Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions.
Canonical Wnt/beta-catenin signaling has central roles in development and diseases, and is initiated by the action of the frizzled (Fz) receptor, its coreceptor LDL receptor-related protein 6 (Lrp6), and the cytoplasmic dishevelled (Dvl) protein. The functional relationships among Fz, Lrp6 and Dvl have long been enigmatic. We demonstrated previously that Wnt-induced Lrp6 phosphorylation via glycogen synthase kinase 3 (Gsk3) initiates Wnt/beta-catenin signaling. Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. We also show that axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3, and inhibition of Gsk3 at the plasma membrane blocks Wnt/beta-catenin signaling. Our results suggest a model that upon Wnt-induced Fz-Lrp6 complex formation, Fz recruitment of Dvl in turn recruits the axin-Gsk3 complex, thereby promoting Lrp6 phosphorylation to initiate beta-catenin signaling. We discuss the dual roles of the axin-Gsk3 complex and signal amplification by Lrp6-axin interaction during Wnt/beta-catenin signaling.
Zeng
Xin
X
The F. M. Kirby Neurobiology Center, Children's Hospital Boston, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
Huang
He
H
Tamai
Keiko
K
Zhang
Xinjun
X
Harada
Yuko
Y
Yokota
Chika
C
Almeida
Karla
K
Wang
Jianbo
J
Doble
Brad
B
Woodgett
Jim
J
Wynshaw-Boris
Anthony
A
Hsieh
Jen-Chieh
JC
He
Xi
X
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D060466:Axin Protein; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000072261:Dishevelled Proteins; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051157:Frizzled Receptors / Q000737:chemistry / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008954:Models, Biological; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D004791:Enzyme Inhibitors; D051157:Frizzled Receptors; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D010750:Phosphoproteins; D011973:Receptors, LDL; D012097:Repressor Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3