Protein Tyrosine Phosphatases: Mechanisms in Cancer

Protein tyrosine kinases, especially receptor tyrosine kinases, have dominated the cancer therapeutics sphere as proteins that can be inhibited to selectively target cancer. However, protein tyrosine phosphatases (PTPs) are also an emerging target. Though historically known as negative regulators of the oncogenic tyrosine kinases, PTPs are now known to be both tumor-suppressive and oncogenic. This review will highlight key protein tyrosine phosphatases that have been thoroughly investigated in various cancers. Furthermore, the different mechanisms underlying pro-cancerous and anti-cancerous PTPs will also be explored.

Functional interrogation and therapeutic targeting of protein tyrosine phosphatases

Protein tyrosine phosphatases (PTPs) counteract the enzymatic activity of protein tyrosine kinases to modulate levels of both normal and disease-associated protein tyrosine phosphorylation. Aberrant activity of PTPs has been linked to the progression of many disease states, yet no PTP inhibitors are currently clinically available. PTPs are without a doubt a difficult drug target. Despite this, many selective, potent, and bioavailable PTP inhibitors have been described, suggesting PTPs should once again be looked at as viable therapeutic targets. Herein, we summarize recently discovered PTP inhibitors and their use in the functional interrogation of PTPs in disease states. In addition, an overview of the therapeutic targeting of PTPs is described using SHP2 as a representative target.

TYK2 as a therapeutic target in the treatment of autoimmune and inflammatory diseases

JAKs are intracellular protein tyrosine kinases that, through activation of STATs, are responsible for signal transduction pathways that regulate cellular responses to numerous cytokines, growth factors and hormones in many different cells. JAK-STAT signaling plays a key role in regulating immune function, and cytokines – such as IL-23, IL-12 and type I interferons – are central to the pathogenesis of autoimmune diseases, including psoriasis, inflammatory bowel disease and systemic lupus erythematosus. Here the authors review the evidence for targeting TYK2 as a more specific approach to treating these conditions. TYK2 inhibitors are clinically effective in autoimmune and inflammatory diseases and may avoid some of the complications reported with nonselective JAK inhibitors.

Role of Receptor Protein Tyrosine Phosphatases (RPTPs) in Insulin Signaling and Secretion

Changes in lifestyle in developed countries have triggered the prevalence of obesity and type 2 diabetes mellitus (T2DM) in the latest years. Consequently, these metabolic diseases associated to insulin resistance, and the morbidity associated with them, accounts for enormous costs for the health systems. The best way to face this problem is to identify potential therapeutic targets and/or early biomarkers to help in the treatment and in the early detection. In the insulin receptor signaling cascade, the activities of protein tyrosine kinases and phosphatases are coordinated, thus, protein tyrosine kinases amplify the insulin signaling response, whereas phosphatases are required for the regulation of the rate and duration of that response. The focus of this review is to summarize the impact of transmembrane receptor protein tyrosine phosphatase (RPTPs) in the insulin signaling cascade and secretion, and their implication in metabolic diseases such as obesity and T2DM.

FAK and PYK2 are specifically associated with the activated phagocytic receptor complexes from human U937 cells.

The innate immune system is the first shield against foreign attack inside the human body, and it is usually carried out with phagocytosis. An essential macrophage cell surface protein is the Fc receptor which contributes to the engulfment of unknown antigens. One of the important members of Fc receptors is the gamma receptor that binds to the immunoglobulin G (IgG) ligand. Another key receptor in this study is the CD36 receptor, which plays a crucial role in the progression of atherosclerosis, the hardening of arteries, with its ligand oxidized low-density lipoprotein (OxLDL). In this report, protein tyrosine kinase enzymes have been detected in the involvement of receptor complexes with human U937 macrophages, specifically PTK2 and PTK2b genes. Protein tyrosine kinases were known to promote cell migration as a main player in intracellular signal transduction cascades in relation to extracellular stimuli. Cell surface proteins are essential for the immunization of various diseases; yet, the molecular machinery of surface receptors remains unclear. This research primarily examined the dynamic nature of protein tyrosine kinases in an ongoing investigation of macrophage cell surface receptors, particularly the role of Fc γ and CD36 receptors with their ligands IgG and oxLDL coated beads in phagocytosis. Our report demonstrates a novel role of PTK2 and PTK2b functions in relation to U937 CD36-mediated phagocytosis. The Phagocytic efficiency of U937 macrophages was analyzed using laser scanning confocal microscope after silencing the cells with siRNA followed by quantitative counting of phagocytosis. The PF drug FAK inhibitor was also introduced to compare the phagocytic efficiency of siRNA cells.

FAK and PYK2 are specifically associated with the activated phagocytic receptor complexes from human U937 cells.

The innate immune system is the first shield against foreign attack inside the human body, and it is usually carried out with phagocytosis. An essential macrophage cell surface protein is the Fc receptor which contributes to the engulfment of unknown antigens. One of the important members of Fc receptors is the gamma receptor that binds to the immunoglobulin G (IgG) ligand. Another key receptor in this study is the CD36 receptor, which plays a crucial role in the progression of atherosclerosis, the hardening of arteries, with its ligand oxidized low-density lipoprotein (OxLDL). In this report, protein tyrosine kinase enzymes have been detected in the involvement of receptor complexes with human U937 macrophages, specifically PTK2 and PTK2b genes. Protein tyrosine kinases were known to promote cell migration as a main player in intracellular signal transduction cascades in relation to extracellular stimuli. Cell surface proteins are essential for the immunization of various diseases; yet, the molecular machinery of surface receptors remains unclear. This research primarily examined the dynamic nature of protein tyrosine kinases in an ongoing investigation of macrophage cell surface receptors, particularly the role of Fc γ and CD36 receptors with their ligands IgG and oxLDL coated beads in phagocytosis. Our report demonstrates a novel role of PTK2 and PTK2b functions in relation to U937 CD36-mediated phagocytosis. The Phagocytic efficiency of U937 macrophages was analyzed using laser scanning confocal microscope after silencing the cells with siRNA followed by quantitative counting of phagocytosis. The PF drug FAK inhibitor was also introduced to compare the phagocytic efficiency of siRNA cells.