Phosphatase of regenerating liver: a novel target for cancer therapy

Abstract

Introduction: Phosphatases of regenerating livers (PRLs) are novel oncogenes that interact with many well-established cell signaling pathways that are misregulated in cancer, and are known to drive cancer metastasis when overexpressed.

Areas covered: This review covers basic information of the discovery and characteristics of the PRL family. We also report findings on the role of PRL in cancer, cell functions and cell signaling. Furthermore, PRL's suitability as a novel drug target is discussed along with current methods being developed to facilitate PRL inhibition.

Expert opinion: PRLs show great potential as novel drug targets for anticancer 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.

Figure 1

A. Ribbon Diagram of the Structure of PRL-1: The C-terminal end of PRL contains the CAAX prenylation domain and adjoining polybasic region and has been shown to be vital to PRL phosphatase activity. This structure shows the active site sequence, which is located on the P-loop, containing the catalytic Cysteine (6). The WPD-Loop contains Asp72 which acts as a general acid during catalysis (6). The WPD-Loop of PRL contains some variations from other PTPs that may account for low, in vitro activity (6). One difference is that the conserved serine or threonine placed after the invariant Arginine in most PTPs is replaced by an Alanine in PRL (6). PRL also lacks key hydrogen bonds that are known to stabilize the P-Loop of other PTPs for catalysis (6). The Q-Loop is important for hydrogen bonding with scissilie oxygen and active site water molecule (6). B. PRL Trimer: PRL crystalizes in a trimer that fixes the C-Terminal ends of each monomer such that they all face towards the plasma membrane. This trimer is oriented with the C-terminal ends facing out (into the “membrane”) with the active sites on the opposite face (in the “cytoplasm”). This is how the PRL trimer is hypothesized to dock onto the membrane. The trimer state has been shown to be physiologically relevant and targetable for disassociation.

Figure 2

Cell Signaling Pathways Regulated by PRLs: A summarization of the most important oncogenic and tumor suppressive pathways that PRL has been shown to effect including Src/ERK1/2, p53, PTEN/PI3K/Akt, Adhesion proteins, and growth factor receptors.

Figure 3

Spermatogenesis and PRL-2 depletion: A. Healthy seminiferous tubule cross-section of a 3-month old male mouse. The seminiferous tubules sport a distinct cellular structure. a: Basal Lamina, b: Spermatogonial cells, c: Primary Spermatocytes, d: Secondary spermatocytes, e: Spermatids and mature sperm about to eject into the lumen, F: Lumen and maturing sperm tails. B. This is the seminiferous tubule of a 6-month old PRL-2 KO mouse. This cross-section shows complete shedding of the germ cells into the lumen (as indicated). C. Spermatogenesis procession.

Figure 4

Small molecule PRL inhibitors. Compounds 1–5 as described in the text.