1Department of Pharmacology and Toxicology, Cancer Center, and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Sci Signal. 2013 May 28;6(277):ra39. doi: 10.1126/scisignal.2003374.
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.
在转移过程中，癌细胞获得了彼此分离和迁移的能力，这在体外可以通过细胞分散来重现。小分子鸟苷三磷酸酶（GTPase）Rap1 通过促进细胞间粘附来对抗细胞分散，这种功能需要其棕榈酰化，即用羧基末端异戊二烯部分进行翻译后修饰，以使它定位在细胞膜上。因此，调节 Rap1 棕榈酰化的信号级联提供了一种控制 Rap1 膜定位的机制。我们发现了一种由腺苷 A2B 受体启动的信号级联，该级联通过 Rap1B 的磷酸化抑制 Rap1B 的棕榈酰化，从而减少了 Rap1B 与伴侣蛋白 SmgGDS（小 GTPase GDP 解离刺激因子）的相互作用。这些事件促进了非棕榈酰化 Rap1B 的细胞质和核积累，并减少了细胞间粘附，导致细胞分散。我们发现，非棕榈酰化 Rap1 在大鼠的乳腺肿瘤中比在正常乳腺组织中更为丰富，并且激活腺苷受体可延迟乳腺癌、肺癌和胰腺癌细胞系中 Rap1B 的棕榈酰化。我们的研究结果支持这样一种模型，即细胞外腺苷浓度较高，如肿瘤微环境中产生的腺苷浓度较高，可慢性激活 A2B 受体，抑制 Rap1B 棕榈酰化和细胞膜上的信号转导，从而减少细胞间接触并促进细胞分散。抑制 A2B 受体可能是预防转移的有效方法。
