State Key Laboratory of Biomembrane and Mebrane Biotechnology and School of Life Sciences, Tsinghua University, Beijing 100084, China.
J Biol Chem. 2011 Apr 29;286(17):14870-80. doi: 10.1074/jbc.M110.211607. Epub 2011 Jan 24.
Wnt signaling regulates embryo development and tissue homeostasis, and its deregulation leads to an array of diseases, including cancer. Dapper1 has been shown to be a key negative regulator of Wnt signaling. However, its function and regulation remain poorly understood. In this study, we report that 14-3-3β interacts with human Dapper1 (hDpr1). The interaction is dependent on protein kinase A (PKA)-mediated phosphorylation of hDpr1 at Ser-237 and Ser-827. 14-3-3β binding attenuates the ability of hDpr1 to promote Dishevelled (Dvl) degradation, thus enhancing Wnt signaling. We further provide evidence that PKA-mediated Dpr1 phosphorylation may contribute to growth and tumor formation of colon cancer Caco2 cells. Finally, we show that cyclooxygenase-2 expression and PKA activation are positively correlated with Dvl protein levels in colon cancer samples. Together, our findings establish a novel layer of regulation of Wnt signaling by PKA via the 14-3-3-Dpr1-Dvl axis.
Wnt 信号通路调节胚胎发育和组织内稳态，其失调会导致多种疾病，包括癌症。Dapper1 已被证明是 Wnt 信号通路的关键负调控因子。然而，其功能和调控仍知之甚少。在这项研究中，我们报告了 14-3-3β 与人类 Dapper1（hDpr1）相互作用。这种相互作用依赖于蛋白激酶 A（PKA）介导的 hDpr1 在 Ser-237 和 Ser-827 位点的磷酸化。14-3-3β 结合会减弱 hDpr1 促进 Dishevelled（Dvl）降解的能力，从而增强 Wnt 信号通路。我们进一步提供证据表明，PKA 介导的 Dpr1 磷酸化可能有助于结肠癌细胞 Caco2 的生长和肿瘤形成。最后，我们发现环氧化酶-2 的表达和 PKA 的激活与结肠癌样本中 Dvl 蛋白水平呈正相关。总之，我们的研究结果确立了 PKA 通过 14-3-3-Dpr1-Dvl 轴对 Wnt 信号通路的一种新的调控机制。
