Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway.
To understand how the Wnt coreceptor LRP-5 is involved in transducing the canonical Wnt signals, we identified Axin as a protein that interacts with the intracellular domain of LRP-5. LRP-5, when expressed in fibroblast cells, showed no effect on the canonical Wnt signaling pathway by itself, but acted synergistically with Wnt. In contrast, LRP-5 mutants lacking the extracellular domain functioned as constitutively active forms that bind Axin and that induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. Addition of Wnt caused the translocation of Axin to the membrane and enhanced the interaction between Axin and LRP-5. In addition, the LRP-5 sequences involved in interactions with Axin are required for LEF-1 activation. Thus, we conclude that the binding of Axin to LRP-5 is an important part of the Wnt signal transduction pathway.
Mao
J
J
Department of Genetics and Developmental Biology, University of Connecticut, Farmington, CT 06030, USA.
Wang
J
J
Liu
B
B
Pan
W
W
Farr
G H
GH
Flynn
C
C
Yuan
H
H
Takada
S
S
Kimelman
D
D
Li
L
L
Wu
D
D
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D038362:Glycogen Synthase Kinase 3; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008322:Mammals; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D060466:Axin Protein; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D012097:Repressor Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3