The RGS-RhoGEFs control the amplitude of YAP1 activation by serum.
The RGS-RhoGEFs control the amplitude of YAP1 activation by serum.
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DOI：
10.1038/s41598-021-82027-4
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发表时间：
2021-01-27
影响因子：
4.6
通讯作者：
Wells CD
中科院分区：
文献类型：
--
作者：
Lane BS;Heller B;Hollenberg MD;Wells CD
肌动蛋白依赖性机制驱动Yap 1的核转位，使其能够共激活诱导促生长和存活程序的转录因子。虽然Rho GTP酶对于YAP 1的核输入是必需的，但是将该过程连接到上游信号传导的相关鸟嘌呤交换因子（GEF）和GTP酶激活蛋白（GAP）还没有很好地定义。为此，我们测量了表达67个RhoGEF和RhoGAP对TEAD元件转录报告子的YAP 1依赖性活性的影响。含有RhoGEF（ArhGEF 1、ArhGEF 11和ArhGEF 12）的G蛋白信号传导（RGS）结构域调节因子的所有三个成员的强大作用促使研究将它们在血清信号传导中的已知作用与Yap 1的调节相关联。在所有检测条件下，ArhGEF 12优先介导血清对YAP 1/TEAD的激活，而不是ArhGEF 1或ArhGEF 11。相反，在多种情况下，ArhGEF 1通过其Gα13的GAP活性抑制基础和血清升高的YAP 1活性。这种抑制对细胞密度和血清信号传导的低状态的敏感性支持ArhGEF 1是YAP 1的环境依赖性调节剂。总之，RGS-RhoGEFs的相对活性决定了血清信号促进YAP 1活性的程度。
Actin-dependent mechanisms drive the nuclear translocation of Yap1 to enable its co-activation of transcription factors that induce pro-growth and survival programs. While Rho GTPases are necessary for the nuclear import of YAP1, the relevant Guanine Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs) that connect this process to upstream signaling are not well defined. To this end, we measured the impact of expressing sixty-seven RhoGEFs and RhoGAPs on the YAP1 dependent activity of a TEAD element transcriptional reporter. Robust effects by all three members of the regulator of G-protein signaling (RGS) domain containing RhoGEFs (ArhGEF1, ArhGEF11 and ArhGEF12) prompted studies relating their known roles in serum signaling onto the regulation of Yap1. Under all conditions examined, ArhGEF12 preferentially mediated the activation of YAP1/TEAD by serum versus ArhGEF1 or ArhGEF11. Conversely, ArhGEF1 in multiple contexts inhibited both basal and serum elevated YAP1 activity through its GAP activity for Gα13. The sensitivity of such inhibition to cellular density and to low states of serum signaling supports that ArhGEF1 is a context dependent regulator of YAP1. Taken together, the relative activities of the RGS-RhoGEFs were found to dictate the degree to which serum signaling promotes YAP1 activity.
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影响因子：
3.7
作者：
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通讯作者：
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