Polo-Like Kinase 2: From Principle to Practice

Abstract

Polo-like kinase (PLK) 2 is an evolutionarily conserved serine/threonine kinase that shares the n-terminal kinase catalytic domain and the C-terminal Polo Box Domain (PBD) with other members of the PLKs family. In the last two decades, mounting studies have focused on this and tried to clarify its role in many aspects. PLK2 is essential for mitotic centriole replication and meiotic chromatin pairing, synapsis, and crossing-over in the cell cycle; Loss of PLK2 function results in cell cycle disorders and developmental retardation. PLK2 is also involved in regulating cell differentiation and maintaining neural homeostasis. In the process of various stimuli-induced stress, including oxidative and endoplasmic reticulum, PLK2 may promote survival or apoptosis depending on the intensity of stimulation and the degree of cell damage. However, the role of PLK2 in immunity to viral infection has been studied far less than that of other family members. Because PLK2 is extensively and deeply involved in normal physiological functions and pathophysiological mechanisms of cells, its role in diseases is increasingly being paid attention to. The effect of PLK2 in inhibiting hematological tumors and fibrotic diseases, as well as participating in neurodegenerative diseases, has been gradually recognized. However, the research results in solid organ tumors show contradictory results. In addition, preliminary studies using PLK2 as a disease predictor and therapeutic target have yielded some exciting and promising results. More research will help people better understand PLK2 from principle to practice.

Identification of differential polypharmacology between the PARP inhibitor rucaparib and its major metabolite

“…Therefore, it is difficult to draw strong conclusions but given that the reported, steady-state C max concentrations of rucaparib oscillate between 2-9 µM (McCrudden et al, 2015), it is possible that M324 could significantly inhibit PLK2 in humans (EC 50 = 5.08 µM, Figure 5b ). Unfortunately, the physiological roles of PLK2 in health and disease have not been deeply studied (Zhang et al, 2022a). Regarding the effect of inhibiting PLK2 on human safety, a recent report suggests that the loss of function of PLK2 kinase could induce cardiac fibrosis and promote atrial fibrillation (Kunzel et al, 2021).…”

“…Regarding the potential effects of PLK2 inhibition in clinical efficacy, limited literature reports suggest PLK2 could be either an oncogene or a tumour suppressor depending on the context (Ou et al, 2016; Zhang et al, 2022a). Analysis of CRISPR and siRNA screens across large pan-cancer cell line panels (Dwane et al, 2021; Mitsopoulos et al, 2021; Tsherniak et al, 2017) supports this view, uncovering a few cancer cell lines that are sensitive to PLK2 knock-out, including non-small cell lung cancer and liver cancer models ( Table S11 ).…”

“…Unfortunately, the physiological roles of PLK2 in health and disease have not been deeply studied (Zhang et al, 2022a). Regarding the effect of inhibiting PLK2 on human safety, a recent report suggests that the loss of function of PLK2 kinase could induce cardiac fibrosis and promote atrial fibrillation (Kunzel et al, 2021).…”

Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells

“…The inhibition of PLK1 results in aberrant chromosome segregation, mitotic block, and cell death [ 2 ]. Notably, PLK2, PLK3, and PLK4 have also been implicated in various aspects of cell cycle control [ 3 , 4 ]. PLK5 lacks a functional kinase domain and is included in the family only because of homology in its other domains.…”

Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells

“…Inhibition of PLK1 results in aberrant chromosome segregation, mitotic block, and cell death [2]. Notably, PLK2, PLK3, and PLK4 have also been implicated in various aspects of cell cycle control [3,4]. PLK5 lacks a functional kinase domain and is included in the family only because of homology in its other domains.…”