Non-canonical Wnt induces chondrocyte de-differentiation through Frizzled 6 and DVL-2/B-raf/CaMKIIα/syndecan 4 axis

被引：15

作者：

Xie, Zhe ^{[1
]}

Khair, Mostafa ^{[1
]}

Shaukat, Irfan ^{[1
]}

Netter, Patrick ^{[1
]}

Mainard, Didier ^{[1
]}

Barre, Lydia ^{[1
]}

Ouzzine, Mohamed ^{[1
]}

机构：

[1] Univ Lorraine, Fac Med, CNRS, UMR7365,Biopole, F-54505 Vandoeuvre Les Nancy, France

来源：

CELL DEATH AND DIFFERENTIATION | 2018年 / 25卷 / 08期

关键词：

WNT/BETA-CATENIN; KINASE-II; CARTILAGE; EXPRESSION; ACTIVATION; MEMBRANE; PATHWAYS; PROTEINS; POLARITY; BIOLOGY;

D O I：

10.1038/s41418-017-0050-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Dysregulation of Wnt signaling has been implicated in developmental defects and in the pathogenesis of many diseases such as osteoarthritis; however, the underlying mechanisms are poorly understood. Here, we report that non-canonical Wnt signaling induced loss of chondrocyte phenotype through activation of Fz-6/DVL-2/SYND4/CaMKII alpha/B-raf/ERK1/2 cascade. We show that in response to Wnt-3a, Frizzled 6 (Fz-6) triggers the docking of CaMKII alpha to syndecan 4 (SYND4) and that of B-raf to DVL-2, leading to the phosphorylation of B-raf by CaMKII alpha and activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling, which leads to chondrocyte de-differentiation. We demonstrate that CaMKII alpha associates and phosphorylates B-raf in vitro and in vivo. Our study reveals the mechanism by which non-canonical Wnt activates ERK1/2 signaling that induces loss of chondrocyte phenotype, and demonstrates a direct functional relationship between CaMKII alpha and B-raf during chondrocyte de-differentiation. The identification of Fz-6, SYND4, and B-raf as novel physiological regulators of chondrocyte phenotype may provide new potential anti-osteoarthritic targets.

引用

页码：1442 / 1456

页数：15