title: Receptor heterodimerization as a novel mechanism for the regulation of Wnt/β-catenin signaling.
abstract: The Wnt pathway plays important roles in multiple physiological and pathophysiological processes. Here, we report a novel mechanism that regulates the Wnt pathway through heterodimerization of the Wnt co-receptor low-density lipoprotein-receptor-related protein 6 (LRP6) and very low-density lipoprotein receptor (VLDLR); the latter belongs to the same protein family as LRP6 and was originally known as a receptor for lipoproteins. Knockdown of Vldlr expression elevated LRP6 protein levels and activated Wnt/β-catenin signaling, whereas overexpression of Vldlr suppressed Wnt signaling. Moreover, we demonstrate that the VLDLR ectodomain is essential and sufficient for inhibition of Wnt signaling. The VLDLR ectodomain accelerated internalization and degradation of LRP6 through heterodimerization with the LRP6 extracellular domain. Monoclonal antibodies specific for the VLDLR ectodomain blocked VLDLR-LRP6 heterodimerization, resulting in enhanced Wnt/β-catenin signaling in vitro and in vivo. Taken together, these findings suggest that heterodimerization of receptors in the membrane accelerates the turnover of LRP6, and represent a new mechanism for the regulation of Wnt/β-catenin signaling.
authors.affiliation: Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Kyungwon
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: McBride
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Xuemin
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA jian-xing-ma@ouhsc.edu.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000818:Animals; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D034741:RNA, Small Interfering; D011973:Receptors, LDL; C036053:VLDL receptor; D051176:beta Catenin
keywords: LRP; Lipoprotein receptor-related protein; VLDL; Wnt signaling