Phosphatase of regenerating liver: a novel target for cancer therapy

Abstract

Importance in the Field Phosphatases of Regenerating Liver (PRLs) are novel oncogenes that interact with many, well-established cell signaling pathways that are misregulated in cancer and is known to drive cancer metastasis when overexpressed. Areas Covered in this Review This review will cover basic information of the discovery and characteristics of the PRL family. We will also report findings on the role of PRL in cancer, cell functions, and cell signaling. Furthermore, PRL’s suitability as a novel drug target will be discussed along with current methods being developed to facilitate PRL inhibition. Expert Opinion PRLs show great potential as novel drug targets for anti-cancer therapeutics. Studies indicate that PRL can perturb major cancer pathways such as Src/ERK1/2 and PTEN/PI3K/Akt. Upregulation of PRLs has also been shown to drive cancer metastasis. However, in order to fully realize its therapeutic potential, a deeper understanding of the function of PRL in normal tissue and in cancer must be obtained. Novel and integrated biochemical, chemical biological and genetic approaches will be needed to identify PRL substrate(s) and to provide proof-of-concept data on the druggability of the PRL phosphatases.

Phosphatase of regenerating liver in hematopoietic stem cells and hematological malignancies

“…There are several excellent reviews about PRLs and human cancer. [11][12][13][14] Here, we will summarize recent findings related to the emerging roles of PRLs in normal and malignant hematopoiesis and discuss their potential in cancer therapy.…”

“…This demands a complex crosstalk between extrinsic signals from the microenvironment and the cellintrinsic regulators of HSCs. 28,29 Given that PRLs are known to modulate several signaling pathways in normal and cancer cells, [11][12][13][14] it is possible that PRLs are also important for hematopoietic stem cell maintenance.…”

“…[11][12][13][14] Accumulating evidence indicates that PRLs potentially regulate several signaling pathways essential for HSPC proliferation and survival. functions by binding to and activating the receptor tyrosine kinase KIT.…”

“…Thus, one signal can therefore increase HSC proliferation, competitiveness and self-renewal through bimodal effects on HSC gene expression, cycling and reconstituting potential. 65 Given that ectopic PRL expression activates the ERK pathway, [11][12][13][14] it is likely that increased association of PRLs with RAS may activate the MEK/ERK signaling pathway in hematopoietic stem and progenitor cells (HSPCs) and enhance their proliferation and survival [ Figure 2]. …”

“…3,4 The PRL (Phosphatase of Regenerating Liver) phosphatases constitute a novel class of prenylated phosphatases (PRL1, 2, and 3) that share a high degree (>76%) of sequence identity. [11][12][13][14] This family of phosphatases are also known as protein tyrosine phosphatase 4As (PTP4As). The PRLs are relatively small proteins of about 20 kDa.…”