However, this hypothesis is supported by the auto-inhibitory intramolecular interactions known to regulate p47 phox, a homologous protein that is structurally highly similar to the N-terminal regions of TKS4 and TKS5. Direct evidence for these conformational states is still limited. The transition between these states is most likely regulated by phosphorylation. The Regulated Localization of TKS Proteins Determines Their Signal Recruiting Functionīoth TKS4 and TKS5 have a cytoplasmic, inactive state, and a membrane-bound, active state in cells. They are also expressed in several transformed cell lines. TKS scaffold proteins are broadly expressed in tissues except for the testis for TKS4, and the spleen and testis for TKS5. The TKS proteins are phylogenetically related and are expressed in vertebrates, and TKS-like genes are widely present in invertebrates. It is likely that the PRMs of the TKS proteins represent contact sites for SH3 domain-containing molecules ( Figure 1). The SH3 domains serve as docking sites for signaling molecules and mediate protein-protein interactions. The main function of the PX domain is to link the TKS scaffold proteins to the cell membrane via phosphoinositide binding. Other names for TKS5 are SH3 and PX domain-containing protein 2A (SH3PXD2A) and Five SH3 domains (FISH), while TKS4 is also known as SH3 and PX domain-containing protein 2B (SH3PXD2B), Homolog of FISH (HOFI), and a factor of adipocyte differentiation 49 (Fad49), reflecting some of their known characteristics. TKS4 and TKS5 contain one Phox Homology (PX) domain, conserved linear motifs, e.g., several proline-rich motifs (PRMs), and four or five SRC Homology 3 (SH3) domains, respectively. TKS molecules are large scaffold proteins earning their name from the early observation that they serve as tyrosine kinase substrates of SRC kinase. Scaffold proteins modulate intracellular signaling by bringing regulatory proteins, enzymes, or cytoskeletal structures in close proximity. We also describe related pathologies and the established mouse models. In this review, we attempt to cover the diverse nature of the TKS molecules by discussing their structure, regulation by SRC kinase, relevant signaling pathways, and interaction partners, as well as their involvement in cellular processes, including migration, invasion, differentiation, and adipose tissue and bone homeostasis. However, a number of novel functions have been discovered for these molecules in recent years. Until recently, TKS4 and TKS5 had been recognized for their involvement in cellular motility, reactive oxygen species-dependent processes, and embryonic development, among others. Their structural features allow them to recruit and bind a variety of signaling proteins and to anchor them to the cytoplasmic surface of the cell membrane. The TKS4 and the TKS5 scaffold proteins are tyrosine kinase substrates with four or five SH3 domains, respectively. The TKS proteins serve as a platform for the recruitment of key players in EGFR signal transduction, promoting cell spreading and migration. This process leads to the phosphorylation of SRC-substrates, including the tyrosine kinase substrates (TKS) scaffold proteins. In the case of epidermal growth factor (EGF)-epidermal growth factor receptor (EGFR) binding, the activated EGFR contacts cytosolic SRC tyrosine-kinase, which then becomes activated. Scaffold proteins are typically thought of as multi-domain “bridging molecules.” They serve as crucial regulators of key signaling events by simultaneously binding multiple participants involved in specific signaling pathways.
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