Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

Abstract

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. 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. This process leads to the phosphorylation of SRC-substrates, including the tyrosine kinase substrates (TKS) scaffold proteins. The TKS proteins serve as a platform for the recruitment of key players in EGFR signal transduction, promoting cell spreading and migration. The TKS4 and the TKS5 scaffold proteins are tyrosine kinase substrates with four or five SH3 domains, respectively. 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. Until recently, TKS4 and TKS5 had been recognized for their involvement in cellular motility, reactive oxygen species-dependent processes, and embryonic development, among others. However, a number of novel functions have been discovered for these molecules in recent years. 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. We also describe related pathologies and the established mouse models.

Tks5 Regulates Synaptic Podosome Formation and Stabilization of the Postsynaptic Machinery at the Neuromuscular Junction

“…The molecular mechanism for Tks5-driven podosome formation has been previously described in other cell types, and chances are that similar processes take place in myotubes [ 39 ] ( Figure 4 D). Tks5 is initially phosphorylated by non-receptor tyrosine kinase, c-SRC, and is recruited to the cell membrane by an adaptor protein GRB2, which has been also shown to interact with αDB1 in the muscle, where it is required for AChR organization [ 21 , 28 , 40 ].…”

YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through enhancer in breast cancer

“…Invadopodia are actin-rich protrusions of the basolateral plasma membrane and are associated with degradation of the extracellular matrix in cancer invasiveness and metastasis [ 16 , 17 ]. Previous studies have revealed that invadopodia are composed of structural proteins, such as cortactin, TKS4, and TKS5 [ 18 – 20 ], and are regulated by numerous regulatory proteins that control actin dynamics [ 21 ]. EMT-related genes, such as TWIST1, and Rho GTPases, such as RAC/CDC42, reportedly play important roles in invadopodia formation [ 22 – 25 ].…”

Characterization of the Intramolecular Interactions and Regulatory Mechanisms of the Scaffold Protein Tks4

“…Both Tks4 and Tks5 have roles in cell motility by affecting the formation of podosomes and invadopodia [ 13 , 15 , 16 ]. However, despite the structural similarities, their functions are not totally overlapping [ 15 , 17 ]. In Src-transformed fibroblasts, only Tks4 recruits membrane type-1 matrix metalloproteinase to podosomes, thus playing a role in extracellular matrix degradation in these migrating cells [ 13 ].…”

“…Upon phosphorylation, Tks4 translocates to the plasma membrane where it binds phosphatidylinositol lipids via its PX domain. Membrane-anchored Tks4 can then interact with other signaling molecules [ 17 ]. The cytosol-to-cell membrane translocation of signaling molecules is a widespread regulatory mechanism in signal transduction [ 4 , 30 , 31 ].…”