title: An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering.
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.
authors.affiliation: 1Department of Pharmacology and Toxicology, Cancer Center, and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ntantie
authors.forename: Patrick
authors.initials: P
authors.lastname: Gonyo
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Lorimer
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hauser
authors.forename: Nathan
authors.initials: N
authors.lastname: Schuld
authors.forename: Donna
authors.initials: D
authors.lastname: McAllister
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
authors.forename: John A
authors.initials: JA
authors.lastname: Auchampach
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D008954:Models, Biological; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D054876:Prenylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D059016:Tumor Microenvironment; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C115955:RAP1GDS1 protein, human; D043704:Receptor, Adenosine A2B; C116753:RAP1B protein, human; D020668:rap GTP-Binding Proteins; D000241:Adenosine