Huang Eric J, Reichardt Louis F
Department of Pathology, University of California Veterans Administration Medical Center, San Francisco, California 94143, USA.
Annu Rev Biochem. 2003;72:609-42. doi: 10.1146/annurev.biochem.72.121801.161629. Epub 2003 Mar 27.
Trk receptors are a family of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C-gamma (PLC-gamma). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. p75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. p75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences.
Trk受体是一个由三种受体酪氨酸激酶组成的家族，其中每一种都可被四种神经营养因子中的一种或多种激活，这四种神经营养因子分别是神经生长因子（NGF）、脑源性神经营养因子（BDNF）以及神经营养因子3和4（NT3和NT4）。通过这些受体进行的神经营养因子信号传导可调节细胞存活、增殖、神经前体细胞的命运、轴突和树突的生长及模式形成，以及功能重要蛋白质（如离子通道和神经递质受体）的表达和活性。在成体神经系统中，Trk受体调节突触强度和可塑性。Trk受体的胞质结构域包含几个酪氨酸磷酸化位点，这些位点可募集细胞内信号级联反应中的中间体。因此，Trk受体信号传导可激活几种小G蛋白，包括Ras、Rap-1以及Cdc-42-Rac-Rho家族，同时也可激活由丝裂原活化蛋白激酶（MAP激酶）、磷脂酰肌醇-3激酶（PI 3-激酶）和磷脂酶C-γ（PLC-γ）调节的信号通路。Trk受体激活在不同细胞中会产生不同的结果，下游Trk受体介导的信号传导特异性是通过这些信号通路中中间体的表达以及调节不同信号成分定位的膜运输来控制的。Trk受体介导的信号传导最引人入胜的方面或许是其与泛神经营养因子受体p75NTR所促进的信号传导之间的相互作用。p75NTR在细胞内激活一组独特的信号通路，这些信号通路在某些情况下与Trk受体激活的信号通路协同，而在其他情况下则相互拮抗。其中一些是促凋亡的，但会被Trk受体启动的信号传导所抑制。p75NTR还会影响Trk受体的构象；这会改变配体结合特异性和亲和力，并产生重要的发育后果。
