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 C-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. Here, 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 G-protein dissociation stimulator). These events promoted the cytosolic and nuclear accumulation of non-prenylated Rap1B and diminished cell-cell adhesion, resulting in cell scattering. We found that non-prenylated 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.

Adenosine 2B Receptor Expression on Cancer Cells Promotes Metastasis

“…(31) and invasiveness in breast carcinoma (40). In fact, A2BR has been suggested to negatively regulate cell adhesion by modulating the localization of Rap1 protein (41). Others have suggested that A2BR controls carcinoma proliferation via HIF1a activation, indicating that A2BR may have several mechanisms to regulate tumor progression (42,43).…”

Targeting Cancer-Derived Adenosine:New Therapeutic Approaches

“…Most interestingly, the A 2B adenosine receptor has recently been identifi ed as a target of the metastasis-inducing transcription factor FOS -related antigen 1 (FRA1) in TNBC ( 27 ). Ntantie and colleagues ( 28 ) further unraveled a signaling pathway linking A 2B adenosine receptor signaling and tumor cell adhesion. Taken together, these studies converge to suggest an important role for the CD73-A 2B axis in metastatic dissemination, independently of immunosuppression.…”

Arg188 drives RhoC membrane binding

“…21 Williams has extended this finding to hypothesize that prenylation of RhoA might be similarly negatively regulated by phosphorylation of Ser188. 22 It follows that reduction of Myc-RhoC-R188S membrane association might also be due to acquisition of phospho-Ser188 regulation of prenylation that obstructs processing events needed for effective membrane intercalation of the GTPase.…”