The First Propeller Domain of LRP6 Regulates Sensitivity to DKK1

被引：19

作者：

Binnerts, Minke E. ^{[1
]}

Tomasevic, Nenad ^{[1
]}

Bright, Jessica M. ^{[1
]}

Leung, John ^{[1
]}

Ahn, Victoria E. ^{[2
,3
]}

Kim, Kyung-Ah ^{[1
]}

Zhan, Xiaoming ^{[1
]}

Liu, Shouchun ^{[1
]}

Yonkovich, Shirlee ^{[1
]}

Williams, Jason ^{[1
]}

Zhou, Mei ^{[1
]}

Gros, Delphine ^{[1
]}

Dixon, Melissa ^{[1
]}

Korver, Wouter ^{[1
]}

Weis, William I. ^{[2
,3
]}

Abo, Arie ^{[1
]}

机构：

[1] Arca Biopharma, San Carlos, CA 94070 USA

[2] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA

来源：

MOLECULAR BIOLOGY OF THE CELL | 2009年 / 20卷 / 15期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

HIGH-BONE-MASS; RECEPTOR-RELATED PROTEIN-5; WNT CORECEPTOR LRP6; MUTATION; MICE; INHIBITION; MECHANISM; PHOSPHORYLATION; INTERNALIZATION; ACTIVATION;

D O I：

10.1091/mbc.E08-12-1252

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：3552 / 3560

页数：9

共 35 条

[1] Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling [J].