Protein tyrosine phosphatases as potential therapeutic targets

Abstract

Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs.

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

“…Firstly, because they are intracellular proteins, a potential RGS-modulating drug needs to be both cell permeable as well as stable in the intracellular environment. However, this is not a particularly high obstacle to overcome, and advances have been made in the drug discovery of many other intracellular protein families, such as kinases, phosphatases and nuclear receptors (Rask-Andersen et al, 2011;He et al, 2014;Barnes, 2016;Shang et al, 2016). Indeed, small molecules have recently emerged that are active as RGS inhibitors both in cells and in vivo (see below).…”

Copurification of chicken liver soluble thiamine monophosphatase and low molecular weight acid phosphatase

“…Indeed, LMWAP was shown to be capable of hydrolyzing a variety of phosphorylated protein substrates, including platelet derived growth factor, ephrin and insulin receptors [38]. However, the physiological meaning of such activity was challenged and the involvement of the enzyme in riboflavin metabolism was proposed instead [39,40].…”

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

“…For example, as has recently been reported for mouse muscle, stimulation of protein kinase A results in increased proteasome‐mediated protein degradation, whereas treatment with protein phosphatase 1 decreases proteasome‐mediated protein degradation 50. Thus, with further work, it is highly probable that protein kinase and phosphatase inhibitors can be used to modulate protein degradation levels in either direction, work that will no doubt be accelerated by the cancer field's push to identify effective protein kinase and phosphatase inhibitors that are safe for human use 51, 52. Inhibition/activation of kinases and phosphatases may also prove useful in other respects.…”