Lamballe F, Tapley P, Barbacid M
Department of Molecular Biology, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08543-4000.
EMBO J. 1993 Aug;12(8):3083-94. doi: 10.1002/j.1460-2075.1993.tb05977.x.
The trkC gene product gp145trkC is a high affinity signaling receptor for neurotrophin-3 (NT-3), a member of the NGF family of neurotrophic factors. We now report that trkC encodes at least two additional tyrosine protein kinase receptors. These receptors, designated TrkC K2 and TrkC K3, have the same amino acid sequences as gp145trkC (now designated TrkC K1) except for the presence of 14 and 25 additional amino acid residues between kinase subdomains VII and VIII, just downstream from the TDYYR motif which encompasses the putative autophosphorylation site of the Trk receptor family. Upon interaction with their cognate ligand, NT-3, all three TrkC receptor isoforms become rapidly phosphorylated on tyrosine residues and induce DNA synthesis in quiescent cells. However, only TrkC K1 has mitogenic activity in NIH3T3 cells and induces neuronal differentiation of PC12 cells. The different biological properties of these TrkC receptor isoforms probably result from their engagement with different signaling pathways. Whereas TrkC K1 phosphorylates phospholipase C gamma 1 and phosphatidylinositol-3 kinase, TrkC K2 and TrkC K3 do not. TrkC K2 and transcripts encoding TrkC K3 have been identified in various structures of the adult murine brain. These observations suggest that the trophic activities of NT-3 in the mammalian nervous system might be mediated by different TrkC receptor isoforms.
trkC基因产物gp145trkC是神经营养因子-3（NT-3）的高亲和力信号受体，NT-3是神经营养因子NGF家族的成员。我们现在报告trkC至少编码另外两种酪氨酸蛋白激酶受体。这些受体，命名为TrkC K2和TrkC K3，与gp145trkC（现命名为TrkC K1）具有相同的氨基酸序列，只是在激酶亚结构域VII和VIII之间分别存在14个和25个额外的氨基酸残基，就在包含Trk受体家族假定自磷酸化位点的TDYYR基序下游。与它们的同源配体NT-3相互作用后，所有三种TrkC受体亚型的酪氨酸残基都会迅速磷酸化，并在静止细胞中诱导DNA合成。然而，只有TrkC K1在NIH3T3细胞中具有促有丝分裂活性，并诱导PC12细胞的神经元分化。这些TrkC受体亚型不同的生物学特性可能源于它们与不同信号通路的结合。TrkC K1使磷脂酶Cγ1和磷脂酰肌醇-3激酶磷酸化，而TrkC K2和TrkC K3则不会。在成年小鼠大脑的各种结构中已鉴定出TrkC K2和编码TrkC K3的转录本。这些观察结果表明，NT-3在哺乳动物神经系统中的营养活性可能由不同的TrkC受体亚型介导。
