Signaling through sphingolipid microdomains of the plasma membrane: The concept of signaling platform
Signaling through sphingolipid microdomains of the plasma membrane: The concept of signaling platform
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DOI：
10.1023/a:1026585006064
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发表时间：
2000-03-01
影响因子：
3
通讯作者：
Din, NU
中科院分区：
文献类型：
--
作者：
Hoessli, DC;Ilangumaran, S;Din, NU
跨膜信号传导需要信号蛋白之间的模块化相互作用，相互作用蛋白伴侣的磷酸化或去磷酸化[1]以及超分子结构的临时加工[2]，以将分子信息从细胞表面传递到细胞核。质膜上的这种信号复合物有助于将细胞外信号转化为细胞内信号以激活基因。在最直接的情况下，配体结合促进跨膜受体的同源二聚化，这促进受体的胞质结构域与胞内信号传导和衔接蛋白之间的模块化相互作用[3]。例如，大多数生长因子受体含有细胞质蛋白酪氨酸激酶（PTK）结构域，配体介导的受体二聚化导致受体细胞质结构域中酪氨酸的交叉磷酸化，这是一种启动信号级联反应的事件[4]。在受体不具有内在激酶活性的其它信号传导途径中，细胞内非受体PTK（即Src家族PTK，JAK）被募集到接合受体的胞质结构域。这些初始磷酸化的执行及其转化为有效的细胞刺激需要多种信号通路的伴随激活。质膜上稳定的预组装基质的可用性将促进大量受体、共受体、酪氨酸激酶和其他信号传导和衔接蛋白的支架化，如通过T细胞抗原受体进行信号传导的情况[5]。信号平台[6]的概念已被用于表征膜结构，其中许多不同的膜结合组件需要以协调的方式组装以进行信号传递。信号平台的结构基础在于某些类别的脂质优先组装成质膜内不同的物理和功能区室[7，8]。这些膜微区或筏（图1）作为受体和近端信号分子最佳相互作用的特权位点[9]。在这篇综述中，我们将首先讨论信号平台是如何组装的，以及受体和它们的信号机制如何在这样的结构中功能性地连接。我们的审查的第二部分将处理选定的例子筏为基础的信号通路在T淋巴细胞和NK细胞来说明筏可能促进信号的方式。
Transmembrane signaling requires modular interactions between signaling proteins, phosphorylation or dephosphorylation of the interacting protein partners [1] and temporary elaboration of supramolecular structures [2], to convey the molecular information from the cell surface to the nucleus. Such signaling complexes at the plasma membrane are instrumental In translating the extracellular cues into intracellular signals for gene activation. In the most straightforward case, ligand binding promotes homodimerization of the transmembrane receptor which facilitates modular interactions between the receptor's cytoplasmic domains and intracellular signaling and adaptor proteins [3]. For example, most growth factor receptors contain a cytoplasmic protein tyrosine kinase (PTK) domain and ligand-mediated receptor dimerization leads to cross phosphorylation of tyrosines in the receptor's cytoplasmic domains, an event that initiates the signaling cascade [4]. In other signaling pathways where the receptors have no intrinsic kinase activity, intracellular nonreceptor PTKs (i.e. Src family PTKs, JAKs) are recruited to the cytoplasmic domain of the engaged receptor. Execution of these initial phosphorylations and their translation into efficient cellular stimulation requires concomitant activation of diverse signaling pathways. Availability of stable, preassembled matrices at the plasma membrane would facilitate scaffolding of a large array of receptors, coreceptors, tyrosine kinases and other signaling and adapter proteins, as it is the case in signaling via the T cell antigen receptor [5]. The concept of the signaling platform [6] has gained usage to characterize the membrane structure where many different membrane-bound components need to be assembled in a coordinated manner to carry out signaling. The structural basis of the signaling platform lies in preferential assembly of certain classes of lipids into distinct physical and functional compartments within the plasma membrane [7,8]. These membrane microdomains or rafts (Figure 1) serve as privileged sites where receptors and proximal signaling molecules optimally interact [9]. In this review, we shall discuss first how signaling platforms are assembled and how receptors and their signaling machinery could be functionally linked in such structures. The second part of our review will deal with selected examples of raft-based signaling pathways in T lymphocytes and NK cells to illustrate the ways in which rafts may facilitate signaling.