Protein Tyrosine Signaling and its Potential Therapeutic Implications in Carcinogenesis

Abstract

Protein tyrosine phosphorylation is a crucial signaling mechanism that plays a role in epithelial carcinogenesis. Protein tyrosine kinases (PTKs) control various cellular processes including growth, differentiation, metabolism, and motility by activating major signaling pathways including STAT3, AKT, and MAPK. Genetic mutation of PTKs and/or prolonged activation of PTKs and their downstream pathways can lead to the development of epithelial cancer. Therefore, PTKs became an attractive target for cancer prevention. PTK inhibitors are continuously being developed, and they are currently used for the treatment of cancers that show a high expression of PTKs. Protein tyrosine phosphatases (PTPs), the homeostatic counterpart of PTKs, negatively regulate the rate and duration of phosphotyrosine signaling. PTPs initially were considered to be only housekeeping enzymes with low specificity. However, recent studies have demonstrated that PTPs can function as either tumor suppressors or tumor promoters, depending on their target substrates. Together, both PTK and PTP signal transduction pathways are potential therapeutic targets for cancer prevention and treatment.

Keywords: AKT; Carcinogenesis; EGFR; IGF-1R; PTK; PTP; STAT3; tyrosine phosphorylation.

Figure 1.. Schematic representation of the RTK signaling network and nodes of therapeutic blockade.

Activation of RTKs can result in signaling via two pathways: PI3/AKT and RAS/RAF/MEK/ERK. PI3K/AKT signaling induces cell survival, increases protein synthesis, activates glucose metabolism, and decreases apoptosis. RAS/RAF/MEK/ERK increases cellular proliferation, angiogenesis, migration, and differentiation by activating transcriptional factors in a cascade. Each ligand binds to RTK and transfers the extracellular signal to the cytosol and then, ultimately, to the nucleus. Targeted therapy using monoclonal antibody (-MAB or -IB) or TKI can block the extracellular signals which enter the cell through the RTK pathway.

Figure 2.. The era of chemotherapy.

Since the discovery of nitrogen mustards and folic acid antagonist drugs in the 1940s, the history of chemotherapy has begun. In the mid-2000s, when PTKs were discovered and revealed to be involved in carcinogenesis, the approach toward chemotherapy evolved to target specific cancer-associated molecules like PTKs. However, due to chemoresistance, targeted therapy has still been challenged by combination chemotherapy in clinical trials.

Figure 3.. EGF/EGFR signal transduction and its targeted therapy.

The binding of EGF to its receptor initiates a variety of signaling cascade via five main pathways; 1) RAS/RAF/MAPK, 2) PI3K/AKT, 3) JAK/STAT, 4) PLCγ/PKC/Ca2+-dependent, and 5) Src/FAK/MMP. Furthermore, the EGF/EGFR dimer can directly regulate the expression of specific genes through an endocytosis mechanism. Constitutive activation of EGFR as a result of mutation of the EGFR gene can promote cancer by facilitating DNA synthesis, cell proliferation, angiogenesis, invasion, and metastasis. Ongoing clinical trials of anticancer drugs, like monoclonal antibodies of the EFG binding site or small molecules against the EGF catalytic domain, may prove to inhibit EGF/EGFR signaling by blocking its autophosphorylation.

Figure 4.. The role of Src in cells.

Src may interact with a number of kinases which can regulate cell proliferation, migration, adhesion, and angiogenesis. RTKs can trigger the phosphorylation of the Src Tyr416 residue and promote activation of the transcription factor STAT3, which can regulate gene expression to stimulate cell migration, angiogenesis, and cell survival. PI3K activation following loss of PTEN may induce Src/AKT cascade signaling to enhance cell growth. Moreover, Src can mediate cell adhesion and migration by interacting with catenin or integrin/focal adhesion proteins, such as FAK, CSK, Paxillion, and RhoA.