An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering.
An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering.
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DOI：
10.1126/scisignal.2003374
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发表时间：
2013-05-28
影响因子：
7.3
通讯作者：
Williams CL
中科院分区：
文献类型：
--
作者：
Ntantie E;Gonyo P;Lorimer EL;Hauser AD;Schuld N;McAllister D;Kalyanaraman B;Dwinell MB;Auchampach JA;Williams CL
在转移过程中，癌细胞获得彼此分离和迁移的能力，这在体外概括为细胞散射。小的鸟苷三磷酸酶（GTdR）Rap 1通过促进细胞-细胞粘附来对抗细胞散射，这一功能需要其异戊烯化或C-末端类异戊二烯部分的翻译后修饰，以使其能够定位在细胞膜上。因此，调节Rap 1异戊烯化的信号级联提供了控制Rap 1膜定位的机制。在这里，我们确定了腺苷A2 B受体，抑制Rap 1B的异戊二烯化通过Rap 1B的磷酸化，这减少了其与伴侣蛋白SmgGDS（小G蛋白解离刺激剂）的相互作用启动的信号级联。这些事件促进了非异戊二烯化Rap 1B的胞质和核积累，并减少了细胞-细胞粘附，导致细胞分散。我们发现，非异戊二烯化Rap 1是更丰富的乳腺肿瘤比在正常的乳腺组织大鼠，腺苷受体的激活延迟Rap 1B异戊二烯化在乳腺癌，肺癌和胰腺癌细胞系。我们的研究结果支持了一种模型，其中高浓度的细胞外腺苷，例如肿瘤微环境中产生的腺苷，可以长期激活A2 B受体，以抑制Rap 1B异戊二烯化和细胞膜上的信号传导，从而减少细胞与细胞的接触，促进细胞分散。抑制A2 B受体可能是预防转移的有效方法。
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.
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Rap1 可稳定 β-连环蛋白并增强头颈部鳞状细胞癌中 β-连环蛋白依赖性转录和侵袭。
DOI：
10.1158/1078-0432.ccr-09-1122
发表时间：
2010-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Goto M;Mitra RS;Liu M;Lee J;Henson BS;Carey T;Bradford C;Prince M;Wang CY;Fearon ER;D'Silva NJ
通讯作者：
D'Silva NJ
DOI：
10.1074/jbc.m110.129916
发表时间：
2010-11-12
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Berg TJ;Gastonguay AJ;Lorimer EL;Kuhnmuench JR;Li R;Fields AP;Williams CL
通讯作者：
Williams CL
DOI：
10.1016/j.bbrc.2009.11.159
发表时间：
2010-01-01
影响因子：
3.1
作者：
Goalstione, Marc;Kamath, Vasudeva;Kowluru, Anjaneyulu
通讯作者：
Kowluru, Anjaneyulu
影响因子：
4.8
作者：
Lanning, CC;Ruiz-Velasco, R;Williams, CL
通讯作者：
Williams, CL
影响因子：
4.1
作者：
Forget, MA;Desrosiers, RR;Béliveau, R
通讯作者：
Béliveau, R