AI Article Synopsis
- The Wnt coreceptor LRP6 is crucial for activating canonical Wnt signaling and is influenced by specific monoclonal antibodies to regulate its function.
- mAb135, a high-affinity antibody, enhances Wnt signaling while blocking the inhibitory effects of DKK1, indicating its potential role in modulating LRP6.
- Research identified Ser 243 in LRP6's first propeller domain as key for mAb135 binding, revealing this domain's significance in the interaction between LRP6 and DKK1, and suggesting that mAb135 can effectively prevent DKK1 from internalizing LRP6.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719573 | PMC |
| http://dx.doi.org/10.1091/mbc.e08-12-1252 | DOI Listing |
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