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TrkA Immunoglobulin-Like Ligand Binding Domains Inhibit Spontaneous Activation of the Receptor

机译：TrkA免疫球蛋白样配体结合域抑制受体的自发激活。

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The extracellular region of the nerve growth factor (NGF) receptor, TrkA, contains two immunoglobulin (Ig)-like domains that are required for specific ligand binding. We have investigated the possible role of these two Ig-like domains in receptor dimerization and activation by using different mutants of the TrkA extracellular region. Deletions of each Ig-like domain, of both, and of the entire extracellular region were made. To probe the structural constraints on ligand-independent receptor dimerization, chimeric receptors were generated by swapping the Ig-like domains of the TrkA receptor for the third or fourth Ig-like domain of c-Kit. We also introduced single-amino-acid changes in conserved residues within the Ig-like domains of TrkA. Most of these TrkA variants did not bind NGF, and their expression in PC12nnr5 cells, which lack endogenous TrkA, promoted ligand-independent neurite outgrowth. Some TrkA mutant receptors induced malignant transformation of Rat-1 cells, as assessed by measuring proliferation in the absence of serum, anchorage-independent growth, and tumorigenesis in nude mice. These mutants exhibited constitutive phosphorylation and spontaneous dimerization consistent with their biological activities. Our data suggest that spontaneous dimerization of TrkA occurs when the structure of the Ig-like domains is altered, implying that the intact domains inhibit receptor dimerization in the absence of NGF.
机译：神经生长因子（NGF）受体TrkA的胞外区域包含两个免疫球蛋白（Ig）样结构域，它们是特定配体结合所必需的。我们已经通过使用TrkA细胞外区域的不同突变体调查了这两个Ig样域在受体二聚化和激活中的可能作用。缺失每个Ig样结构域，两者以及整个细胞外区域。为了探究对配体非依赖性受体二聚化的结构限制，通过将TrkA受体的Ig样结构域交换为c-Kit的第三或第四Ig样结构域来生成嵌合受体。我们还介绍了TrkA Ig样域内的保守残基中的单氨基酸变化。这些大多数TrkA变体不结合NGF，并且它们在缺乏内源性TrkA的PC12nnr5细胞中的表达促进了不依赖配体的神经突生长。一些TrkA突变受体诱导了Rat-1细胞的恶性转化，这是通过测量裸鼠不存在血清，不依赖锚定生长和肿瘤发生的增殖来评估的。这些突变体表现出组成型磷酸化和自发二聚化与其生物学活性一致。我们的数据表明，当Ig样结构域的结构发生改变时，TrkA会自发发生二聚化，这意味着在没有NGF的情况下，完整域会抑制受体二聚化。

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