Tamir I, Cambier J C
Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Oncogene. 1998 Sep 17;17(11 Reviews):1353-64. doi: 10.1038/sj.onc.1202187.
Antigen receptors on T and B cells function to transduce signals leading to a variety of biologic responses minimally including antigen receptor editing, apoptotic death, developmental progression, cell activation, proliferation and survival. The response to antigen depends upon antigen affinity and valence, involvement of coreceptors in signaling and differentiative stage of the responding cell. The requirement that these receptors integrate signals that drive an array of responses may explain their evolved structural complexity. Antigen receptors are composed of multiple subunits compartmentalized to provide antigen recognition and signal transduction function. In lieu of on-board enzymatic activity these receptors rely on associated Protein Tyrosine Kinases (PTKs) for their signaling function. By aggregating the receptors, and hence their appended PTKs, antigens induce PTK transphosphorylation, activating them to phosphorylate the receptor within conserved motifs termed Immunoreceptor Tyrosine-based Activation Motifs (ITAMs) found in transducer subunits. The tyrosyl phosphorylated ITAMs then interact with Src Homology 2 (SH2) domains within the PTKs leading to their further activation. As receptor phosphorylation is amplified, other effectors, such as Shc, dock by virtue of SH2 binding, and serve, in-turn, as substrates for these PTKs. This sequence of events not only provides a signal amplification mechanism by combining multiple consecutive steps with positive feedback, but also allows for signal diversification by differential recruitment of effectors that provide access to distinct parallel downstream signaling pathways. The subject of antigen receptor signaling has been recently reviewed in depth (DeFranco, 1997; Kurosaki, 1997). Here we discuss the biochemical basis of antigen receptor signal transduction, using the B cell receptor (BCR) as a paradigm, with specific emphasis on the involved PTKs. We review several specific mechanisms by which responses through these receptors are propagated and modified by accessory molecules, and discuss how signal amplification and diversification are achieved.
T细胞和B细胞上的抗原受体发挥功能，转导信号，引发多种生物学反应，至少包括抗原受体编辑、凋亡性死亡、发育进程、细胞活化、增殖和存活。对抗原的反应取决于抗原亲和力和价态、共受体在信号传导中的参与情况以及反应细胞的分化阶段。这些受体整合驱动一系列反应的信号这一需求，或许可以解释其进化而来的结构复杂性。抗原受体由多个亚基组成，这些亚基被分隔开来以提供抗原识别和信号转导功能。这些受体没有自身的酶活性，而是依靠相关的蛋白酪氨酸激酶（PTK）来实现其信号传导功能。通过使受体聚集，进而使与其相连的PTK聚集，抗原诱导PTK发生反式磷酸化，激活它们使其在位于转导亚基中被称为基于免疫受体酪氨酸的激活基序（ITAM）的保守基序内对受体进行磷酸化。酪氨酸磷酸化的ITAM随后与PTK内的Src同源2（SH2）结构域相互作用，导致其进一步激活。随着受体磷酸化的放大，其他效应分子，如Shc，通过SH2结合停靠，并依次作为这些PTK的底物。这一系列事件不仅通过将多个连续步骤与正反馈相结合提供了一种信号放大机制，还通过差异招募效应分子实现信号多样化，这些效应分子能够进入不同的平行下游信号通路。抗原受体信号传导的主题最近已得到深入综述（DeFranco，1997；Kurosaki，1997）。在这里，我们以B细胞受体（BCR）为例，讨论抗原受体信号转导的生化基础，特别强调所涉及的PTK。我们综述了通过这些受体的反应被辅助分子传播和修饰的几种具体机制，并讨论了如何实现信号放大和多样化。
