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.
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Cover Image
Cover Image
The cover image is an illustration of the ER with (nascent) lipid droplets and represents the phenotype of CDS2-KO macrophages. In this issue, Collins and colleagues (pp. 1449–1473) demonstrate that genetic deletion of CDS2 in macrophages leads to rewiring of lipid metabolism and enhanced synthesis of 2-LPA (depicted in red), PA (depicted in green), DAG (depicted in orange) and TG (yellow), leading to enhanced accumulation of lipid droplets. The image is by Tamara Chessa (Babraham Institute, UK).
Adapting to change: resolving the dynamic and dual roles of NCK1 and NCK2
Valentine Teyssier, Casey R. Williamson, Erka Shata, Stephanie P. Rosen, Nina Jones, Nicolas Bisson; Adapting to change: resolving the dynamic and dual roles of NCK1 and NCK2. Biochem J 16 October 2024; 481 (20): 1411–1435. doi: https://doi.org/10.1042/BCJ20230232
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