FGFR3 induces degradation of BMP type I receptor to regulate skeletal development.
FGFR3 induces degradation of BMP type I receptor to regulate skeletal development.
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DOI：
10.1016/j.bbamcr.2014.03.011
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发表时间：
2014-07
影响因子：
5.1
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Qi, Huabing;Jin, Min;Duan, Yaqi;Du, Xiaolan;Zhang, Yuanquan;Ren, Fangli;Wang, Yinyin;Tian, Qingyun;Wang, Xiaofeng;Wang, Quan;Zhu, Ying;Xie, Yangli;Liu, Chuanju;Cao, Xu;Mishina, Yuji;Chen, Di;Deng, Chu-xia;Chang, Zhijie;Chen, Lin
成纤维细胞生长因子（FGF）及其受体（FGFR）在脊椎动物器官发生和形态发生中发挥重要作用。 FGFR3 是软骨形成的负调节因子，具有 FGFR3 组成型活性的多重突变会导致软骨发育不全，这是人类最常见的侏儒症之一，但其分子机制仍不清楚。在这项研究中，我们发现软骨细胞特异性删除 BMP I 型受体 a (Bmpr1a) 通过减少软骨细胞分化来挽救 Fgfr3 缺陷小鼠中观察到的骨过度生长表型。一致地，使用体外软骨形成分化测定系统，我们证明 FGFR3 抑制 BMPR1a 介导的软骨形成分化。此外，我们发现 FGFR3 过度激活会导致小鼠生长板软骨细胞中的 BMP 信号传导受损。我们还发现 FGFR3 通过与其酪氨酸激酶活性无关的机制抑制 BMP-2 或组成型激活的 BMPR1 诱导的 Smads 磷酸化。我们发现FGFR3通过Smurf1介导的泛素化途径促进BMPR1a降解。我们证明，BMPR1 抑制剂 Dorsomorphin 下调 BMP 信号传导导致软骨形成分化延迟，这类似于 FGF-2 对软骨细胞的作用，并且 BMP-2 治疗部分挽救了死亡死亡发育不良 II 型小鼠的培养骨基体的生长延迟。我们的研究结果表明，FGFR3 促进 BMPR1a 的降解，这在 FGFR3 相关骨骼发育不良的发病机制中发挥重要作用。
Fibroblast growth factors (FGFs) and their receptors (FGFRs) play significant roles in vertebrate organogenesis and morphogenesis. FGFR3 is a negative regulator of chondrogenesis and multiple mutations with constitutive activity of FGFR3 result in achondroplasia, one of the most common dwarfisms in humans, but the molecular mechanism remains elusive. In this study, we found that chondrocyte-specific deletion of BMP type I receptor a (Bmpr1a) rescued the bone overgrowth phenotype observed in Fgfr3 deficient mice by reducing chondrocyte differentiation. Consistently, using in vitro chondrogenic differentiation assay system, we demonstrated that FGFR3 inhibited BMPR1a-mediated chondrogenic differentiation. Furthermore, we showed that FGFR3 hyper-activation resulted in impaired BMP signaling in chondrocytes of mouse growth plates. We also found that FGFR3 inhibited BMP-2- or constitutively activated BMPR1-induced phosphorylation of Smads through a mechanism independent of its tyrosine kinase activity. We found that FGFR3 facilitates BMPR1a to degradation through Smurf1-mediated ubiquitination pathway. We demonstrated that down-regulation of BMP signaling by BMPR1 inhibitor dorsomorphin led to the retardation of chondrogenic differentiation, which mimics the effect of FGF-2 on chondrocytes and BMP-2 treatment partially rescued the retarded growth of cultured bone rudiments from thanatophoric dysplasia type II mice. Our findings reveal that FGFR3 promotes the degradation of BMPR1a, which plays an important role in the pathogenesis of FGFR3-related skeletal dysplasia.
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DOI：
10.1073/pnas.0503617102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Kobayashi, T;Lyons, KM;Kronenberg, HM
通讯作者：
Kronenberg, HM
影响因子：
2.1
作者：
Kurozumi, K;Nishita, M;Shibuya, H
通讯作者：
Shibuya, H
影响因子：
3.5
作者：
Iwata, T;Li, CL;Francomano, CA
通讯作者：
Francomano, CA
影响因子：
15.9
作者：
Chen, L;Adar, R;Deng, CX
通讯作者：
Deng, CX
影响因子：
3.5
作者：
Li, CL;Chen, L;Deng, CX
通讯作者：
Deng, CX