PTPase

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Introduction

Nowadays, the important roles of phosphorylation and protein kinases have been fully demonstrated. Recent studies have shown that protein phosphatases are no longer regarded as passive housekeeping enzymes in these processes. In contrast, phosphatases and kinases coordinate with each other in the regulation of signal responses. Kinases are involved in controlling the amplitude of the signalling response, while phosphatases are involved in controlling the rate and duration of the response. Protein tyrosine phosphatases (PTPases, or PTPs) are encoded by the largest family of phosphatase genes. These enzymes are defined by the active-site signature motif HCX₅R, in which the cysteine residue as a nucleophile is essential for catalysis. After understanding the composition of the PTP family in humans and other organisms, scientists turned their attention to functional analysis.  

Figure 1. The classical PTPs (Tonks, N.K. 2006)

PTPs and human disease

It has long been recognized that PTP, in addition to its function as an inhibitor of pTyr-dependent signaling, can also act as a positive regulator that promotes signaling. Several PTPs have been shown to be the products of tumor suppressor genes. An exciting new development is the identification of the first oncogene encoding PTP. Just as several components of the phosphatidylinositol 3-kinase signaling pathway are targeted for cancer and cancer predisposition syndromes, it is now clear that various syndromes can be explained by aberrant regulation of the Ras-MAPK signalling pathway. Notably, dysregulation of the PTP-superfamily members has also been implicated in diseases other than cancer. A single nucleotide polymorphism (SNP) identified in the study of the PTPN22 gene encoding PTP Lyp that produces a tryptophan point mutation has been identified as a common risk factor for autoimmune diseases, including type I diabetes, Graves' disease, rheumatoid arthritis, and systemic lupus erythematosus. PTPN22 Lyp is expressed in hematopoietic cells and acts as an inhibitor of T-cell activation. The initial studies of the PTPN22-Arg620Trp SNP revealed that this mutation occurs in the proline-rich stretch of the non-catalytic segment of the enzyme. Further studies showed that this was actually a gain-of-function mutation that produced a more active PTP that could act as a more potent inhibitor of T-cell signalling than the wild-type enzyme. The mechanism by which this mutation in the non-catalytic segment leads to phosphatase activation remains to be determined. Small-molecule inhibitors of PTP-Lyp may have therapeutic benefits in autoimmune diseases.

Future directions

The characterization of the functions of members of the PTP superfamily provides new insights into the regulation of signal transduction. Ligands for some RPTPs, and the signaling pathways they regulate have been identified. It is particularly important to determine the link between oxidation of specific PTPs and the regulation of pTyr-dependent signalling in the physiological condition and to define the link between disruption of PTP function and the aetiology of human disease. As the physiological importance of PTP is better understood, so does the enthusiasm for developing PTP-based therapies, especially after studies have demonstrated PTP1B as an outstanding target for the treatment of diabetes and obesity.

However, developing active-site-directed inhibitors of PTP is challenging. Antisense-based therapies targeting PTP1B have shown efficacy in type 2 diabetes and are now in phase 2 clinical trials. The PTP-based dimerization model also proposes a new strategy for PTP inhibition. Recent studies have highlighted the importance of RPTPσ in regulating post-injury axon regrowth in the peripheral and central nervous system, and these data suggest that therapeutics targeting extracellular fragments of RPTP may also be useful in certain circumstances. Nonetheless, the field of PTPs is still in its infancy, and many of these enzymes remain uncharacterized. The application of substrate-trapping mutant technologies will largely aid in the determination of the physiological substrate specificity of members of the PTP superfamily. As research progresses in defining the signalling functions of PTPs and elucidating novel links to human disease, it is expected to reveal new insights into therapeutic development, either at the level of PTPs themselves or from targets within the pathways they regulate.

Figure 2. Regulation of receptor PTP function by dimerization (Tonks, N.K. 2006)