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Constitutive activation of fibroblast growth factor receptors in human developmental syndromes

机译：人发育综合征中成纤维细胞生长因子受体的组成性激活

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Fibroblast growth factor receptors (FGFRs) represent specific receptors for the fibroblast growth factors (FGFs), a family of at least 13 polypeptides. Ligand/receptor interactions between FGFs and their receptors are involved in many fundamental biological processes, particularly cell growth and differentiation during chondrogenesis and myogenesis. The four different human FGFR genes encode related glycoproteins with a common structure consisting of an N-terminal signal peptide, three immunoglobulin (Ig)-like domains, a single transmembrane domain, and an intracellular split tyrosine-kinase domain. FGFs, acting in concert with heparan sulfate proteoglycans, bind to FGFRs and result in their activation, involving homo- or hetero-dimerization of receptors, leading to trans-phosphorylation of the kinase domains. The activated receptors can then phosphorylate various intracellular proteins involved in signal transduction, although much remains to be learned concerning these signal transduction pathways downstream of activated FGFRs. Many mutations in different domains of FGFR1, FGFR2 and FGFR3 have recently been identified as causing various human craniosynostosis and dwarfism syndromes, and the molecular consequences of these mutations are beginning to be unraveled. Craniosynostosis syndromes, characterized by premature ossification and fusion of the cranial sutures of the skull, arise primarily from mutations in the extracellular domain FGFR2, although specific mutations in other FGFRs may also underlie related craniosynostosis syndromes. Skeletal dwarfism syndromes, characterized by disproportionate short stature and macrocephaly, arise predominantly from mutations in FGFR3 and include achondroplasia, the most common genetic form of dwarfism, as well as the thanatophoric dysplasias (type I and type II). Recent studies demonstrate that a common mechanism, constitutive activation of receptor signaling, underlies most of these disorders. The mutations responsible for the craniosynostosis and skeletal dwarfism syndromes map variously to either the extracellular domain, the transmembrane domain, or the tyrosine kinase domain of these receptors, suggesting multiple mechanisms of aberrant receptor activation. An overview of the developmental consequences arising from mutations in FGFR family members will be presented, including an examination of the molecular mechanisms underlying these defects.
机译：成纤维细胞生长因子受体（FGFR）代表成纤维细胞生长因子（FGFs）（至少13种多肽的家族）的特异性受体。 FGF及其受体之间的配体/受体相互作用涉及许多基本生物学过程，尤其是软骨形成和肌生成过程中的细胞生长和分化。四种不同的人类FGFR基因编码具有相同结构的相关糖蛋白，该结构由N端信号肽，三个免疫球蛋白（Ig）样结构域，单个跨膜结构域和细胞内分裂酪氨酸激酶结构域组成。与硫酸乙酰肝素蛋白聚糖协同作用的FGF与FGFR结合并导致其活化，包括受体的同二聚或异二聚化，导致激酶结构域的反磷酸化。然后，活化的受体可以使参与信号转导的各种细胞内蛋白磷酸化，尽管关于活化的FGFRs下游的这些信号转导途径尚有许多知识要学习。最近已鉴定出FGFR1，FGFR2和FGFR3不同域中的许多突变会导致各种人类颅前突增生和侏儒症综合征，并且这些突变的分子后果已开始阐明。以颅骨的颅骨缝线过早骨化和融合为特征的颅前突综合征主要来自细胞外域FGFR2中的突变，尽管其他FGFR中的特定突变也可能是相关的颅前突综合征的基础。骨骼矮化综合症的特征是矮小的身材和大头畸形，主要是由于FGFR3突变引起的，包括软骨发育不全，侏儒症的最常见遗传形式，以及畸胎不典型增生（I型和II型）。最近的研究表明，一种常见的机制，即受体信号传导的组成性激活，是大多数此类疾病的基础。负责颅突神经突增生和骨骼侏儒症综合征的突变分别映射到这些受体的细胞外结构域，跨膜结构域或酪氨酸激酶结构域，提示异常的受体激活机制多种。将概述由FGFR家族成员突变引起的发育后果，包括检查这些缺陷的分子机制。

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