Abstract
The phosphatase of regenerating liver (PRL) family, also known as protein tyrosine phosphatase 4A (PTP4A), are dual-specificity phosphatases with largely unknown cellular functions. However, accumulating evidence indicates that PRLs are oncogenic across a broad variety of human cancers. PRLs are highly expressed in advanced tumors and metastases compared to early stage cancers or matched healthy tissue, and high expression of PRLs often correlates with poor patient prognosis. Consequentially, PRLs have been considered potential therapeutic targets in cancer. Persistent efforts have been made to define their role and mechanism in cancer progression and to create specific PRL inhibitors for basic research and drug development. However, targeting PRLs with small molecules remains challenging due to the highly conserved active site of protein tyrosine phosphatases and a high degree of sequence similarity between the PRL protein families. Here, we review the current PRL inhibitors, including the strategies used for their identification, their biological efficacy, potency, and selectivity, with a special focus on how PRL structure can inform future efforts to develop specific PRL inhibitors.
Highlights
Protein tyrosine phosphatases (PTPs) are a large family of enzymes that catalyze the removal of phosphate groups that are attached to tyrosine residues on their substrates
Protein tyrosine phosphatase 1B (PTP1B) is reported to play a tumor-promoting role in prostate and colorectal cancer (Lessard et al, 2012), and high PTPB1 expression is associated with poor prognosis in colorectal cancer patients (Hoekstra et al, 2016; Lessard et al, 2012)
The protein tyrosine phosphatase 4A (PTP4A) family, commonly known as phosphatase of regenerating liver (PRLs) are dual-specificity phosphatases, which can act on both tyrosine residues and serine/threonine residues (Bessette, Qiu, & Pallen, 2008)
Summary
Protein tyrosine phosphatases (PTPs) are a large family of enzymes that catalyze the removal of phosphate groups that are attached to tyrosine residues on their substrates. PTPs, together with protein tyrosine kinases (PTKs), precisely maintain the appropriate phosphorylation level of proteins, which is critical for normal cellular functions. Y.A Zhang, 2017), suggesting both PTPs and PTKs are potential therapeutic targets. PTPs have not received attention as therapeutic targets until the past decade, due to misconceptions that phosphatases are only tumor suppressors or that they lack regulatory roles in disease Protein tyrosine phosphatase 1B (PTP1B) is reported to play a tumor-promoting role in prostate and colorectal cancer (Lessard et al, 2012), and high PTPB1 expression is associated with poor prognosis in colorectal cancer patients (Hoekstra et al, 2016; Lessard et al, 2012). Protein tyrosine phosphatase SHP2 increases tumor progression and maintains tumor-initiating cells in breast cancer (Aceto et al, 2012; Hu, Li, Gao, Wei, & Yang, 2017). The interest in exploring phosphatases as drug targets to treat cancer has risen sharply in the last decade
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