Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias.
Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias.
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DOI：
10.1002/humu.21636
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发表时间：
2012-01
期刊：
影响因子：
3.9
通讯作者：
Krejci, Pavel
中科院分区：
文献类型：
--
作者：
Foldynova-Trantirkova, Silvie;Wilcox, William R.;Krejci, Pavel
1994 年，由于发现 FGFR3 受体酪氨酸激酶的激活突变导致了人类侏儒症的常见遗传形式——软骨发育不全，骨生物学领域取得了重大进展。其他疾病很快接踵而至，由 FGFR3 突变引起的人类疾病清单现已达到至少 10 种。 FGFR3 的相似突变引起一系列截然不同的诊断，包括影响骨骼发育（软骨发育不全、软骨发育不全、致死性发育不良）、皮肤（表皮痣、脂溢性角化病、棘皮症）的综合征 黑种人）和癌症（多发性骨髓瘤、前列腺癌和膀胱癌、精原细胞瘤）。尽管经过多年的研究，FGFR3 在疾病中的功能的几个方面仍然不清楚或存在争议。由于 FGFR3 相关的骨骼发育不良是由软骨生长减弱引起的，因此软骨细胞对 FGFR3 激活的反应似乎是独特的。然而，FGFR3 抑制软骨细胞生长同时导致癌症细胞过度增殖的原因尚不清楚。同样，FGFR3 介导其信号传导的全部分子事件才刚刚开始出现。本文描述了揭示 FGFR3 在骨骼发育不良中的功能机制的挑战性旅程、FGFR3 信号在软骨细胞中的非凡细胞表现，以及最后，软骨发育不全和癌症治疗的进展。
In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the FGFR3 receptor tyrosine kinase account for the common genetic form of dwarfism in humans, achondroplasia. Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia, achondroplasia, thanatophoric dysplasia), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans) and cancer (multiple myeloma, prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress towards therapy for achondroplasia and cancer.
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