) Rap1 opposes cell scattering by promoting cell-cell adhesion, a function that requires its prenylation, or posttranslational modification with a carboxyl-terminal isoprenoid moiety, to enable its localization at cell membranes. Thus, signaling cascades that regulate the prenylation of Rap1 offer a mechanism to control the membrane localization of Rap1. We identified a signaling cascade initiated by adenosine A2B receptors that suppressed the prenylation of Rap1B through phosphorylation of Rap1B, which decreased its interaction with the chaperone protein SmgGDS (small GTPase guanosine diphosphate dissociation stimulator). These events promoted the cytosolic and nuclear accumulation of nonprenylated Rap1B and diminished cell-cell adhesion, resulting in cell scattering. We found that nonprenylated Rap1 was more abundant in mammary tumors than in normal mammary tissue in rats and that activation of adenosine receptors delayed Rap1B prenylation in breast, lung, and pancreatic cancer cell lines. Our findings support a model in which high concentrations of extracellular adenosine, such as those that arise in the tumor microenvironment, can chronically activate A2B receptors to suppress Rap1B prenylation and signaling at the cell membrane, resulting in reduced cell-cell contact and promoting cell scattering. Inhibiting A2B receptors may be an effective method to prevent metastasis.

Author List

Ntantie E, Gonyo P, Lorimer EL, Hauser AD, Schuld N, McAllister D, Kalyanaraman B, Dwinell MB, Auchampach JA, Williams CL

Authors

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics 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

Adenosine
Amino Acid Sequence
Animals
Cell Adhesion
Cell Movement
Guanine Nucleotide Exchange Factors
HEK293 Cells
Humans
Immunoblotting
Immunoprecipitation
Microscopy, Confocal
Models, Biological
Molecular Sequence Data
Neoplasm Metastasis
Prenylation
Rats
Rats, Sprague-Dawley
Receptor, Adenosine A2B
Signal Transduction
Tumor Microenvironment
rap GTP-Binding Proteins