Regulatory Mechanisms and Novel Therapeutic Targeting Strategies for Protein Tyrosine Phosphatases

Abstract

Appropriate level of protein phosphorylation on tyrosine is essential for cells to react to extracellular stimuli and keep cellular homeostasis. Faulty operation of signal pathways mediated by protein tyrosine phosphorylation causes numerous human diseases, which presents enormous opportunities for therapeutic interventions. While the importance of protein tyrosine kinases in orchestrating the tyrosine phosphorylation networks and in target-based drug discovery has long been recognized, the significance of protein tyrosine phosphatases (PTPs) in cellular signaling and disease biology has historically been underappreciated, due to a large extent an erroneous assumption that they are largely constitutive and housekeeping enzymes. Here, we provide a comprehensive examination on a number of regulatory mechanisms including redox modulation, allosteric regulation, and protein oligomerization, in controlling PTP activity. These regulatory mechanisms are integral to the myriad PTP-mediated biochemical events and reinforce the concept that PTPs are indispensable and specific modulators of cellular signaling. We also discuss how disruption of these PTP regulatory mechanisms can cause human diseases and how these diverse regulatory mechanisms can be exploited for novel therapeutic development.

Cell‐Compatible Nanoprobes for Imaging Intracellular Phosphatase Activities

“…The recently reported d ‐peptide‐based phosphatase probes are more suitable for imaging ectophosphatases than for imaging the intracellular phosphatases of live cells. However, many phosphatases‐associated cellular processes occur intracellularly, such as the phosphoprotein phosphatase (PPP) family of Ser/Thr protein phosphatases and intracellular pTyr‐specific phosphatases (PTPs) including PTP1B, SHP2, and MEG2 . Therefore, there still are unmet needs that require the development of functional probes to image the activity of the intracellular phosphatases of live cells with high spatiotemporal resolution.…”

The Role of the Phosphorus Atom in Drug Design

“…Prodrugs of α‐methyl 1,1‐bisphosphonates that contain a triazole ring represent a recent example in which the presence of the POM protecting group, as in compound 125 , enhanced the biological activity relative to the free 1,1‐bisphosphonate 124 , taking geranylgeranyl diphosphate synthase as the target (Figure ) . Protein tyrosine phosphatases control a wide range of cellular activities, particularly proliferation, differentiation, survival, metabolism, and immune response . In addition, striatal‐enriched protein tyrosine phosphatase (STEP) is a brain‐specific phosphatase that controls crucial signaling compounds involved in synaptic plasticity and neuronal function .…”

“…[118] Protein tyrosine phosphatases control aw ide range of cellular activities,p articularly proliferation, differentiation, survival,m etabolism,a nd immune response. [119] In addition, striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that controls crucial signaling compounds involved in synaptic plasticity and neuronal func-Scheme6.Synthetic approach for the preparation of pyrrolidine-containing 1,1-bisphosphonates (107-109, 111-115).…”

Exploring the effect of N308D mutation on protein tyrosine phosphatase‐2 cause gain‐of‐function activity by a molecular dynamics study

“…However, in the vicinity of the allosteric site and the catalytic site (Q-loop), [48][49][50] there were two large differences in fluctuations between the two systems. The deltas in the RMSF of those regions in the two systems were 0.04, 0.03, 0.04, and 0.03 nm, respectively, indicating that there were little differences of the four large fluctuations of those regions in the two systems.…”