Activation of FGF receptors by mutations in the transmembrane domain
Activation of FGF receptors by mutations in the transmembrane domain
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DOI：
10.1038/sj.onc.1200983
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发表时间：
1997-03-27
期刊：
影响因子：
8
通讯作者：
Basilico, C
中科院分区：
文献类型：
--
作者：
Li, Y;Mangasarian, K;Basilico, C
FGF受体是跨膜酪氨酸激酶家族的一员，通过FGF受体的信号传导可以刺激细胞增殖，诱导或抑制细胞分化，并在发育中发挥重要作用。最近，FGF受体的突变已被证明与许多遗传显性人类骨骼疾病相关。FGFR-3的跨膜区中的显著保守突变（Gly 380->Arg）已被证明是软骨发育不全（ACH）的原因，但尚不清楚此类突变是否导致受体功能丧失或组成性激活。因此，我们在鼠FGFR-2和FGFR-3的跨膜区进行了突变，并研究了它们对受体活性的影响。我们在这里表明，ACH突变FGFR-3以及两个类似的突变FGFR-2导致这些受体的组成性激活。这表现在它们在L 6细胞中不存在配体的情况下自身磷酸化的能力、对NIH 3 T3成纤维细胞的转化活性以及在不存在生长因子的情况下抑制肌源性分化的能力。因此，FGFR-2和FGFR-3的跨膜区在受体功能中起调节作用，并且ACH突变产生不再受FGF结合调节的显性过度信号传导受体。这些发现也支持了FGF信号作为骨生长负调节剂的新发现的作用。
Signaling through FGF receptors, which constitute a family of membrane-spanning tyrosine kinases, can stimulate cell proliferation, induce or inhibit cell differentiation and plays an important role in development. Recently, mutations in FGF receptors have been shown to be associated with a number of genetically dominant human skeletal disorders. A remarkably conserved mutation (Gly 380-->Arg) in the transmembrane region of FGFR-3 has been shown to be responsible for achondroplasia (ACH) but it was not clear whether such mutations result in loss of receptor function or constitutive activation. We have therefore made mutations in the transmembrane regions of murine FGFR-2 and FGFR-3 and studied their effect on receptor activity. We show here that the ACH mutation in FGFR-3 as well as two similar mutations in FGFR-2 result in constitutive activation of these receptors. This is manifested in their ability to become autophosphorylated in the absence of ligand in L6 cells, transforming activity on NIH3T3 fibroblasts, and the ability to inhibit myogenic differentiation in the absence of growth factor. Thus the transmembrane region of FGFR-2 and FGFR-3 plays a regulatory role in receptor function and the ACH mutation produces a dominant oversignaling receptor which is no longer regulated by FGF binding. These findings also support the newly identified role of FGF signaling as a negative regulator of bone growth.