| Protein tyrosine kinases (PTK) initiate intracellular pathways that influence many aspects of cellular communication through its ability to phosphorylate tyrosines and recruit multi-protein complexes. The formation of such complexes is primarily mediated by Src homology 2 (SH2) domains, which selectively recognize phosphotyrosine (pTyr)-containing motifs, thereby coupling PTKs to specific downstream targets. However, the role of SH2 domains in phosphotyrosine signaling has yet to be further explored at the systems-level.;Here we present a comprehensive bioinformatics, structural and functional perspective of the 110 human and mouse complement of SH2 domain proteins. Additionally, we discuss the origin and evolution of the 38 SH2 domain families in 13 organisms ranging from a unicellular choanoflagellate up through to mammals. We reveal that SH2 domains have co-evolved and expanded alongside protein tyrosine kinases to facilitate the development of the phosphotyrosine signaling network. Our analysis highlights evolutionary events such as gene duplication and domain shuffling by which phosphotyrosine-based cell communication has integrated into diverse signal transduction networks.;This study provides evidence of the complexity of SH2-mediated interactions in numerous metazoan species.;SH2 domains also exhibit a remarkable degree of selectivity in the manner in which they discriminate binding partners. Here we explore the physiological selectivity of 50 SH2 domains from an extensive set of physiological ligands from the insulin, 1GF-1 and FGF signaling proteins on high-density peptide arrays. We establish, through peptide arrays and structural analysis, that ligand recognition by SH2 domains is context-dependent and incorporates both permissive and non-permissive factors. These factors illustrate co-evolution between SH2 domains and residues within physiological ligands that direct selectivity for the recruitment of specific SH2 domains. This provides valuable insight into the physiological ligand selectivity of SH2 domains that underpins complex signaling networks that are assembled from modular protein interaction domains. |
