Vaccinia-related kinase (VRK) signaling

Abstract

VRK (vaccinia-related kinase) is a group of three proteins in the human kinome. These proteins, mainly VRK1 and VRK2, have been studied in the context of their substrates and interacting proteins in order to identify and characterize their signaling pathway, as well as their effect on other signaling pathways. VRK1 is mostly a nuclear kinase that specifically phosphorylates p53, c-Jun, ATF2, CREB, BAF and histone H3. VRK1 is an early response gene and is implicated in regulation of cell cycle progression. VRK1 is activated in response to DNA damage phosphorylating p53, which is stabilized and activated; this active p53 induces a downregulatory mechanism of VRK1 that permits the reversal of p53 induced effects. The activity of nuclear VRK1 is regulated by its interaction with the Ran small GTPase. Also, VRK1 is a downstream component of the signaling pathway of MEK-Plk3 that induces Golgi fragmentation in mitosis. VRK2 has two isoforms; VRK2A is cytosolic and bound to endoplasmic reticulum and mitochondrial membranes. VRK2B is a shorter isoform free in cytosol and nucleus. VRK2A affects cellular signaling by interaction with scaffold proteins, as JIP1. The JIP1-VRK2A signalosome blocks the incorporation of JNK, preventing its activation,and thus reducing the stress response to inflammatory cytokines as interleukin-1β and to hypoxia.