Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Division Oncologie, Québec, QC, Canada.
Centre de recherche sur le cancer de l'Université Laval, Québec, QC, Canada.
Biochem J. 2024 Oct 16;481(20):1411-1435. doi: 10.1042/BCJ20230232.
Adaptor proteins play central roles in the assembly of molecular complexes and co-ordinated activation of specific pathways. Through their modular domain structure, the NCK family of adaptor proteins (NCK1 and NCK2) link protein targets via their single SRC Homology (SH) 2 and three SH3 domains. Classically, their SH2 domain binds to phosphotyrosine motif-containing receptors (e.g. receptor tyrosine kinases), while their SH3 domains bind polyproline motif-containing cytoplasmic effectors. Due to these functions being established for both NCK1 and NCK2, their roles were inaccurately assumed to be redundant. However, in contrast with this previously held view, NCK1 and NCK2 now have a growing list of paralog-specific functions, which underscores the need to further explore their differences. Here we review current evidence detailing how these two paralogs are unique, including differences in their gene/protein regulation, binding partners and overall contributions to cellular functions. To help explain these contrasting characteristics, we then discuss SH2/SH3 structural features, disordered interdomain linker regions and post-translational modifications. Together, this review seeks to highlight the importance of distinguishing NCK1 and NCK2 in research and to pave the way for investigations into the origins of their interaction specificity.
衔接蛋白在分子复合物的组装和特定途径的协调激活中发挥核心作用。通过其模块化结构域，衔接蛋白 NCK 家族（NCK1 和 NCK2）通过其单个 SRC 同源（SH）2 和三个 SH3 结构域将蛋白靶标连接起来。传统上，它们的 SH2 结构域与含有磷酸酪氨酸基序的受体（例如受体酪氨酸激酶）结合，而它们的 SH3 结构域与含有多脯氨酸基序的细胞质效应物结合。由于这两个功能都已在 NCK1 和 NCK2 中建立，因此它们的作用被错误地认为是冗余的。然而，与之前的观点相反，NCK1 和 NCK2 现在具有越来越多的同工型特异性功能，这突显了需要进一步探索它们之间的差异。在这里，我们回顾了详细说明这两个同源物如何独特的现有证据，包括它们在基因/蛋白调控、结合伙伴以及对细胞功能的整体贡献方面的差异。为了帮助解释这些对比鲜明的特征，我们随后讨论了 SH2/SH3 结构特征、无规卷曲的结构域间连接区和翻译后修饰。总的来说，这篇综述强调了在研究中区分 NCK1 和 NCK2 的重要性，并为探索它们相互作用特异性的起源铺平了道路。
