The low-density lipoprotein receptor-related protein 10 is a negative regulator of the canonical Wnt/beta-catenin signaling pathway.
Wnt signaling pathways play fundamental roles in the differentiation, proliferation and functions of many cells as well as developmental, growth, and homeostatic processes in animals. Low-density lipoprotein receptor (LDLR)-related protein (LRP) 5 and LRP6 serve as coreceptors of Wnt proteins together with Frizzled receptors, triggering activation of canonical Wnt/beta-catenin signaling. Here, we found that LRP10, a new member of the LDLR gene family, inhibits the canonical Wnt/beta-catenin signaling pathway. The beta-catenin/T cell factor (TCF) transcriptional activity in HEK293 cells was activated by transfection with Wnt3a or LRP6, which was then inhibited by co-transfection with LRP10. Deletion of the extracellular domain of LRP10 negated its inhibitory effect. The inhibitory effect of LRP10 was consistently conserved in HEK293 cells even when GSK3beta phosphorylation was inhibited by incubation with lithium chloride and co-transfection with constitutively active S33Y-mutated beta-catenin. Nuclear beta-catenin accumulation was unaffected by LRP10. The present studies suggest that LRP10 may interfere with the formation of the beta-catenin/TCF complex and/or its binding to target DNA in the nucleus, and that the extracellular domain of LRP10 is critical for inhibition of the canonical Wnt/beta-catenin signaling pathway.
Jeong
Young-Hee
YH
Department of Molecular and Biochemical Nutrition, Graduate School of Human Life Science, Osaka City University, Osaka 558-8585, Japan.
Sekiya
Manami
M
Hirata
Michiko
M
Ye
Mingjuan
M
Yamagishi
Azumi
A
Lee
Sang-Mi
SM
Kang
Man-Jong
MJ
Hosoda
Akemi
A
Fukumura
Tomoe
T
Kim
Dong-Ho
DH
Saeki
Shigeru
S
D000595:Amino Acid Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
C495270:CTNNB1 protein, human; D026502:LDL-Receptor Related Proteins; C510813:LRP10 protein, human; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D004247:DNA; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride