1. Introduction

        Scaffold proteins modulate intracellular signaling by bringing regulatory proteins, enzymes, or cytoskeletal structures in close proximity [1]. TKS molecules are large scaffold proteins earning their name from the early observation that they serve as tyrosine kinase substrates of SRC kinase ^[2][3][4][2–4]. 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. 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 ^[3][5][3,5]. The main function of the PX domain is to link the TKS scaffold proteins to the cell membrane via phosphoinositide binding ^[2][6][2,6]. The SH3 domains serve as docking sites for signaling molecules and mediate protein-protein interactions [7]. It is likely that the PRMs of the TKS proteins represent contact sites for SH3 domain-containing molecules (Figure 1). The TKS proteins are phylogenetically related and are expressed in vertebrates, and TKS-like genes are widely present in invertebrates [8]. TKS scaffold proteins are broadly expressed in tissues except for the testis for TKS4, and the spleen and testis for TKS5 ^[2][3][2,3]. They are also expressed in several transformed cell lines ^[2][9][2,9].

Figure 1. Members of the p47 organizer protein family. The p47 organizer family consists of five structurally similar adaptor/scaffold proteins containing an N-terminal PX domain followed by several SH3 domains, namely p40^phox, NOXO1, p47^phox, TKS4, and TKS5. Experimentally confirmed SRC kinase tyrosine phosphorylation sites (“Y”) in the human and mouse TKS proteins are shown above and below the depicted domain architecture, respectively.

2. TKS4 and TKS5 Affect Multiple Biological Processes from Growth Factor Receptor Signaling to Metastasis to Homeostasis of Adipose and Bone Tissue

EGFR Signaling via TKS4 and TKS5

Receptor tyrosine kinases (RTK) are transmembrane proteins that control several cellular processes, ranging from proliferation to differentiation and cell migration. Following the binding of their extracellular ligands, RTKs dimerize, undergo auto-phosphorylation on multiple tyrosine residues in their cytoplasmic region, and associate with intracellular signaling molecules. Diverse molecular cascades transmit the signal from RTKs to their final effector molecules, ultimately leading to the modulation of distinct biological processes within the cell [20].

Epidermal growth factor receptor (EGFR) is one of the most well-studied RTKS. Upon activation, it initiates several signal transduction cascades, including the RAS-RAF-MEK, phosphatidylinositol 3 (PI3)- kinase-AKT, PLCγ, and JAK-STAT pathways [21]. Moreover, active EGFR binds cytosolic SRC tyrosine-kinase, which then becomes activated ^{[22][23][24][25]}[22–25]. This process leads to the phosphorylation of SRC-substrates, including the TKS scaffold proteins, which are known to be involved in EGFR signaling ^[11][26][27][11,26,27]. The TKS proteins serve as a platform for the recruitment of key players in EGFR signal transduction (Figure 2, Table 1), promoting cell spreading and migration ^{[9][11][28][29][30]}[9,11,28–30]. In response to EGFR activation, PI3 kinases are activated, and lipids are phosphorylated in the plasma membrane. For example, phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P₂) is converted to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P₃) [31]. According to a model proposed by Bögel et al., the phosphorylated lipid residues anchor the PX domain of TKS4 and translocate the scaffold protein from the cytoplasm to the plasma membrane [11]. On the other arm of the signaling pathway, SRC kinase is also activated by binding to the intracellular tail of EGFR ^{[22][23][24][25]}[22–25] subsequently phosphorylating tyrosine residues on TKS4 (i.e., Tyr25, Tyr373, Tyr508) (Figure 1) [2]. Phosphorylated TKS4 can bind activated SRC by interacting with both its SH2 and SH3 domains. In this complex, SRC remains active for a prolonged period of time and may phosphorylate multiple downstream molecules/partners [32]. This direct interaction between TKS4 with SRC was shown to involve the proline-rich region PSRPLPDAP (residues 466–474) and the tyrosine-phosphorylated pYEEI motif (residues 508–511) of TKS4 (both located between the third and fourth SH3 domains) and the SH3 and SH2 domains of SRC, respectively [32]. Upon PI3 kinase activation, TKS5 also translocates to the plasma membrane in epidermal growth factor (EGF)-stimulated cells [26]. The PX domain of both TKS4 and 5 was found to be essential for the participation of the molecules in EGFR signaling and for the phosphorylation of TKS4 and 5 by activated SRC ^[11][26][11,26]. TKS4 forms a complex with EGFR in which either SRC or a yet unidentified protein may serve as a bridge between the two molecules ^[11][32][11,32]. For example, growth factor receptor binding protein 2 (GRB2) has been identified as a binding partner of both EGFR and TKS4 [28]. No strong interaction between TKS5 and EGFR or SRC has been detected so far, suggesting that, despite their structural similarities, there is only a partial overlap between the regulation of TKS4 and TKS5 in EGF signaling ^[11][26][11,26].

Figure 2. The role of TKS proteins in the recruitment of signaling molecules. ADAM12/15/19 – a disintegrin and metalloprotease 12/15/19, ARP2/3 – actin-related protein 2/3, GRB2 – growth factor receptor binding protein 2, MT1MMP – membrane type 1 matrix metalloprotease, NCK – non-catalytic region of tyrosine kinase adaptor protein, N-WASP – neural Wiskott-Aldrich syndrome protein, PtdIns – phosphatidylinositol, RUK/CIN85 - regulator of ubiquitous kinase/Cbl-interacting protein of 85 kDa, SRC - proto-oncogene tyrosine-protein kinase Src.

Table 1. Known protein binding partners of TKS4 and TKS5. The known binding partners of (a) TKS4 and (b) TKS5 are shown with the methods of detection and the binding sites within the TKS molecules. Some of the well-described functions of the binding partners are also listed. ECM – extracellular matrix, EMT – epithelial-mesenchymal transition, ITC – isothermal titration calorimetry, NOX1 – NADPH oxidase 1, PRR – proline-rich region, ROS – reactive oxygen species, RTK – receptor tyrosine kinase. * The first and second SH3 domains cooperate to form a common “super SH3 platform” and allow the binding of the proline-rich region of the partner protein [33].

Table 1

a.

Table 1

b.

In recent years, more possible interaction partners of TKS4 have been identified (Table 1(A)). One possible partner is cortactin [9], a well-known substrate of SRC localized to cortical actin structures within cells. Cortactin can bind the actin-related protein-2/3 (ARP2/3) and neural Wiskott-Aldrich syndrome protein (N-WASP) proteins, and it mediates actin polymerization ^[75][76][77][75–77]. Therefore, TKS4 was expected to be involved in EGFR signaling-mediated actin cytoskeleton assembly and rearrangement. This proposed mechanism was confirmed by Lányi et al. [9]. They found that, in response to EGF stimulation, TKS4 associates with cellular motility-associated membrane ruffles. They also showed that, when constitutively active SRC is present, TKS4 accumulates in podosomes (actin-rich membrane protrusions involved in cell motility, see below) while forming a complex with SRC and cortactin [9]. TKS5 has also been reported to bind cortactin and other proteins important in the regulation of actin cytoskeleton assembly, including N-WASP, non-catalytic region of tyrosine kinase adaptor protein (NCK), and GRB2 (for a full list, see Table 1b) ^{[10][29][52][78][79]}[10,29,52,78,79].

Long version of the text: https://doi.org/10.3390/ijms21218117 

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

Int. J. Mol. Sci. 2020, 21(21), 8117

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