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首页> 外文期刊>Science Signaling >Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple
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Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple

机译：鸟嘌呤核苷酸交换因子Daple上的Wnt，生长因子和异趾蛋白信号的收敛性

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摘要

Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades, and their dys-regulation plays an integral role in cancer progression. Three cascades that contribute to oncogenic potential are those mediated by Wnt proteins and the receptor Frizzled (FZD), growth factor receptor tyrosine kinases (RTKs), and heterotrimeric G proteins and associated GPCRs. Daple is a guanine nucleotide exchange factor (GEF) for the G protein G(alpha i). Daple also binds to FZD and the Wnt/FZD mediator Dishevelled (Dvl), and it enhances beta-catenin-independent Wnt signaling in response to Wnt5a-FZD7 signaling. We identified Daple as a substrate of multiple RTKs and non-RTKs and, hence, as a point of convergence for the three cascades. We found that phosphorylation near the Dvl-binding motif in Daple by both RTKs and non-RTKs caused Daple/Dvl complex dissociation and augmented the ability of Daple to bind to and activate G(alpha i), which potentiated beta-catenin-independent Wnt signals and stimulated epithelial-mesenchymal transition (EMT) similarly to Wnt5a/FZD7 signaling. Although Daple acts as a tumor suppressor in the healthy colon, the concurrent increased abundance of Daple and epidermal growth factor receptor (EGFR) in colorectal tumors was associated with poor patient prognosis. Thus, the Daple-dependent activation of G(alpha i) and the Daple-dependent enhancement of beta-catenin-independent Wnt signals are not only stimulated by Wnt5a/FZD7 to suppress tumorigenesis but also hijacked by growth factor-activated RTKs to enhance tumor progression. These findings identify a cross-talk paradigm among growth factor RTKs, heterotrimeric G proteins, and the Wnt/FZD pathway in cancer.
机译：细胞增殖，分化和形态发生是由多个信号级联的成形，并且它们的性能调节在癌症进展中起重要作用。有助于致癌潜力的三个级联是由Wnt蛋白和受体释放的受体（FZD），生长因子受体酪氨酸激酶（RTKS）和异映酰基蛋白和相关的GPCR介导的那些。 Daple是G蛋白G（alpha i）的鸟嘌呤核苷酸交换因子（GEF）。 Daple还绑定到FZD，WNT / FZD介体饰有折叠（DVL），并响应于WNT5A-FZD7信号传导而增强了β-连环蛋白无关的WNT信号传导。我们将Daple识别为多个RTK和非RTK的基板，因此，作为三个级联的收敛点。我们发现，通过RTK和非RTK，DVL结合基序附近的磷酸化引起了Daple / DVL复合解离并增强了Daple结合和激活G（αI）的能力，其具有增强的β-catenin-Indelly-Wnt与WNT5A / FZD7信号相似的信号和刺激的上皮 - 间充质转换（EMT）。虽然Daple作为健康结肠中的肿瘤抑制剂，但结直肠肿瘤中的雏菊和表皮生长因子受体（EGFR）的同步增加与患者预后差有关。因此，G（αI）的缺乏依赖性激活和β-连环蛋白无关的Wnt信号的似依赖性增强不仅受到Wnt5a / fzd7刺激以抑制肿瘤发生，而且均被生长因子活化RTK刺激以增强肿瘤进展。这些发现识别生长因子RTK，异映酰基蛋白质和癌症中的WNT / FZD途径之间的串扰范式。

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