Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA.
Cell Commun Signal. 2012 Sep 14;10(1):27. doi: 10.1186/1478-811X-10-27.
Specific peptide ligand recognition by modular interaction domains is essential for the fidelity of information flow through the signal transduction networks that control cell behavior in response to extrinsic and intrinsic stimuli. Src homology 2 (SH2) domains recognize distinct phosphotyrosine peptide motifs, but the specific sites that are phosphorylated and the complement of available SH2 domains varies considerably in individual cell types. Such differences are the basis for a wide range of available protein interaction microstates from which signaling can evolve in highly divergent ways. This underlying complexity suggests the need to broadly map the signaling potential of systems as a prerequisite for understanding signaling in specific cell types as well as various pathologies that involve signal transduction such as cancer, developmental defects and metabolic disorders. This report describes interactions between SH2 domains and potential binding partners that comprise initial signaling downstream of activated fibroblast growth factor (FGF), insulin (Ins), and insulin-like growth factor-1 (IGF-1) receptors. A panel of 50 SH2 domains screened against a set of 192 phosphotyrosine peptides defines an extensive potential interactome while demonstrating the selectivity of individual SH2 domains. The interactions described confirm virtually all previously reported associations while describing a large set of potential novel interactions that imply additional complexity in the signaling networks initiated from activated receptors. This study of pTyr ligand binding by SH2 domains provides valuable insight into the selectivity that underpins complex signaling networks that are assembled using modular protein interaction domains.
特定的肽配体识别由模块化的相互作用域是至关重要的信息流的保真度通过信号转导网络控制细胞的行为响应外在的和内在的刺激。Src 同源 2 （SH2）域识别独特的磷酸酪氨酸肽基序，但具体的站点被磷酸化和互补的可用的 SH2 域在个体细胞类型中变化很大。这种差异是一个广泛的可用的蛋白质相互作用微状态的基础，信号可以从其中进化出高度不同的方式。这种潜在的复杂性表明需要广泛地绘制信号系统的潜力作为理解特定细胞类型中的信号以及涉及信号转导的各种病理的先决条件，如癌症、发育缺陷和代谢紊乱。本报告描述了 SH2 域与潜在结合伙伴之间的相互作用，这些伙伴构成了激活的成纤维细胞生长因子（FGF）、胰岛素（Ins）和胰岛素样生长因子-1（IGF-1）受体下游的初始信号转导。一组 50 个 SH2 域对一组 192 个磷酸酪氨酸肽进行筛选，定义了一个广泛的潜在相互作用组，同时展示了单个 SH2 域的选择性。所描述的相互作用证实了几乎所有以前报道的关联，同时描述了一组潜在的新的相互作用，这意味着从激活的受体启动的信号网络的额外的复杂性。这项 SH2 域对 pTyr 配体结合的研究为复杂信号网络的选择性提供了有价值的见解，这些网络是使用模块化的蛋白质相互作用域组装的。
