The role of the Ser/Thr cluster in the phosphorylation of PPPSP motifs  in Wnt coreceptors.
Wnt/beta-catenin signaling controls a variety of cellular processes, including cell growth, oncogenesis, and development. Upon Wnt stimulation, the intracellular region of the coreceptor, LRP6 or 5, is phosphorylated by the membrane-recruited GSK3beta and CK1. The cytoplasmic domain of LRP6/5 contains one Ser/Thr cluster and the PPPSP motifs, both of which are essential for propagation of the signal. While the phosphorylated PPPSP motifs are known to directly inhibit GSK3beta, the biochemical role of the phosphorylated Ser/Thr cluster remains to be elucidated. Herein, we reveal that the Ser/Thr cluster plays an important role in the phosphorylation of the PPPSP motif. Interestingly, we observe that GSK3beta activity on the PPPSP motif requires a high ATP concentration, close to that of the physiological condition. Taken together, these data suggest that the phosphorylated Ser/Thr cluster serves as a docking site for GSK3beta to promote the phosphorylation of the PPPSP motif. Our results provide insight into the molecular mechanism for the initial events of the Wnt/beta-catenin signaling.
Yum
Soohwan
S
College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 609-735, Republic of Korea.
Lee
Su-Jin
SJ
Piao
Shunfu
S
Xu
Yongbin
Y
Jung
Jiyoung
J
Jung
Yunjin
Y
Oh
Sangtaek
S
Lee
Jaewon
J
Park
Bum-Joon
BJ
Ha
Nam-Chul
NC
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D047389:Casein Kinase I / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011973:Receptors, LDL / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; D011973:Receptors, LDL; D051153:Wnt Proteins; D051176:beta Catenin; D013912:Threonine; D012694:Serine; D047389:Casein Kinase I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3