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 (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.
State Key Laboratory of Biomembrane and Mebrane Biotechnology and School of Life Sciences, Tsinghua University, Beijing 100084, China.
Hua
H
Chen
Linhua
L
Liu
Benyu
B
Ma
Ting Martin
TM
Ma
Jun-Jie
JJ
Hou
Guo-Ming
GM
Xie
Wei
W
Wu
Fu-Quan
FQ
Yang
Ye-Guang
YG
Chen
D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D000072261:Dishevelled Proteins; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; C491683:DACT1 protein, human; D000072261:Dishevelled Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; D017868:Cyclic AMP-Dependent Protein Kinases
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