Molecular Biology of the Cell click for CBE Life Science Education Page

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Originally published as MBC in Press, 10.1091/mbc.E08-12-1252 on May 28, 2009

Vol. 20, Issue 15, 3552-3560, August 1, 2009

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
E08-12-1252v1
20/15/3552    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Binnerts, M. E.
Right arrow Articles by Abo, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Binnerts, M. E.
Right arrow Articles by Abo, A.

The First Propeller Domain of LRP6 Regulates Sensitivity to DKK1

Minke E. Binnerts*, Nenad Tomasevic*, Jessica M. Bright*, John Leung*, Victoria E. Ahn{dagger}, Kyung-Ah Kim*, Xiaoming Zhan*, Shouchun Liu*, Shirlee Yonkovich*, Jason Williams*, Mei Zhou*, Delphine Gros*, Melissa Dixon*, Wouter Korver*, William I. Weis{dagger}, and Arie Abo*

*Arca Biopharma, San Carlos, CA 94070-6211; and {dagger}Departments of Structural Biology, and Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305

Submitted December 30, 2008; Revised May 13, 2009; Accepted May 20, 2009
Monitoring Editor: Jonathan Chernoff

The Wnt coreceptor LRP6 is required for canonical Wnt signaling. To understand the molecular regulation of LRP6 function, we generated a series of monoclonal antibodies against the extra cellular domain (ECD) of LRP6 and selected a high-affinity mAb (mAb135) that recognizes cell surface expression of endogenous LRP6. mAb135 enhanced Wnt dependent TCF reporter activation and antagonized DKK1 dependent inhibition of Wnt3A signaling, suggesting a role in modulation of LRP6 function. Detailed analysis of LRP6 domain mutants identified Ser 243 in the first propeller domain of LRP6 as a critical residue for mAb135 binding, implicating this domain in regulating the sensitivity of LRP6 to DKK1. In agreement with this notion, mAb135 directly disrupted the interaction of DKK1 with recombinant ECD LRP6 and a truncated form of the LRP6 ECD containing only repeats 1 and 2. Finally, we found that mAb135 completely protected LRP6 from DKK1 dependent internalization. Together, these results identify the first propeller domain as a novel regulatory domain for DKK1 binding to LRP6 and show that mAb against the first propeller domain of LRP6 can be used to modulate this interaction.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-12-1252) on May 28 2009.

Address correspondence to: Minke Binnerts (minkebinnerts{at}mindspring.com) or Arie Abo (arieabo{at}yahoo.com)






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Copyright © 2009 by The American Society for Cell Biology. Terms of copyright protection, warranties, and disclaimers.