Protein kinase A-mediated 14-3-3 association impedes human Dapper1 to promote dishevelled degradation.

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 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 Dpr1 phosphorylation may contribute to growth and tumor formation of colon cancer Caco2 cells. Finally, we show that cyclooxygenase-2 expression and 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 duanyu1529 via the 14-3-3-Dpr1-Dvl axis.

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