The docking proteins of the Grb2-associated binder (Gab) family have emerged as crucial signaling compartments in metazoans. In mammals, the Gab proteins, consisting of Gab1, Gab2, and Gab3, are involved in the amplification and integration of signal transduction evoked by a variety of extracellular stimuli, including growth factors, cytokines, antigens, and other molecules. Gab proteins lack the enzymatic activity themselves; however, when phosphorylated on tyrosine residues, they provide binding sites for multiple Src homology-2 (SH2) domain-containing proteins, such as SH2-containing protein tyrosine phosphatase 2 (SHP2), phosphatidylinositol 3-kinase regulatory subunit p85, phospholipase Cγ, Crk, and GC-GAP. Through these interactions, the Gab proteins transduce signals from activated receptors into pathways with distinct biological functions, thereby contributing to signal diversification. They are known to play crucial roles in numerous physiological processes through their associations with SHP2 and p85. In addition, abnormal Gab protein signaling has been linked to human diseases including cancer, cardiovascular disease, and inflammatory disorders. In this paper, we provide an overview of the structure, effector functions, and regulation of the Gab docking proteins, with a special focus on their associations with cardiovascular disease, cancer, and inflammation. 1. Introduction The mammalian Grb2-associated binder (Gab) proteins are homologs of Drosophila DOS (Daughter Of Sevenless) and Caenorhabditis elegans SOC-1 (Suppressor Of Clear). These proteins define a family of docking proteins closely related to the insulin receptor substrate (IRS-1, IRS-2, IRS-3), fibroblast growth factor substrate (FRS2), linker of T cell (LAT), and downstream of kinase (Dok) families [1]. In contrast to adaptor proteins such as growth factor receptor bound protein 2 (Grb2) and Shc, which are usually smaller and often function as a molecular bridge between two proteins in the assembly of larger protein complexes, docking proteins contain a membrane-targeting region at the N-terminus, binding sites for src homology 3 (SH3) domain-containing proteins, and multiple tyrosine phosphorylation sites that, when phosphorylated, function as binding sites for the src homology 2 (SH2) domains of a variety of effectors. Consequently, the docking proteins are significantly larger than adaptor proteins. In addition, docking proteins usually contain one or more moieties that mediate their recruitment to plasma membranes through protein-protein or protein-lipid interactions. Their
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