A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation
A novel mutation within the extracellular domain of TrkA causes constitutive receptor activation
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DOI：
10.1038/sj.onc.1204215
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发表时间：
2001-03-08
期刊：
影响因子：
8
通讯作者：
Pérez, P
中科院分区：
文献类型：
--
作者：
Arevalo, JC;Conde, B;Pérez, P
TrkA NGF受体胞外区含有三个亮氨酸重复序列，两侧为半胱氨酸簇和两个特异性配体结合所需的免疫球蛋白样结构域。免疫球蛋白样结构域的缺失消除了NGF结合并引起受体的配体非依赖性活化。在这里，我们报告了一个特定的突变，增加了结合亲和力的TrkA受体的NGF，脯氨酸203丙氨酸（P203 A）之间的亮氨酸重复序列和第一个Ig样结构域的连接器区域的变化增加了NGF的结合，通过降低配体解离速率，这种突变的受体适当地表达在细胞表面上，并促进配体非依赖性的神经突起生长在PC 12 nr 5细胞。该突变体受体能够自发二聚化，并且在配体不存在的情况下组成性磷酸化。此外，TrkA-P203 A受体在成纤维细胞中的表达诱导DNA合成和转化，并在裸鼠中产生肿瘤。这些数据表明，免疫球蛋白样结构以外的结构域有助于配体结合和组成型激活Trk受体。
The TrkA NGF receptor extracellular region contains three leucine repeats flanked by cysteine clusters and two immunoglobulin-like domains that are required for specific ligand binding. Deletion of the immunoglobulinlike domains abolishes NGF binding and causes ligand independent activation of the receptor. Here we report a specific mutation that increases the binding affinity of the TrkA receptor for NGF, A change of proline 203 to alanine (P203A) in the linker region between the leucine repeats and the first Ig-like domain increased NGF binding by decreasing the ligand rate of dissociation, This mutated receptor was appropriately expressed on the cell surface and promoted ligand-independent neurite outgrowth in PC12nnr5 cells. The mutant receptor was capable of spontaneous dimerization and was constitutively phosphorylated in the absence of ligand, Moreover, expression of TrkA-P203A receptor in fibroblasts induced DNA synthesis and transformation and generated tumours in nude mice. These data suggest that domains outside of the immunoglobulin-like structure contribute to ligand binding and constitutive activation of Trk receptors.